Abstract:
The present invention provides a superior method of diagnosing Chronic Pelvic Pain Syndrome in men comprising measuring levels of cytokines in semen or components or fractions of semen. The invention also provides a method of treating a condition associated with elevated levels of a cytokine, such as TNF-α, in semen or a component or fraction thereof, comprising administering a therapeutically effective amount of an ant-cytokine compound or composition, such as an anti-TNF-α compound or composition.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application claims benefit of U.S. Provisional Application No. 60/084,668, filed on May 7,1998. 
    
    
     BACKGROUND OF THE INVENTION 
     Chronic prostatitis/chronic pelvic pain syndrome (collectively referred to herein as CPPS) is a syndrome of undetermined etiology occurring in men. CPPS is the third of four subgroups of prostatitis recognized by the NIH. Category I encompasses acute bacterial prostatitis, and Category II covers chronic bacterial infection. Category III, CPPS, includes all remaining prostatitis syndromes, and is subdivided into III a  (inflammatory) and III b  (non-inflammatory). These sub-categories can be distinguished by the presence of leukocytosis in expressed prostatic secretions or sediment in a post-massage urine sample. Finally, Category IV represents asymptomatic prostatitis, which often is associated with benign prostate hyperplasia. 
     Prostatitis is extraordinarily common, resulting in approximately 2 million office visits to primary care physicians and urologists in the United States annually [1997 American Urological Association Annual Meeting, National Ambulatory Medical Care Survey, National Center for Health Statistics, 1990 to 1994]. Patients with CPPS suffer from chronic, episodic pain in the perineum or pelvic region, irritative and obstructive voiding symptoms, and adverse effects upon sexual function [Alexander et al.,  Urology  48:568-574 (1996)]. Men with chronic prostatitis often require repeated physician visits, commonly to different physicians. Medical expenditures relating to CPPD are conservatively estimated to exceed half a billion dollars annually. 
     Bacterial vs. Non-Bacterial Prostatitis 
     Given its apparent prevalence, CPPS has defied characterization to an almost astonishing extent. While an enormous number of patients seek the care of a physician because of prostatitis-like symptoms, almost nothing is known about diagnostic criteria, etiology, or objective signs for CPPS. In a survey conducted through the Internet of 163 men with a diagnosis of prostatitis, Alexander and Trissel found that pain in the pelvic region was the most frequently reported and the most severe symptom in such patients [Alexander et al.,  Urology  48:568-74 (1996)]. It was because of these observations and the paucity of objective criteria for defining the disease, that the National Institute of Diabetes and Digestive and Kidney Diseases working group in prostatitis suggested that the disease be named Chronic Pelvic Pain Syndrome. 
     One reason for the present state of confusion regarding CPPS is the similarity of CPPS symptoms to the symptoms of bacterial prostatitis. Only about 5 to 10% of patients whose symptoms are consistent with bacterial prostatitis are shown to have infection in the prostate gland [Weidner et al.,  Infection  19:S109-S190 (1991)]. The misdiagnosis of CPPS as infectious prostatitis, commonly results in unnecessary treatment with multiple courses of antibiotics at enormous cost to patients and to the health care system with no clearly demonstrated benefit to patients. 
     An enormous amount of effort has attended the search for a fastidious organism as the cause of CPPS. No clear consensus has emerged identifying any such organism as the causative agent. Published studies have proven difficult to interpret due to lack of a standardized definition of CPPS and the variability in methodologies for detecting infectious organisms. Another difficulty with published studies is that the presence of normal flora in the male urethra complicates the interpretation of culture data. Further, many published studies lack control groups to which the findings in men with prostatitis must be compared. 
     Recently, Krieger et al. reported an extensive study examining trans-perineal prostate biopsies in 135 men with CPPS for bacterial 16s rRNA-encoding DNA sequences [Krieger et al,  J. Clin. Microbiol  34:3120-3128 (1996)]. Krieger et al. found that 77% of the CPPS patients had bacterial DNA sequences in their prostatic tissue that were distinct from normal bowel and skin flora. Patients with bacterial DNA sequences in the prostate also had higher numbers of leukocytes in the prostatic fluid compared to patients without such DNA sequences. Krieger et al. concluded that bacteria distinct from the normal bowel and skin flora are present in the prostatic tissue of men with CPPS and are therefore a potential causative agent of CPPS. 
     In another study by the same group, Berger et. al reported that an aerobic or anaerobic bacterial organism could be cultured from the prostate tissue in 32% of 85 symptomatic men by performing cultures of trans-perineal needle biopsies in a specialized microbiology laboratory [Berger et al.,  J. Urol.  157:863-865 (1997)]. 
     However, the Krieger et al. and Berger et al. data cannot be interpreted as positively identifying a causative agent for prostatitis because neither study compared the CPPS group with a control group lacking symptoms of CPPS to demonstrate that the prostate tissue of subjects without CPPS symptoms does not contain such bacterial DNA sequences. Furthermore, in preliminary data, the present inventors have detected similar diverse bacterial 16s rRNA-encoding DNA sequences in 8/9 patients undergoing transperineal radioactive seed implantation for localized adenocarcinoma of the prostate, all of whom had no antecedent history of CPPS symptoms [S. Keay et al,  Urology  53: 487-491, 1999]. Thus, while the data of Krieger et. al. show that bacterial DNA sequences exist in the prostate of men with CPPS, the presence of these sequences is not sufficient to demonstrate a bacterial origin for CPPS. 
     What is clear, however, is that some men with CPPS have evidence of inflammation of the prostate. While the cellular and cytokine mediators involved in the inflammatory process have been increasingly clarified in the immunologic literature, few studies have investigated the immunobiology of the prostate gland to determine whether CPPS might be arise from an auto-immune condition. 
     Autoimmunity and the Prostate 
     Many diseases are known to result from autoimmunity. The present inventors have discovered that CPPS has an autoimmune component. The inventors hypothesize that either (1) the autoimmune component of CPPS results from an autoimmune attack upon the prostate, or (2) that a chronic inflammatory process is maintained in CPPS patients as a result of a breakdown of immunoregulatory mechanisms in the immediate environment of the prostate. 
     There is a substantial body of evidence demonstrating the occurrence of immunological activity within the prostate gland. However, the nature and cause of this activity, and whether it is detrimental to the host, has not been determined. Inflammatory infiltrates in the prostate are very common. In one study of 162 cases of surgically resected prostatic tissue inflammatory infiltrates were found in 98% [Kohnen et al.,  J. Urology  121:755-60 (1979)]. The infiltrating cells consist of monocytes and activated T and B lymphocytes [Theyer et al.,  Lab Invest.  66:96-107 (1992); Steiner et al.,  J. Urology  151:480-84 (1994)]. 
     A rare form of prostatic inflammation, granulomatous prostatitis, has been characterized, although the etiology of the inflammation is also unknown. One of the major theories about this disease, however, is that it represents an immune reaction against self prostatic proteins induced by infection or manipulation of the gland by previous biopsy or surgical procedure [Stillwell et al.,  J. Urology  138:320-23 (1987); Dhundee et al.,  Histopathology  18:435-41 (1991)]. 
     The disease is also observed after instillation of Bacillus Calmette-Guerin (BCG) into the bladder as a treatment for superficial bladder cancer [Bahnson,  J. Urology  146:1368-69(1991)]. 
     Recent observations about the existence of subsets of CD4 +  T cells has yielded fundamental information about immune responses in humans. CD4 +  T cells can be separated into subsets based upon the patterns of cytokines they secrete [Mosmann,  Ann NY Acad. Sci.  664:89-92 (1992)). CD4 +  T cells that secrete IFN-γ and IL-2 are called T helper 1 (Th1) cells. Th1 cells mediate cellular immunity, such as delayed hypersensitivity responses. CD4 +  T cells that secrete IL-4 and IL-10 are termed T helper 2 (Th2). Th2 cells are associated with antibody production and allergy. Immune responses mediated by Th1 and Th2 cells can be characterized by the local cytokine environment during the developing immune response. 
     Zisman et al. found IgG anti-PSA antibody titers to be higher in the serum of men with benign prostate hyperplasia (BPH) compared to controls [Zisman et al.,  J. Urology  154:1052-55 (1995)]. However, of 17 men with chronic prostatitis, Zisman et al. found no difference in mean antibody titer as compared to controls. Zisman et al. speculate that an immunologic mechanism may play a role in the symptomatology of BPH. An alternative explanation is that a Th1 type of response may be occurring in patients with chronic prostatitis/chronic pelvic pain syndrome. In this event, no antibody response would be expected. A further understanding of the local cytokine environment in the prostate will be critical to understanding the nature of the inflammatory response that is occurring in order to more clearly understand the disease. 
     There remains a major need in the art for an objective means for diagnosing CPPS, to identify the cause or causes of the syndrome and for CPPS treatments that can result in an improvement in symptoms in men with the disease. 
     Cytokines 
     Cytokines are small to medium-sized proteins or glycoproteins which mediate potent biological effects on most cell types. [See Mire-Sluis, et al., eds.  Cytokines  (1998); also see Thompson, Angus, ed.  The Cytokine Handbook  (1998)] While cytokines were originally identified as key components in inflammatory processes, it is now known that cytokines are involved in many non-inflammatory physiological processes. Cytokines mediate their effects by binding to specific cell surface receptors which are coupled to intracellular signal transduction and second messenger pathways. More than one hundred cytokines have been identified to date. The inventors have identified the following cytokines as having particular importance in the operation of the present invention: IL8, GM-CSF, IL-β and TNF-α. 
     IL-8 is a member of the chemokine family of cytokines. IL-8 is produced by many cell types. In general, the biological activity of IL-8 results from its ability to activate the CXC chemokine receptors CXCR1 and CXCR2. Among many other functions, IL-8 acts as a neutrophil chemoattractant and activating factor [Matsushima et al.,  Cytokine  1:2-13 (1989); Matsushima et al.,  J. Exp. Med.  167:1883-1893 (1988); Oppenheim et al.,  Annu. Rev. Immunol.  9:617-648 (1991)]. Synonyms for IL-8 include neutrophil attractant/activating protein (NAP-1), monocyte derived neutrophil activating peptide (MONAP), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), leukocyte adhesion inhibitor (LAI), Granulocyte chemotactic protein (GCP). IL-8 can be obtained from known commercial sources. 
     GM-CSF, or granulocytelmacrophage colony stimulating factor, is a survival and growth factor for haematopoietic progenitor cells, a differentiation and activating factor for granulocytic and monocytic cells, and a growth factor for endothelial cells, erythroid cells, megakaryocytes and T cells [Wong et al.,  Science  228:810-815 (1985); Gough et al.,  EMBO. J.  4:645-653 (1985); Clarke et al.,  Science  236: 1229-1237 (1987); Groopman et al.,  New Eng. J. Med.  321, 1449-1459 (1989)]. GM-CSF is also known as CSFa or pluripoietin-a. GM-CSF can be obtained from known commercial sources. 
     IL-1β has a wide range of biological activities on many different target cell types including B cells, T cells, and monocytes (Dinarello et al.,  Adv. Immunol.  44:153-205 (1989); Fuhlbrigge et al.,  In The Year in Immunology  1988: Immunoregulatory Cytokines and Cell Growth, Vol. 5, Cruse et al., pp.21-37 (1989); di Giovine et al. lmmunol.  Today  11:13-20 (1990)]. In vivo, IL-1β induces hypotension, fever, weight loss, neutrophilia, and acute phase response. IL-1β can be obtained from known commercial sources. 
     IL-6 is a multifunctional cytokine secreted by both lymphoid and non-lymphoid cells which regulates B and T cell function, haematopoiesis and acute phase reactions [Hirano, in The Cytokine Handbook, Thomson, ed.,  Academic Press , London, pp. 169-190 (1991); Kishimoto,  Blood  74:1-10 (1989); Kishimoto, et al.,  Science  258:593-597 (1992)]. Synonyms for IL-6 include interferon-β 2,  26-kDa protein, B cell stimulatory factor 2 (BSF-2), hybridoma/plasmacytoma growth factor (HPGF or IL-HP1), hepatocyte stimulating factor (HSF), monocyte granulocyte inducer type 2 (MGI-2), cytotoxic T cell differentiation and thrombopoietin. IL-6 is produced by a large member of cell types, including lymphoid cells (T cells, B cells) and many non-lymphoid cells including macrophages, bone marrow stromal cells, fibroblasts, keratinocytes, mesangium cells, astrocytes and endothelial cells. IL-6 can be obtained from known commercial sources. 
     TNF-α is a potent paracrine and endocrine mediator of inflammatory and immune functions. It is also known to regulate growth and differentiation of a wide variety of cell types. TNF-α is selectively cytotoxic for many transformed cells, especially in combination with IFN-γ. In vivo, it leads to necrosis of methylcholanthrene-induced murine sarcomas. Many of the actions of TNF-α occur in combination with other cytokines as part of the “cytokine network” [Manogue et al. In The Cytokine Handbook, Thomson ed.,  Academic Press , London, p. 241-256 (1991); Fiers,  FEBS  285:241-256 (1991); Ruddle,  Curr. Opin. Immunol.  4: 327-332 (1992)]. TNF-α is expressed as a type 11 membrane protein attached by a signal anchor transmembrane domain in the propeptide and is processed by a matrix metalloproteinase (Gearing et al.,  Nature  338:225-228 (1994). TNF-α can be obtained from known commercial sources. 
     SUMMARY OF THE INVENTION 
     The present invention, in one embodiment, provides a superior method of diagnosing CPPS in men. This aspect of the invention is based on the discovery that the seminal plasma levels of certain cytokines are elevated in patients with CPPS. The cytokine measurements may be accomplished by any available method; however, the sandwich ELISA is the most preferred method. Preferred cytokines include GM-CSF, IL-1-β,IL-8, IL-6, and TNF-α. TNF-α is the most preferred cytokine for use in the diagnostic methods according to the present invention. 
     In another embodiment, the invention provides a method of treating a condition associated with elevated levels of a cytokine, such as TNF-α, in seminal plasma, comprising administering a therapeutically effective amount of an anti-cytokine compound or composition, such as an anti-TNF-α compound or composition. 
     The present invention also provides a method for treating CPPS comprising administering a therapeutically effective amount of an ant-cytokine compound or composition, such as an anti-TNF-α compound or composition. 
     Many anti-cytokine agents, such as anti-TNF-α agents, are known in the art. In one aspect of the present invention, the anti-cytokine agent is selected from the group consisting of inhibitors of cytokine synthesis, inhibitors of cytokine processing, and inhibitors of cytokine activity. In another aspect, the anti-cytokine agent is an anti-TNF-α agent selected from the group consisting of inhibitors of TNF-α synthesis, inhibitors of TNF-α processing, and inhibitors of TNF-α activity. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIGS. 1A and B show the results of recall antigen proliferation assays performed on CD4 +  T lymphocytes. The A) panel represents patients with a history of CPPS, and B) panel represents normal patients. 
     FIG. 2 shows the mean (SEM) counts per minute of recall proliferation assay data from FIG.  1 . 
     FIG. 3 shows the seminal plasma TNF-α levels as measured by the sandwich ELISA. 
     FIG. 4 shows the seminal plasma IL-8 levels as measured by the sandwich ELISA. 
     FIG. 5 shows the seminal plasma GM-CSF levels as measured by the sandwich ELISA. 
     FIG. 6 shows the seminal plasma IL-1β levels as measured by the sandwich ELISA. 
     FIG. 7 shows the seminal plasma IL-6 levels as measured by the sandwich ELISA. 
     FIG. 8 shows a comparison of seminal plasma TNF-α levels versus IL-1β levels in prostatitis patients. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present invention provides a method for diagnosing CPPS comprising analyzing a semen component for an elevated level of a cytokine. The semen component is preferably seminal plasma, and the cytokine is preferably selected from the group consisting of GM-CSF, IL-1-β, IL-8, IL-6, and TNF-. More preferably, the cytokine is TNF-α. The present invention also provides a method for treating the CPPS by administering a cytokine inhibitor, such as a TNF-α inhibitor. 
     The present inventors evaluated a group of men with a history of CPPS for reactivity with normal seminal plasma as compared to a control group. The control group consisted of 15 individuals, including 3 individuals with no history of any urologic problem or symptoms who underwent leukopheresis, and 12 volunteer male blood donors whose buffy coat leukocytes were obtained 24 hours after blood donation. The CPPS group consisted of 10 men who were referred to the VA Maryland Health Care System Urology Section or the University of Maryland Division of Urology with a history of CPPS. 
     The results of the proliferation assay are shown in FIG.  1 . The mean SEM (counts per minute) for the proliferation assay are shown in FIG.  2 . These data show that a subpopulation of men with CPPS had a significant recall proliferative response to seminal plasma pulsed PBMCs, and that this response was not observed in the control group. Both normal subjects and patients with CPPS had equivalent and significant responses to the recall antigens tetanus toxoid and  Candida  extract. The recall response to seminal plasma was dose-dependent and the antigen appears to be contained within the secretions of the prostate. A similar recall response was observed when the seminal plasma was obtained from men with seminal vesicle atresia or from normal male volunteers. 
     The data clearly show that an autoimmune response to self prostatic proteins is occurring in men with the clinical syndrome of CPPS. The antigenic material in seminal plasma is presumably processed and presented by antigen-presenting cells in PBMCs. 
     To further characterize the observed autoimmune response, the present inventors analyzed seminal plasma for the presence of cytokines. Measurement of cytokine levels in the semen of men with CPPS represents an objective measure of genital tract inflammation as cytokines are mediators of the inflammatory response. 
     The pattern of seminal cytokines observed so far suggests that macrophage products proximal in the inflammatory cytokine cascade are elevated in men with chronic non-bacterial prostatitis. The T-cell cytokine IFN-γ was not detected in controls or CPPS patients (data not shown). The correlation of IL-1α and TNF-α levels (FIG. 8) strongly suggests that these cytokines are physiologically present in the semen because of some stimulus. 
     Elevated levels of TNF-α in these patients is particularly intriguing. TNF-α is a critical proximal mediator in several known autoimmune conditions including rheumatoid arthritis and Crohn&#39;s disease. Recent prospective, randomized, blind trials in these two diseases have clearly shown that blocking TNF-α with antibodies or receptor antagonists improves symptoms and signs of these diseases in patients [Moreland et al.,  N.Engl.J.Med.  337:141-47 (1997); Targan et al.,  N.Engl.J.Med.  337:1029-35 (1997)]. 
     The inventors have discovered that cytokines useful in the diagnosis of CPPS include GM-CSF, IL-1-β, IL-8, IL-6, and TNF-. However, it will be apparent to those in the art that it is a routine matter in light of the instant disclosure to test seminal fluid of subjects with CPPS symptoms for all known cytokines to determine whether further cytokines are elevated in such subjects. 
     The most sensitive method ever applied to detect circulating human TNF-α, based on extremely high binding specificity and affinity of the p55 TNF-α receptor for TNF-α, failed to detect any circulating TNF-α protein in healthy humans [Poltorak et al.,  J. Immunol. Methods  169:93-99 (1994)]. The detection limit of this assay is 200 attomolar (10 −18   mol L −1 ), which equals 120,000 TNF-α trimers or 10 femtograms in 1 ml plasma. By contrast, in acute diseases such as septic shock, TNF-α circulates in nanomolar (10 −9  mol L −1 ) concentrations. 
     Methods for Diagnosing CPPS 
     The methods of the subject invention exploit the inventors&#39; discovery of the relationship between cytokine levels in seminal plasma to CPPS. The inventors have shown that cytokines are secreted in measurable quantities in the semen of men with CPPS, and hence can be used for diagnostic purposes. The diagnostic methods of the present invention provide a more objective, accurate, and quantifiable measure of inflammation in the prostate of men with CPPS. 
     Collection of semen from men suspected of having CPPS may be accomplished via any known method. Semen is preferably incubated at ambient temperature for 30 minutes, followed by centrifugation, results in the recovery of supernatant, referred to herein as “seminal plasma.” Cytokine levels are preferably measured in this seminal plasma, but may also be measured in other semen components or fractions, such as expressed prostatic secretions 
     Cytokine assay of the seminal plasma may be accomplished by any known method for identifying and quantifying a protein or peptide in a body sample. Preferred assays are immunoassays, such as radioimmunoassays. The most preferred method is the sandwich enzyme-linked immunosorbant assay (ELISA) employing commercially available monoclonal antibodies. Various receptor binding assays may also be employed in the diagnostic methods of the present invention. 
     Methods for Treating CPPS 
     The invention also provides a method for treating men determined to be suffering from a disorder associated with elevated levels of one or more cytokines in one or more components or fractions of semen, preferably seminal plasma, comprising administering one or more anti-cytokine agents, such as anti-TNF-α agents. In preferred embodiments of the claimed methods, the anti-cytokine agent is administered to a patient suffering from a disorder falling within the definition of CPPS, including prostatitis. 
     The anti-cytokine agent may be provided in a formulation suitable for administration to a patient. Such formulations are known in the art and depend on the chemical and physiological characteristics of the particular anti-cytokine agent. 
     The dosage regimen is readily determined by one of skill in the art, taking into account various factors which affect the action of the particular anti-TNF-α agent. For example, dosage may vary depending on the condition, type and/or severity of damaged tissue; the patient&#39;s age and/or diet; time, mode, and/or route of administration, as well as other clinical factors known in the art. Generally, systemic or injectable administration, such as intravenous (IV), intramuscular (IM) or subcutaneous (Sub-Q) injection, will be initiated at a dose which is minimally effective. The dose will then be gradually increased until a positive effect is observed. Incremental increases should be continued, so long as such increases produce a corresponding increase in effect, while taking into account any adverse affects that may appear. The addition of any other anti-TNF-α agents to the final composition may also affect the final dosage. Progress may be monitored by analyzing the cytokine levels by the diagnostic assay previously described in the subject invention. 
     Anti-Cytokine Agents 
     Compounds which interfere with the production and/or activity of various cytokines, such as TNF-α, are widely known. The term “anti-cytokine compound” as used herein includes compounds which inhibit production, processing or activity of a cytokine or its receptor. Likewise, the term “anti-TNF-α compound” as used herein includes compounds which inhibit production, processing or activity TNF-α or its receptor(s). Such compounds may, for example, bind to the cytokine or its receptor, thereby preventing the natural cytokine-receptor interaction. 
     Many anti-TNF-α compounds are known and/or are under development for treatment of other conditions associated with TNF-α, such as rheumatoid arthritis, insulin dependent diabetes, sepsis and Crohn&#39;s disease [see Haworth et al., “Cytokine and Anti-Cytokine Therapy”,  The Cytokine Handbook,  Thomson, Angus, ed., pp. 777-801 (1998)]. Synthesis of TNF-α can be inhibited by a variety of known agents, including phosphodiesterase inhibitors, prostanoids, adenosine, corticosteroids and IL-10. Glucocorticoids and prostaglandin E 2  (PGE 2 ) also inhibit TNF synthesis. Processing of the TNF-α pro-protein can be inhibited by specific inhibitors of the TNF-α metalloprotease. The effects of released TNF-α protein can be antagonized by TNF-α antagonists, such as soluble TNF-α receptors or anti-TNF-α antibodies. 
     Anti-TNF-α agents which can be used in the methods of the subject invention also include various cytokines, endogenous mediators, and synthetic drugs. Cytokines useful as anti-TNF-α agents include, for example, IL-4, IL-10, TGFβ, and ciliary neurotrophic factor. 
     Endogenous mediators which can be used as anti-TNF-α agents include, for example, corticosteroids, prostanoids, adenosine, histamine, nitric oxide, retinoic acid, and n-3 polyunsaturated fatty acids. 
     Synthetic drugs useful in the methods of the present invention as anti-TNF-α agents include, for example, pentoxifylline, rodipram, cyclosporin A, chlorpromazine, thalidomide, antisense oligonucleotides, tetravalent guanylhydrazone (CNI-1493), and bicyclic imidazoles (SK&amp;F 86002). 
     Compounds which inhibit TNF processing include, for example, compound 2, and GI 129471. 
     Compounds which inhibit TNF-α effects useful according to the present invention include, for example, anti-TNF-α antibodies and soluble TNF receptors, and TNF receptor chimeras. 
     Inhibition of TNF synthesis can be achieved by several means: (1) inhibition of transcription; (2) decrease of the mRNA half-life; and (3) inhibition of translation. Phosphodiesterase inhibitors pentoxifylline act mainly on transcription. Dexamethasone inhibits translation. Thalidomide specifically decreases the half-life of TNF mRNA. Furthermore, antisense oligonucleotides allow specific suppression of TNF translation. 
     Phosphodiesterase inhibitors are also known to suppress TNF activity. Among the clinically used phosphodiesterase inhibitors, pentoxifylline has been the most extensively studied with regard to TNF-suppressing activity. Patients receiving anti-CD3 mAbs to treat acute graft rejection have been administered pentoxifylline to decrease harmful TNF synthesis. Rolipram, a specific type IV phosphodiesterase inhibitor, is 500-fold more potent than pentoxifylline at suppressing TNF synthesis. Type IV phosphodiesterase is predominant in monocytes and is therefore an excellent target for suppression of cAMP-sensitive functions in this cell type. Moreover, rolipram synergizes with prostanoids (prostaglandin E 2  (PGE 2 ), prostacyclin analogs) both in elevating cAMP concentrations and in suppressing TNF synthesis. This may confer a tropism towards inflamed tissue with high interstitial concentrations of PGE 2 . Several animal studies show the efficacy of specific phosphodiesterase inhibition in vivo: in a rat model of experimental autoimmune encephalomyelitis (EAE), TNF suppression and amelioration by rolipram was confirmed for EAE in non-human primates (marmosets); and suppression of TNF synthesis and enhanced survival has been demonstrated following rolipram treatment in a rat model of acute respiratory distress syndrome. Rolipram was first synthesized in the early 1980s. It has been tested in clinical trials as an antidepressant but has not been marketed. 
     In a preferred aspect of the present invention, the anti-chemokine compound is etanercept, a dimeric fusion protein marketed under the name ENBREL. Etanercept consists of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Etanercept consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Etanercept is preferably supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration after reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol). Following reconstitution, the solution of etanercept is preferably clear and colorless, with a pH of 7.4±0.3. Each single-use vial of etanercept preferably contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine. 
     The patents listed in Table 2, in Section 6.4 of the present application describe various illustrative anti-cytokine compounds which are also within the scope of the present invention. 
     Compositions Comprising Anti-TNF Agents and Modes of Administration 
     EXAMPLES 
     The following examples are intended to illustrate but not limit the invention. 
     All subjects were required to fulfill the NIDDK Prostatitis Workshop criteria for CPPS. For every protocol included an age and race-matched control group without CPPS symptoms. 
     EXAMPLE 1: Determination of Seminal Plasma Reactivity in CD4 +  Cells 
     Seminal Plasma Used as Principal Source of Antigen 
     Normal seminal plasma was used as the principal source of antigen. This material was obtained from pooled normal semen donors examined in the University of Maryland Andrology/In Vitro Fertilization laboratory. Semen was used for these studies if the semen analysis showed normal sperm count, motility, volume, pH and liquefaction and no leukospermia. Semen from normal donors was allowed to liquefy by incubation for 30 minutes at room temperature and centrifuged to remove spermatozoa. The supernatant was diluted in PBS and filter sterilized through a 0.2 μm filter and cryopreserved at 70° C. in aliquots. Several specimens were pooled and frozen in aliquots to allow for multiple experiments. Seminal plasma preparations were tested for endotoxin by the Limulus amebocyte lysis (LAL) assay. It was ensured that endotoxin levels in semen were low and standardized between lots of pooled seminal plasma. Control antigens were tetanus toxoid and candida extract. 
     CD4 +  Proliferation Assay 
     Recall antigen proliferation assays were performed on CD4 +  T lymphocytes from the PBMC of all subjects enrolled in the protocol as described previously [Cohen et al.,  J. Immunother.  14:242-252 (1993)]. Complete medium (CM) consists of RPMI-1640 containing 10% pooled human serum plus penicillin/streptomycin. PBMC was produced from leukopheresis packs by centrifugation over Lymphocyte Separation Medium. Aliquots of PBMC were cryopreserved in 10% DMSO in human serum avoiding exposure to potential bovine antigens in fetal bovine serum. Human serum from males may contain prostatic antigens, such as PSA. However, PSA is present in normal male serum in low amounts and all comparisons of reactivity to antigen are made to unpulsed antigen presenting cells cultured in the same medium alone. Hence any effect of traces of prostate antigens in human serum cannot explain differences between pulsed and unpulsed groups. PBMC was enriched for CD4 +  T cells by immunoaffinity column chromatography by negative selection (R &amp; D Systems, Minneapolis, Minn.). This was the responding population. 
     The stimulator cells consisted of autologous whole PBMC pulsed with various dilutions of pooled human seminal plasma, salt cut proteins, purified prostatic proteins or control antigens in CM for 18 hours. Antigens were added to 3×10 6  PBMC/well in 24 well plates containing 2 ml CM/well. Dilutions of seminal plasma and control antigens from 1:50 to 1:500 were used to determine antigen dose. Pulsed APC was washed, irradiated (3000 cGy,  137 Cs source) and mixed with the responder population in triplicate in 96 well plates at various stimulator:responder ratios. APC alone and T cells alone were set up as controls. Other wells received PHA 1 μg/mI or PHA plus unpulsed PBMC to ensure that the responder population can proliferate. The plates were incubated for 5 days at 37° C. and  3 H-thymidine 1 μCi/well was added for the last 18 hours of the incubation. The cells were then harvested onto filtermats and the incorporated counts per minute (CPM) in the cells determined by liquid scintillation counting with the BetaPlate instrument (Wallac, Gaithersburg, Md.). 
     Data were analyzed by determining the mean of triplicate wells. CPM from stimulator PBMC alone was subtracted. A patient was considered a responder to seminal plasma if the mean CPM obtained from seminal plasma-pulsed APC exceeds the mean plus 3 standard deviations of the CPM obtained from unpulsed APC. Differences between the response of subjects within a group (prostatitis, normal volunteer) to recall and seminal plasma antigens was evaluated by the Wilcoxon Signed-Ranks test. This is a non-parametric test appropriate for a response which is not normally distributed as our preliminary data show for the response to seminal plasma. Differences in the overall mean CPM response to the antigens compared between groups (prostatitis versus normal, for example) was performed by the Wilcoxon Rank Sum test. A 2 tailed p value of less than 0.05 was interpreted as excluding the null hypothesis for each comparison. 
     The results of these experiments are shown in FIGS. 1 and 2. 
     EXAMPLE 2: Measurement of Inflammatory Cytokine Levels in Semen 
     Semen Collection 
     Semen was obtained by masturbation into a sterile container. Subjects were abstinent for 3 days prior to sample collection. Semen was allowed to liquefy by incubation at ambient temperature for 30 minutes and then centrifuged. The supernatant seminal plasma was collected and frozen at −30° C. in aliquots until cytokine assay were performed. 
     Sandwich ELISA for Cytokines in Semen and Culture Supernatants 
     Two-antibody ELISAs were performed using commercially available paired monoclonal antibodies and recombinant standards (cytokines IL-8, GM-CSF, IL-1β, IL-6 and TNF-α were purchased from Endogen). Cytokine capture antibodies diluted in PBS were coated in polystyrene microtiter plates (Maxisorb; Nunc, Denmark) overnight at 25° C. and blocked for 2 hours with PBS containing 2% BSA and 12 mg/ml casein (Sigma) and 0.01% thimerosal. The plate was washed with TBS/Tween and 50 μl assay buffer (PBS/4% BSA/0.01% thimerosal) was added to each well. 
     Based on preliminary experiments, samples were diluted with PBS to adjust cytokine concentrations within the detection range of each cytokine ELISA assay. Diluted samples and recombinant standards (50 μl/well) were incubated in duplicate for 2 hours at 37° C. After thorough washing with PBS/Tween, 100 μl biotinylated detecting antibodies diluted in assay buffer were added to each well and incubated for 1 hour at 25° C. 
     After washing with PBS/Tween, 100 βl of streptavidin horseradish peroxidase conjugate (Dako) was added to each well for 45 min at 25° C. After a final washing, 100 ml commercially prepared peroxidase substrate (Dako) was added for approximately 30 minutes until optimal color change in the standards wells is noted. After the reaction was stopped with 100 ml 2N HCI, the absorption at 450 (minus absorption at 630 nm) was measured using a Dynatech MR 4000 microplate reader (Chantilly, Va.). The concentration of cytokine was calculated based on a standard curve performed for each plate by fitting a first or second order polynomial equation to the data using Deltagraph (Deltapoint) on a Macintosh computer. Assay reliability was monitored by including an internal control with each assay. 
     The results of these experiments are shown in FIGS. 3-8. 
     EXAMPLE 3: Effects of Administration of Prednisone on Patients with CPPS 
     To test the methods of the present invention, subjects with negative localization studies were started on a 30 day course of oral prednisone 60 mg once a day. Subject 1 began steroids on May 26, 1998, and stopped early (Jun. 16, 1998) dues to side effects. Subject 2 began steroids on May 26, 1998, and completed the course on approximately Jun, 24, 1998. Subject 3 began steroids on Jul. 22. 1998 and stopped early (Aug. 4, 1998) due to side effects. Subject 4 began steroids on Oct. 13, 1998. Subject 5 began steroids on Sep. 15, 1998 and completed the course on Oct. 15, 1998. All values have been multiplied by the dilution factors. The results are set forth in Table 1: 
     
       
         
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Results of 30 Day Course Oral Prednisone 60 mg 1/day 
               
             
          
           
               
                   
                   
                   
                 time in 
                   
                   
                   
                   
                   
               
               
                   
                 visit 
                   
                 relation to 
                   
                 SFQ 
                 SSI 
                 IL-1B 
                 TNF-a 
               
               
                 Patient 
                 # 
                 DATE 
                 therapy 
                 Age 
                 0-50 
                 0-100 
                 1.56-100 pg/ml 
                 3.9-250 pg/ml 
               
               
                   
               
               
                 SUBJECT 1 
                 0 
                 4/24/98 
                 pre 
                 57 
                 28 
                 51 
                 148 
                 346 
               
               
                   
                 1 
                 6/9/98 
                 mid 
                   
                 31 
                 59 
                 118 
                 280 
               
               
                   
                 2 
                 6/12/98 
                 end 
                   
                 29 
                 42 
                 140 
                 364 
               
               
                   
                 3 
                 8/7/98 
                 post 
                   
                 23 
                 35 
                 84 
                 184 
               
               
                 SUBJECT 2 
                 0 
                 5/1/98 
                 pre 
                 43 
                 21 
                 37 
                 32 
                 44 
               
               
                   
                 1 
                 5/26/98 
                 mid 
                   
                 10 
                 15 
                 8 
                 26 
               
               
                   
                 2 
                 6/12/98 
                 end 
                   
                 15 
                 17 
                 15 
                 45 
               
               
                   
                 3 
                 6/18/98 
                 post 
                   
                 23 
                 32 
                 3 
                 8 
               
               
                   
                 4 
                 7/7/98 
                 post 
                   
                 23 
                 17 
                 3 
                 14 
               
               
                 SUBJECT 3 
                 0 
                 7/22/98 
                 pre 
                 40 
                 9 
                 31 
                 4 
                 8 
               
               
                   
                 1 
                 8/3/98 
                 mid 
                   
                 16 
                 27 
                 19 
                 12 
               
               
                   
                 2 
                 9/8/98 
                 post 
                   
                 7 
                 18 
                 2 
                 8 
               
               
                 SUBJECT 4 
                 0 
                 10/13/98 
                 pre 
                 34 
                 32 
                 14 
                 112 
                 22 
               
               
                   
                 1 
                 10/27/98 
                 mid 
                   
                 13 
                 3 
                 40 
                 109 
               
               
                   
                 2 
                 11/13/98 
                 end 
                   
                 12 
                 0 
                 36 
                 27 
               
               
                   
                 3 
                 2/3/99 
                 post 
                   
                 5 
                 7 
                 4 
                 14 
               
               
                 SUBJECT 5 
                 0 
                 9/15/98 
                 pre 
                 24 
                 34 
                 64 
                 110 
                 284 
               
               
                   
                 1 
                 9/25/99 
                 mid 
                   
                 33 
                 65 
                 — 
                 — 
               
               
                   
                 2 
                 10/23/98 
                 end 
                   
                 24 
                 42 
                 57 
                 154 
               
               
                   
               
             
          
         
       
     
     Seminal plasma was prepared by centrifugation of semen sample at 1500 rpm for 10 min and harvesting the supernatant. Seminal plasma was frozen away at −30° C. All samples were diluted 2× in PBS and subjected to cytokine analysis without any further dilutions. Samples were submitted as 125 ul aliquots for each cytokine. Cytokine analysis was done in duplicates using 50 ul of sample per well. 
     The score of the Symptoms Frequency Questionnaire (SFQ) increases with the frequency of symptoms. The score of the Symptom Severity Index (SSI) increases with the severity of the symptoms. The symptom indices used in the studies are described in J. C. Nickel and R. Sorensen. Transurethral microwave thermotherapy for nonbacterial prostatitis: A randomized double-blind sham controlled study using new prostatitis specific assessment questionnaires.  J. Urol.  155 (6): 1950-1954,1996. 
     The results demonstrate that anti-TNF-α therapy can reduce both the severity and the frequency of symptoms of CPPS. 
     Exemplary Anti-Cytokine Compounds 
     The patents listed in Table 2 below describe various illustrative anti-cytokine compounds which are also within the scope of the present invention. Other such patents are available in various patent databases, such as the Lexis-Nexis patent database, by searching, e.g.,using a boolean search such as “chemokine /2 (antagoni! or inhibit!)” or similarly, “TNF /2 (antagoni! or inhibit!)”, where “!” is a universal character which allows any combination of additional letters. 
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Exemplary Anti-Cytokine Compounds 
               
             
          
           
               
                 Patent 
                 Issue 
                   
                   
               
               
                 No. 
                 Date 
                 Title 
                 Abstract 
               
               
                   
               
               
                 5,900,434 
                 May 4, 
                 Method for inhibiting the 
                 Process for the preparation of (−)-pimara-9(11),15-diene-19-oic acid(acanthoic acid) and 
               
               
                   
                 1999 
                 production of interleukin-1 
                 pharmaceutical compositions comprising acanthoic acid useful for the treatment of 
               
               
                   
                   
                 or tumor necrosis factor- 
                 diseases caused by an excessive production of interleukin-1 or tumor necrosis factor- 
               
               
                   
                   
                 alpha by administering 
                 alpha. 
               
               
                   
                   
                 acanthoic acid 
               
               
                 5,900,430 
                 May 4, 
                 Cytokine inhibitors 
                 Invented are methods of inhibiting the production of cytokines, particularly inhibiting the 
               
               
                   
                 1999 
                   
                 production of interleukin-1 and inhibiting the production of tumor necrosis factor in a 
               
               
                   
                   
                   
                 mammal in need thereof which comprises administering to such mammal an effective 
               
               
                   
                   
                   
                 amount of an azaspirane derivative. 
               
               
                 5,900,417 
                 May 4, 
                 1,3,3- 
                 This invention relates to certain 1,3,34-(trisubstituted)cyclohexane monomers and related 
               
               
                   
                 1999 
                 (Trisubstituted)cyclohexane 
                 compound which are useful in treating allergic and inflammatory diseases and for inhibiting 
               
               
                   
                   
                 monomers and related 
                 the production of Tumor Necrosis Factor (TNF). 
               
               
                   
                   
                 compounds 
               
               
                 5,892,098 
                 Apr. 6, 
                 3,3- 
                 This invention relates to derivatives of 3,3-(disubstituted)cyclohexan-1-one monomers 
               
               
                   
                 1999 
                 (disubstituted)cyclohexan- 
                 and related compounds which are useful for treating allergic and inflammatory diseases. 
               
               
                   
                   
                 1-one monomers and 
               
               
                   
                   
                 related compounds 
               
               
                 5,891,924 
                 Apr. 6, 
                 Curcumin 
                 The present invention provides a method of inhibiting the activation of the NF kappa B 
               
               
                   
                 1999 
                 (diferuloylmethane) 
                 transcription factor in an animal in need of such treatment comprising the step of 
               
               
                   
                   
                 inhibition of NF kappa B 
                 administering to said animal a pharmacologically effective dose of curcumin. Also provided 
               
               
                   
                   
                 activation 
                 is a method of inhibiting the nuclear translocation of the p65 subunit of the NF kappa B 
               
               
                   
                   
                   
                 transcription factor in a cell or in an animal in need of such treatment comprising the step 
               
               
                   
                   
                   
                 of administering to said animal a pharmacologically effective dose of curcumin. 
               
               
                 5,891,883 
                 Apr. 6, 
                 4,4- 
                 The present invention relates to 4,4(disubstituted)cyclohexan-1-ol monomers and related 
               
               
                   
                 1999 
                 (disubstituted)cyclohexan- 
                 compounds, pharmaceutical compositions containing these compounds, and their use in 
               
               
                   
                   
                 1-ols monomers and 
                 treating allergic and inflammatory diseases and for inhibiting the production of Tumor 
               
               
                   
                   
                 related compounds 
                 Necrosis Factor (TNF). 
               
               
                 5,891,878 
                 Apr. 6, 
                 Quinolones and their 
                 1-Alkyl-substituted-quinolone-3-carboxamides have therapeutic utility via inhibition of 
               
               
                   
                 1999 
                 therapeutic use 
                 Phosphodiesterase IV esterase and/or Tumour Necrosis Factor activity. The compounds of 
               
               
                   
                   
                   
                 the invention have the general formula (I): [See Original Patent for Chemical Structure 
               
               
                   
                   
                   
                 Diagram] (I) The compounds of the invention encompassed by formula (I) include 
               
               
                   
                   
                   
                 enantiomers, diastereoisomers and mixtures, including racemic mixtures. 
               
               
                 5,891,675 
                 Apr 6, 
                 TNF receptor death domain 
                 Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed 
               
               
                   
                 1999 
                 ligand proteins 
                 Polynucleotides encoding the TNF-R1-DD ligand protein are also disclosed along with 
               
               
                   
                   
                   
                 vectors, host cells, and methods of making the TNF-R1-DD ligand protein Pharmaceutical 
               
               
                   
                   
                   
                 compositions containing the TNF-R1-DD ligand protein methods of treating inflammatory 
               
               
                   
                   
                   
                 conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. 
               
               
                   
                   
                   
                 Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by 
               
               
                   
                   
                   
                 such methods are also disclosed. 
               
               
                 5,891,618 
                 Apr. 6, 
                 Method for quantifying 
                 The present invention provides a method for quantifying the presence of extracellular LBP 
               
               
                   
                 1999 
                 LBP in body fluids 
                 in body fluids including blood in a subject comprising conducting an LBP immunoassay on 
               
               
                   
                   
                   
                 plasma obtained from said subject. 
               
               
                 5,891,432 
                 Apr. 6, 
                 Membrane-bound cytokine 
                 The present invention provides a cellular vaccine having a membrane-bound fusion 
               
               
                   
                 1999 
                 compositions comprising 
                 protein that includes a non-antibody immunomodulatory molecule such as GM-CSF 
               
               
                   
                   
                 GM = CSF and methods of 
                 operatively fused to a heterologous membrane attachment domain. Non-antibody 
               
               
                   
                   
                 modulating an immune 
                 immunomodulatory molecules useful in the invention include immunostimulatory and 
               
               
                   
                   
                 response using same 
                 immunosuppressive molecules such as cytokines. In one embodiment, the invention 
               
               
                   
                   
                   
                 provides a cellular vaccine having a membrane-bound fusion protein that includes a non- 
               
               
                   
                   
                   
                 antibody immunomodulatory molecule operatively fused to a heterologous membrane 
               
               
                   
                   
                   
                 attachment domain and, additionally, a disease-associated antigen or immunogenic 
               
               
                   
                   
                   
                 epitope thereof. Further provided by the invention are methods of modulating an immune 
               
               
                   
                   
                   
                 response against a disease-associated antigen by administering to an individual a cellular 
               
               
                   
                   
                   
                 vaccine having a membrane-bound fusion protein that includes a non-antibody 
               
               
                   
                   
                   
                 immunomodulatory molecule operatively fused to a heterologous membrane attachment 
               
               
                   
                   
                   
                 domain. 
               
               
                 5,889,011 
                 Mar. 30, 
                 Substituted amino alkyl 
                 Compounds and pharmaceutical compositions thereof comprise the formula: (R)j- (core 
               
               
                   
                 1999 
                 compounds 
                 moiety), including resolved enantiomers and/or diastereomers, hydrates, salts, solvates 
               
               
                   
                   
                   
                 and mixtures thereof, wherein J is an integer from one to three, the core moiety is non- 
               
               
                   
                   
                   
                 cyclic or comprises at least one, five- to seven-membered ring structure, R may be 
               
               
                   
                   
                   
                 selected from the group consisting of hydrogen, halogen, hydroxyl, amino, substituted or 
               
               
                   
                   
                   
                 unsubstituted benzyl, alkyl (C[1-6]) or alkenyl (C[1-6]), and at least one R has the formula 
               
               
                   
                   
                   
                 [See Original Patent for Chemical Structure Diagram] I wherein n is an integer from four 
               
               
                   
                   
                   
                 to eighteen; each R′1 and R′2 is independently hydrogen, alkyl (C[1--4]) or alkenyl (C[1-4]), 
               
               
                   
                   
                   
                 the alkyl or alkenyl groups being preferably substituted by a halogen, hydroxyl, ketone or 
               
               
                   
                   
                   
                 dimethylamino group and/or may be interrupted by an oxygen or hydrogen atom or an alkyl 
               
               
                   
                   
                   
                 (C[1-4]) group; and each R′3 and R′4 is independently hydrogen or methyl. Preferably, n is 
               
               
                   
                   
                   
                 an integer from six to ten, R′1 and R′2 are independently hydrogen or methyl and R′3 and 
               
               
                   
                   
                   
                 R′4 are hydrogen. The compounds are useful in treating or preventing for example sepsis 
               
               
                   
                   
                   
                 syndrome, hematopoietic or organ toxicity, baldness, hair loss or allopecia caused by 
               
               
                   
                   
                   
                 cytotoxic therapies, and progression of an inflammatory or autoimmune disease. 
               
               
                 5,888,977 
                 Mar. 30, 
                 Therapeutic uses of BPI 
                 Methods and materials for the treatment of human meningococcemia are provided in 
               
               
                   
                 1999 
                 protein products for human 
                 which therapeutically effective amounts of BPI protein products are administered. 
               
               
                   
                   
                 meningococcemia 
               
               
                 5,886,010 
                 Mar. 23, 
                 TNF- alpha inhibitor 
                 A method for the prophylaxis and treatment of diseases induced by accelerated INF- 
               
               
                   
                 1999 
                   
                 alpha secretion, such as rheumatoid arthritis, endotoxin shock, adult respiratory distress 
               
               
                   
                   
                   
                 syndrome, thermal burn, asthma, myocardial infarction, acute phase of viral myocardiosis, 
               
               
                   
                   
                   
                 etc. which comprises administering a carbostyril compound of the formula: [See Original 
               
               
                   
                   
                   
                 Patent for Chemical Structure Diagram] [I] wherein R&lt;1&gt; is H or lower alkyl, and R&lt;2&gt; 
               
               
                   
                   
                   
                 is phenyl(lower)alkyl having optionally 1 to 3 lower alkoxy substituents on the phenyl ring, 
               
               
                   
                   
                   
                 or a pharmaceutically acceptable salt thereof to a subject. 
               
               
                 5,883,131 
                 Mar. 16, 
                 Cyclic sulfone derivatives 
                 A compound of the formula [See Original Patent for Chemical Structure Diagram] I 
               
               
                   
                 1999 
                   
                 wherein n, p, q, X, Y, Z and Ar are as defined herein, useful in the treatment of arthritis, 
               
               
                   
                   
                   
                 cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis or 
               
               
                   
                   
                   
                 other diseases characterized by matrix metalloprotenase activity, as well as AIDS, sepsis, 
               
               
                   
                   
                   
                 septic shock or other diseases involving the production of TNF. 
               
               
                 5,877,222 
                 Mar. 2, 
                 Method for treating aids- 
                 The invention comprises inhibiting expression of TNF- alpha by administering an effective 
               
               
                   
                 1999 
                 associated dementia 
                 amount of a stabilized activated oxygen in a matrix of chlorite ions. Preferably, a 
               
               
                   
                   
                   
                 pharmaceutically acceptable formulation of tetrachlorodecaoxide is used, and more 
               
               
                   
                   
                   
                 preferably, WF-10. An effective amount of WF-10 comprises up to about 0.5 ml/kg. Another 
               
               
                   
                   
                   
                 embodiment of the invention is a method of treating AIDS-associated dementia comprising 
               
               
                   
                   
                   
                 the step of administering to a human an amount of a stabilized activated oxygen in a matrix 
               
               
                   
                   
                   
                 of chlorite ions sufficient to inhibit production of TNF- alpha. 
               
               
                 5,877,200 
                 Mar. 2, 
                 Cyclic amides 
                 Cyclic amides are inhibitors of tumor necrosis factor and can be used to combat cachexia, 
               
               
                   
                 1999 
                   
                 endotoxic shock, and retrovirus replication. A typical embodiment is 3-phenyl-3-(1- 
               
               
                   
                   
                   
                 oxoisoindolin-2-yl)propionamide. 
               
               
                 5,877,180 
                 Mar. 2, 
                 Method for treating 
                 Agonists of A[2a]adenosine receptors are effective for the treatment of inflammatory 
               
               
                   
                 1999 
                 inflammatory diseases with 
                 diseases. 
               
               
                   
                   
                 A[2a]adenosine receptor 
               
               
                   
                   
                 agonists 
               
               
                 5,877,151 
                 Mar. 2, 
                 Method for inhibiting 
                 The present invention contemplates a composition and method for treating septic shock in 
               
               
                   
                 1999 
                 production of tumor 
                 a mammal or as a prophylactic treatment prior to a surgical procedure, comprising 
               
               
                   
                   
                 necrosis factor 
                 administering a therapeutically effective amount of a bacterial lipopolysaccharide binding 
               
               
                   
                   
                   
                 peptide derived from CAP37 protein. In a preferred version the composition and method of 
               
               
                   
                   
                   
                 use may comprise a peptide comprising amino acids 20-44 or 120-146 of CAP37 or 
               
               
                   
                   
                   
                 subunits thereof. 
               
               
                 5,874,448 
                 Feb 23, 
                 Substituted 2-(2,6 dioxo-3- 
                 1-Oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindolines and 1,3-dioxo-2-(2,6-dioxo-3 
               
               
                   
                 1999 
                 fluoropiperidin-3-yl) 
                 fluoropiperidin-3-yl)isoindolines reduce the levels of TNF alpha in a mammal. A typical 
               
               
                   
                   
                 isoindolines and method of 
                 embodiment is 1,3-dioxo-2-(2,6-dioxo-34luoropiperidin-3-yl-isoindoline. 
               
               
                   
                   
                 reducing TNF alpha levels 
               
               
                 5,872,146 
                 Feb. 16, 
                 Mercapto alkyl peptidyl 
                 Described herein are compounds of formula (I): [See Original Patent for Chemical 
               
               
                   
                 1999 
                 compounds having MMP 
                 Structure Diagram] (I) which have MMP and TNF inhibitory activity. 
               
               
                   
                   
                 and TNF inhibitory activity 
               
               
                 5,869,677 
                 Feb. 9, 
                 3,3- 
                 The present invention relates to novel 3,3-(disubstituted)cyclohexan-1-carboxylate 
               
               
                   
                 1999 
                 (disubstituted)cyclohexan- 
                 monomers and related compounds, pharmaceutical compositions containing these 
               
               
                   
                   
                 1-carboxylate monomers 
                 compounds, and their use in treating allergic and inflammatory diseases and for inhibiting 
               
               
                   
                   
                 and related compounds 
                 the production of Tumor Necrosis Factor (TNF). 
               
               
                 5,869,660 
                 Feb. 9, 
                 Process of preparing 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1999 
                 imidazole compounds 
                 cytokine inhibitors. 
               
               
                 5,869,612 
                 Feb. 9, 
                 Tumor necrosis factor 
                 The invention concerns new tumor necrosis factor receptor associated factors, 
               
               
                   
                 1999 
                 receptor-associated factors 
                 designated TRAF. The new factors are capable of specific association with the intracellular 
               
               
                   
                   
                   
                 domain of the type 2 TNF receptor (TNF-R2), and are involved in the mediation of TNF 
               
               
                   
                   
                   
                 biological activities. 
               
               
                 5,869,515 
                 Feb. 9, 
                 1,3-dihydro-2H-imidazol-2- 
                 The present invention concerns the compounds of formula [See Original Patent for 
               
               
                   
                 1999 
                 one compounds 
                 Chemical Structure Diagram] (I) the N-oxide forms, the pharmaceutically acceptable acid 
               
               
                   
                   
                   
                 or base addition salts and the stereochemically isomeric forms thereof, wherein R&lt;1&gt; and 
               
               
                   
                   
                   
                 R&lt;2&gt; each independently are hydrogen; C[1-6]alkyl; difluoromethyl; trifluoromethyl, C[3- 
               
               
                   
                   
                   
                 6]cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two 
               
               
                   
                   
                   
                 heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl, 
               
               
                   
                   
                   
                 bicyclo[2.2.1]heptanyl; C[1-6]alkylsulfonyl; arylsulfonyl; or substituted C[1-10]alkyl, R3 is 
               
               
                   
                   
                   
                 hydrogen, halo or C[1-6]alkyloxy [See Original Patent for Chemical Structure Diagram] is 
               
               
                   
                   
                   
                 a bivalent radical of formula [See Original Patent for Chemical Structure Diagram] Alk is 
               
               
                   
                   
                   
                 C1-4alkanediyl; -A-B- is a bivalent radical of formula: -CR&lt;6&gt; ═CR&lt;7&gt;- or -CHR&lt;6&gt;- 
               
               
                   
                   
                   
                 CHR&lt;7&gt;-; L is hydrogen; optionally substituted C[1-6]alkyl; C[1-6]alkylcarbonyl; C[1- 
               
               
                   
                   
                   
                 6]alkyloxycarbonyl; optionally substituted C[3-6]alkenyl; optionally substituted piperidinyl; 
               
               
                   
                   
                   
                 C[1-6]alkylsulfonyl or arylsulfonyl; aryl is optionally substituted phenyl; Het&lt;1&gt; is 
               
               
                   
                   
                   
                 morpholinyl or optionally substituted pyridinyl, -furanyl, -thienyl, -hydroxypyridinyl, 
               
               
                   
                   
                   
                 -imidazolyl, -thiazolyl, -oxazolyl, -isoquinolinyl, -quinolinonyl, -piperidinyl, -piperazinyl; and 
               
               
                   
                   
                   
                 Het&lt;2&gt; is morpholinyl or optionally substituted piperidinyl, -piperazinyl, -pyridinyl, -furanyl 
               
               
                   
                   
                   
                 or -thienyl; having PDE IV and cytokine inhibiting activity. The invention also relates to 
               
               
                   
                   
                   
                 processes for preparing the compounds of formula (I) and pharmaceutical compositions 
               
               
                   
                   
                   
                 thereof. 
               
               
                 5,869,511 
                 Feb. 9, 
                 Isoxazoline compounds as 
                 This invention relates to isoxazoline compounds of formula (I) which are inhibitors of 
               
               
                   
                 1999 
                 inhibitors of TNF release 
                 tumor necrosis factor (TNF). The isoxazoline compounds are useful for inhibiting TNF in a 
               
               
                   
                   
                   
                 mammal in need thereof and in the treatment or alleviation of inflammatory conditions or 
               
               
                   
                   
                   
                 disease, including but not limited to rheumatoid arthritis, osteoarthritis, asthma, bronchitis, 
               
               
                   
                   
                   
                 chronic obstructive airways disease, psoriais, allergic rhinitis, dermatitis and inflammatory 
               
               
                   
                   
                   
                 bowel disease, sepsis, septic shock, tuberculosis, graft versus host disease and cachexia 
               
               
                   
                   
                   
                 associated with AIDS or cancer. This invention also relates to pharmaceutical compositions 
               
               
                   
                   
                   
                 useful therefor comprising such compounds of formula (I) wherein X&lt;1&gt; is —(CH2)[q[OH, 
               
               
                   
                   
                   
                 —CHOHR&lt;5&gt; or —(CH2)[m]CON(R&lt;6&gt;) (OH); wherein q and m are each independently 0 or 
               
               
                   
                   
                   
                 an integer from 1 to 5; R&lt;5&gt; is (C1-C4)alkyl; and R&lt;6&gt; is hydrogen or (C1-C3)alkyl; n is 
               
               
                   
                   
                   
                 0, 1, 2 or 3; Y&lt;1&gt; and Y&lt;2&gt; are as defined in the application. 
               
               
                 5,869,055 
                 Feb. 9, 
                 Anti-inflammatory CD14 
                 The invention relates to anti-inflammatory polypeptides comprising soluble CD14 related 
               
               
                   
                 1999 
                 polypeptides 
                 polypeptides having amino acids at position 7-10 that are different from the native 
               
               
                   
                   
                   
                 sequence or having amino acids 1-14 deleted. 
               
               
                 5,866,717 
                 Feb. 2, 
                 Metalloproteinase inhibitors 
                 Compounds of general formula (I), principally characterized in that R4 is a polyether 
               
               
                   
                 1999 
                   
                 group, are water soluble matrix metalloproteinase inhibitors. [See Original Patent for 
               
               
                   
                   
                   
                 Chemical Structure Diagram] (I) 
               
               
                 5,866,616 
                 Feb. 2, 
                 3,3-(disubstituted) 
                 The present invention relates to novel 3,3-(disubstituted)cyclohexan-1-ol monomers and 
               
               
                   
                 1999 
                 cyclohexan-1-ol monomers 
                 related compounds, pharmaceutical compositions containing these compounds, and their 
               
               
                   
                   
                 and related compounds 
                 use in treating allergic and inflammatory diseases and for inhibiting the production of 
               
               
                   
                   
                   
                 Tumor Necrosis Factor (TNF). 
               
               
                 5,866,570 
                 Feb. 2, 
                 Treatment of vascular 
                 A method for identifying patients at risk of developing vascular leakage syndrome and 
               
               
                   
                 1999 
                 leakage and related 
                 systemic inflammatory response syndrome (SIRS) such as septic shock by determining the 
               
               
                   
                   
                 syndrome such as septic 
                 serum levels of metaltoproteinase expression, in particular type IV collagenase expression, 
               
               
                   
                   
                 shock by administration of 
                 as well as a method of treating or preventing vascular leakage syndrome and SIRS by the 
               
               
                   
                   
                 metalloproteinase inhibitors 
                 administration of one or more metalloproteinase inhibitors, preferably type IV collagenase 
               
               
                   
                   
                   
                 inhibitors is taught. Additionally, the therapeutic efficacy of bis(dioxopiperazine) 
               
               
                   
                   
                   
                 compounds is determined on the basis of collagenase inhibiting activity, and the 
               
               
                   
                   
                   
                 compounds which inhibit collagenase activity are utilized for the treatment of collagenase 
               
               
                   
                   
                   
                 related disorders, e.g., vascular leakage syndrome, septic shock, stroke, cardiac disorders, 
               
               
                   
                   
                   
                 angiogenesis, and arthritis. Finally, a method for preventing or treating toxicity caused by 
               
               
                   
                   
                   
                 endogenous cytokine expression or cytokine administration or by immunotoxin 
               
               
                   
                   
                   
                 administration by the administration of one or more metalloproteinase inhibitors preferably 
               
               
                   
                   
                   
                 type IV cottagenase inhibitors is taught. 
               
               
                 5,864,036 
                 Jan. 26, 
                 Substituted imidazole 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1999 
                 compounds 
                 cytokine inhibitors. 
               
               
                 5,864,028 
                 Jan. 26, 
                 Degradation resistant 
                 This invention describes compounds active against TNF- alpha mRNA. It further 
               
               
                   
                 1999 
                 mRNA derivatives linked to 
                 describes RNA molecules capable of conferring stability to RNA in vivo through an 
               
               
                   
                   
                 TNF- alpha ribozymes 
                 endogenous ribozyme binding protein(s). Possible mRNA molecules to be stabilized 
               
               
                   
                   
                   
                 include ribozymes, antisense molecules and mRNA encoding polypeptides useful for 
               
               
                   
                   
                   
                 protein production. The ribozymes and antisense molecules described herein are useful in 
               
               
                   
                   
                   
                 mammals and plants, particutarty suited for viral diseases. Methods of production and 
               
               
                   
                   
                   
                 methods of use are also described. 
               
               
                 5,863,949 
                 Jan. 26, 
                 Arylsulfonylamino 
                 A compound of formula (I), wherein n, X, R&lt;3&gt;, R&lt;4&gt; and Ar are as defined above, 
               
               
                   
                 1999 
                 hydroxamic acid derivatives 
                 useful in the treatment of a condition selected from the group consisting of arthritis, cancer, 
               
               
                   
                   
                   
                 tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other 
               
               
                   
                   
                   
                 diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock 
               
               
                   
                   
                   
                 and other diseases involving the production of TNF. [See Original Patent for Chemical 
               
               
                   
                   
                   
                 Structure Diagram] (I) 
               
               
                 5,863,926 
                 Jan. 26, 
                 4,4- 
                 The present invention relates to novel 4,4-(disubstituted)cyclohexan-1-carboxylate 
               
               
                   
                 1999 
                 (disubstituted)cyclohexan- 
                 monomers and related compounds, pharmaceutical compositions containing these 
               
               
                   
                   
                 1-carboxylate monomers 
                 compounds, and their use in treating allergic and inflammatory diseases and for inhibiting 
               
               
                   
                   
                 and related compounds 
                 the production of Tumor Necrosis Factor (TNF). 
               
               
                 5,863,786 
                 Jan. 26, 
                 Nucleic acid encoding 
                 A DNA molecule is provided which encodes a polypeptide which is capable of binding 
               
               
                   
                 1999 
                 modified human tnf alpha 
                 human TNF alpha and which has the first three cysteine-rich subdomains, but not the 
               
               
                   
                   
                 (tumor necrosis factor 
                 fourth cysteine-rich subdomain, of the extracellular binding domain of a receptor selected 
               
               
                   
                   
                 alpha) receptor 
                 from the 55 kD and 75 kD receptors for human TNF alpha. The ability of the polypeptide to 
               
               
                   
                   
                   
                 bind to TNF alpha means that it can be used for treating diseases mediated by TNF alpha 
               
               
                   
                   
                   
                 activity, such as rheumatoid arthritis. 
               
               
                 5,861,510 
                 Jan. 19, 
                 Arylsulfonyl hydroxamic 
                 A compound of the formula [See Original Patent for Chemical Structure Diagram] I 
               
               
                   
                 1999 
                 acid derivatives as MMP 
                 wherein R&lt;1&gt;, R&lt;2&gt; R&lt;3&gt;, R&lt;4&gt; R&lt;5&gt;, R&lt;6&gt;, R&lt;7&gt;, R&lt;8&gt;, R&lt;9&gt; and Ar are as 
               
               
                   
                   
                 and TNF inhibitors 
                 defined above, useful in the treatment of a condition selected from the group consisting of 
               
               
                   
                   
                   
                 arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, 
               
               
                   
                   
                   
                 scleritis and other disease characterized by matrix metalloproteinase activity, as well as 
               
               
                   
                   
                   
                 AIDS, sepsis, septic shock and other diseases involving the production of TNF. 
               
               
                 5,861,436 
                 Jan 19, 
                 Hydroxamic acid 
                 The present invention relates to therapeutically active hydroxamic acid derivatives to 
               
               
                   
                 1999 
                 derivatives as 
                 pharmaceutical compositions containing them, and to the therapeutic use of these 
               
               
                   
                   
                 metalloproteinase inhibitors 
                 compounds. In particular, the compounds are inhibitors of matrix metalloproteinases that 
               
               
                   
                   
                   
                 are involved in tissue degradation, and in addition, are inhibitors of the release of tumor 
               
               
                   
                   
                   
                 necrosis factor from cells. 
               
               
                 5,861,421 
                 Jan. 19, 
                 4,4-(disubstituted) 
                 This invention relates to derivatives of 4,4-(disubstituted)cyclohexan-1-ones and related 
               
               
                   
                 1999 
                 cyclohexan-1-one 
                 compounds which are useful for treating allergic and inflammatory diseases. 
               
               
                   
                   
                 monomers and related 
               
               
                   
                   
                 compounds 
               
               
                 5,859,253 
                 Jan. 12, 
                 Metalloproteinase inhibitors 
                 L-tert-leucine-2-pyridlyamide or an acid addition salt thereof. 
               
               
                   
                 1999 
               
               
                 5,859,008 
                 Jan. 12, 
                 Arylalkyl diazinones 
                 Arylalkyl diazinone derivatives of the formula I [See Original Patent for Chemical Structure 
               
               
                   
                 1999 
                   
                 Diagram] I and their physiologically acceptable salts, R&lt;1&gt;, R&lt;2&gt;, R&lt;3&gt;, R&lt;4&gt;, 
               
               
                   
                   
                   
                 Q and X have the meanings indicated in claim 1, exhibit phosphodiesterase IV inhibition 
               
               
                   
                   
                   
                 and can be employed for the treatment of inflammatory processes and also of allergies, 
               
               
                   
                   
                   
                 asthma and autoimmune disorders. 
               
               
                 5,856,161 
                 Jan. 5, 
                 Tumor necrosis factor 
                 The present invention provides an isolated and purified protein that associates with the 
               
               
                   
                 1999 
                 receptor-1-associated 
                 cyloplasmic domain of the p60 form of the tumor necrosis factor receptor, having a 
               
               
                   
                   
                 protein kinase and methods 
                 molecular weight of about 52-55 kDa on SDS-PAGE, is a phosphoprotein, and does not 
               
               
                   
                   
                 for its use 
                 bind to the p80 form of the tumor necrosis factor receptor. Also provided is an isolated and 
               
               
                   
                   
                   
                 purified protein kinase that binds to the cytoplasmic domain of the p60 form of the tumor 
               
               
                   
                   
                   
                 necrosis factor receptor, said kinase phosphoryllates the p60 form of the tumor necrosis 
               
               
                   
                   
                   
                 factor receptor. Also provided are various methods of manipulating this tumor necrosis 
               
               
                   
                   
                   
                 factor receptor-associated protein and kinase in order to reduce various biological effects 
               
               
                   
                   
                   
                 of tumor necrosis factor. 
               
               
                 5,854,275 
                 Dec. 29, 
                 Cyclic imide derivatives 
                 The invention relates to a compound of the formula I [See Original Patent for Chemical 
               
               
                   
                 1998 
                   
                 Structure Diagram] I wherein R&lt;1&gt; is a cyclic imide group and X, Y, R&lt;2&gt;, and R&lt;3&gt; 
               
               
                   
                   
                   
                 are as defined herein. The invention further relates to pharmaceutical compositions 
               
               
                   
                   
                   
                 containing, and methods of using, compounds of the formula I. Compounds of the formula I 
               
               
                   
                   
                   
                 are useful in the treatment of diseases related to the production of matrix 
               
               
                   
                   
                   
                 metalloproteinases and tumor necrosis factor. 
               
               
                 5,854,271 
                 Dec. 29, 
                 Effective method for the 
                 The administration of histidine is able to prevent and ameliorate tissue and cellular 
               
               
                   
                 1998 
                 amelioration and prevention 
                 damage which is caused by damaging levels of cytokines and growth factors. It is shown 
               
               
                   
                   
                 of tissue and cellular 
                 that histidine, when administered in therapeutic quantities is able to inhibit cytokines and 
               
               
                   
                   
                 damage 
                 growth factors involved in cell and tissue damage. In addition, the method of administering 
               
               
                   
                   
                   
                 histidine to inhibit these molecules can prevent and ameliorate tissue, vessel and cell 
               
               
                   
                   
                   
                 damage from restenosis, burns, surgical procedures and other disorders which cause and 
               
               
                   
                   
                   
                 result from damaged tissues, vessels and cells. 
               
               
                 5,854,257 
                 Dec 29, 
                 Naphthyridinone 
                 Compounds of formula I [See Original Patent for Chemical Structure Diagram] I 
               
               
                   
                 1998 
                 derivatives 
                 including pharmaceutically acceptable salts thereof in which R1 represents a phenyl C[1-6] 
               
               
                   
                   
                   
                 alkyl group (in which the phenyl ring is optionally substituted by one or more of the 
               
               
                   
                   
                   
                 following: halo, a C[1-4]alkyl group, a C[1-4]alkoxy group, hydroxy or trifluoromethyl) and 
               
               
                   
                   
                   
                 the alkyl chain is optionally substituted by one or more C[1-2]alkyl groups; R2 represents a 
               
               
                   
                   
                   
                 C[2-6]alkoxycarbonyl group; and R3 represents hydrogen or halo are disclosed, which are 
               
               
                   
                   
                   
                 antirheumatic agents and are useful as modulators of cytokine synthesis, 
               
               
                   
                   
                   
                 immunomodulatory agents, antiinflammatory agents and anti-allergic agents. Compositions 
               
               
                   
                   
                   
                 containing these compounds and processes to make these compounds are also disclosed. 
               
               
                 5,854,028 
                 Dec. 29, 
                 Compositions comprising 
                 A novel mammalian cytokine, IL-11, and processes for producing it are disclosed. IL-11 
               
               
                   
                 1998 
                 IL-11 and methods of 
                 may be used in pharmaceutical preparations for stimulating and/or enhancing cells 
               
               
                   
                   
                 making and using IL-11 
                 involved in the immune response and cells involved in the proper functioning of the 
               
               
                   
                   
                   
                 hematopoietic system. 
               
               
                 5,853,977 
                 Dec. 29, 
                 Mammalian TNF- alpha 
                 The present invention provides isolated human and bovine TNF- alpha convertases, 
               
               
                   
                 1998 
                 convertases 
                 nucleic acids and recombinant vectors encoding the same, host cells comprising the 
               
               
                   
                   
                   
                 nucleic acids and vectors, and methods for making the convertases using the host cells. 
               
               
                   
                   
                   
                 This invention further provides antibodies and antigen binding fragments thereof which 
               
               
                   
                   
                   
                 speciflcally bind to the convertases and are useful for treating medical conditions caused or 
               
               
                   
                   
                   
                 mediated by TNF- alpha. Also provided are screening methods for identifying specific 
               
               
                   
                   
                   
                 inhibitors of mammalian TNF- alpha convertases, and for identifying nucleic acids encoding 
               
               
                   
                   
                   
                 such convertases. 
               
               
                 5,853,623 
                 Dec. 29, 
                 Peptidyl compounds and 
                 The present invention concerns novel mercaptoalkylpeptidyl compounds of formula (I) 
               
               
                   
                 1998 
                 their therapeutic use as 
                 which are useful inhibitors of matrix metalloproteinase and/or TNF-mediated diseases 
               
               
                   
                   
                 inhibitors of 
                 including degenerative diseases and certain cancers. The invention also concerns 
               
               
                   
                   
                 metalloproteinases 
                 methods of treating patients suffering from disorders or diseases which can be attributed to 
               
               
                   
                   
                   
                 or are associated with matrix metalloproteinase or TNF activity. 
               
               
                 5,852,173 
                 Dec. 22, 
                 TNF receptor death ligand 
                 Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed. 
               
               
                   
                 1998 
                 proteins and inhibitors of 
                 Polynucteotides encoding the TNF-R1-DD ligand protein are also disclosed, along with 
               
               
                   
                   
                 ligand binding 
                 vectors, host cells, and methods of making the TNF-R1-DD ligand protein. Pharmaceuticat 
               
               
                   
                   
                   
                 compositions containing the TNF-R1-DD ligand protein, methods of treating inflammatory 
               
               
                   
                   
                   
                 conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. 
               
               
                   
                   
                   
                 Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by 
               
               
                   
                   
                   
                 such methods are also disclosed 
               
               
                 5,851,822 
                 Dec. 22, 
                 Inflammation-induced 
                 The present invention describes methods of controlling and regulating the inflammatory 
               
               
                   
                 1998 
                 expression of a 
                 reaction generated in response to various toxins, immunogens, pathogens and 
               
               
                   
                   
                 recombinant gene 
                 autoimmune insults. The method employs a vector that includes an anti-cytokine protein or 
               
               
                   
                   
                   
                 antibacterial protein gene under the control of a cytokine responsive promoter. In animal 
               
               
                   
                   
                   
                 models, adenoviral vectors successfully delivered the vectors to hepatic cells and were 
               
               
                   
                   
                   
                 subsequently shown to respond only to stimulation by induced cytokines. 
               
               
                 5,851,556 
                 Dec. 22, 
                 Use of a salt of an alkaline- 
                 The invention relates to the use of a salt of an alkaline-earth metal in a cosmetic, 
               
               
                   
                 1998 
                 earth metal as TNF-A or 
                 pharmaceutical, veterinary and/or dermatological composition for treating, in particular, 
               
               
                   
                   
                 substance P inhibitor in a 
                 sensitive skins. It relates, in addition, to the use of a salt of an alkaline-earth metal for 
               
               
                   
                   
                 topical composition and 
                 preventing and/or combating rosacea and/or skin irritation and/or dartre and/or pudic 
               
               
                   
                   
                 composition obtained 
                 erythema and/or dysesthetic sensation and/or sensation of inflammation and/or pruritus of 
               
               
                   
                   
                   
                 the skin and/or of the mucous membranes. The salt is in particular strontium nitrate or 
               
               
                   
                   
                   
                 chloride. 
               
               
                 5,849,501 
                 Dec. 15, 
                 TNF receptor death domain 
                 Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed. 
               
               
                   
                 1998 
                 ligand proteins and method 
                 Polynucleotides encoding the TNF-R1-DD ligand protein are also disclosed, along with 
               
               
                   
                   
                 to identify inhibitors of 
                 vectors, host cells, and methods of making the TNF-R1-DD ligand protein. Pharmaceutical 
               
               
                   
                   
                 ligand binding 
                 compositions containing the TNF-R1-DD ligand protein, methods of treating inflammatory 
               
               
                   
                   
                   
                 conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. 
               
               
                   
                   
                   
                 Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by 
               
               
                   
                   
                   
                 such methods are also disclosed. 
               
               
                 5,847,123 
                 Dec. 8, 
                 Imide derivatives for 
                 Imide compounds having a propioloyl group or pharmaceutically acceptable salts thereof 
               
               
                   
                 1998 
                 inhibiting the production of 
                 which exhibit potent activities to inhibit the production of Interleukin 1-beta and also the 
               
               
                   
                   
                 interleukin-1 beta and the 
                 production of Tumor Necrosis Factor alpha. These imide compounds are useful as a 
               
               
                   
                   
                 production of tumor 
                 prophylactic or therapeutic agent for inhibiting the production of interleukin 1-beta and the 
               
               
                   
                   
                 necrosis factor alpha 
                 production of Tumor Necrosis Factor alpha, typically for such diseases as chronic 
               
               
                   
                   
                   
                 rheumatism, sepsis, ulcerative colitis, Crohn&#39;s disease and many other related diseases in 
               
               
                   
                   
                   
                 which interleukin 1-beta and/or Tumor Necrosis Factor alpha would participate. 
               
               
                 5,847,099 
                 Dec. 8, 
                 TNF receptor death domain 
                 Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed. 
               
               
                   
                 1998 
                 ligand proteins 
                 Polynucleotides encoding the TNF-R1-DD ligand protein are also disclosed, along with 
               
               
                   
                   
                   
                 vectors, host cells, and methods of making the TNF-R1-DD ligand protein. Pharmaceutical 
               
               
                   
                   
                   
                 compositions containing the TNF-R1-DD ligand protein, methods of treating inflammatory 
               
               
                   
                   
                   
                 conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. 
               
               
                   
                   
                   
                 Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by 
               
               
                   
                   
                   
                 such methods are also disclosed. 
               
               
                 5,846,763 
                 Dec. 8, 
                 DNA encoding tumor 
                 TSG-6 protein and functional derivatives thereof, DNA coding therefor, expression 
               
               
                   
                 1998 
                 necrosis factor stimulated 
                 vehicles, such as a plasmids, and host cells transformed or transfected with the DNA 
               
               
                   
                   
                 gene 6 (TSG-6) 
                 molecule, and methods for producing the protein and the DNA are provided, as well as 
               
               
                   
                   
                   
                 antibodies specific for the TSG-6 protein; a method for detecting the presence of TSG-6 
               
               
                   
                   
                   
                 protein in a biological sample; a method for detecting the presence of nucleic acid 
               
               
                   
                   
                   
                 encoding a normal or mutant TSG-6 protein; a method for measuring induction of 
               
               
                   
                   
                   
                 expression of TSG-6 in a cell using either nucleic acid hybridization or immunoassay; a 
               
               
                   
                   
                   
                 method for identifying a compound capable of inducing the expression of TSG-6 in a cell; 
               
               
                   
                   
                   
                 and a method for measuring the ability of a cell to respond to TNF. 
               
               
                 5,846,755 
                 Dec. 8, 
                 Method for determining the 
                 A method for determining the therapeutic potential of peptidomimetic compounds as 
               
               
                   
                 1998 
                 therapeutic activity of 
                 inhibitors of zinc-dependent metalloproteinase activity associated with pathological 
               
               
                   
                   
                 metalloproteinase inhibitor 
                 conditions of humans and animals. 
               
               
                   
                   
                 compounds 
               
               
                 5,843,943 
                 Dec. 1, 
                 Compounds for inhibition 
                 Novel, heterocyclic compounds having at least one ring nitrogen, disclosed side chains 
               
               
                   
                 1998 
                 of ceramide-mediated signal 
                 and, in some embodiments, an oxygen ortho to the ring nitrogen inhibit inflammatory 
               
               
                   
                   
                 transduction 
                 responses associated with TNF- alpha and fibroblast proliferation in vivo and in vitro. The 
               
               
                   
                   
                   
                 compounds of the invention neither appreciably inhibit the activity of cAMP 
               
               
                   
                   
                   
                 phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cylotoxic nor 
               
               
                   
                   
                   
                 cytostatic. Preferred compounds of the invention are esters. Methods for the use of the 
               
               
                   
                   
                   
                 novel compounds to inhibit ceramide-mediated intracellular responses to stimuli in vivo 
               
               
                   
                   
                   
                 (particularly TNF- alpha ) are also described. The methods are expected to be of use in 
               
               
                   
                   
                   
                 reducing inflammatory responses (for example, after angioplasty), in limiting fibrosis (for 
               
               
                   
                   
                   
                 example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV 
               
               
                   
                   
                   
                 induced cutaneous immune suppression. 
               
               
                 5,843,918 
                 Dec. 1, 
                 Anti-endotoxin compounds 
                 Disdosed are lipid A analogs useful for the treatment of septic shock and LPS-mediated 
               
               
                   
                 1998 
                   
                 activation of viral infection. 
               
               
                 5,843,791 
                 Dec. 1, 
                 TNF receptors, TNF binding 
                 DNA sequences adding for a TNF-binding protein and for the TNF receptor of which this 
               
               
                   
                 1998 
                 proteins and DNAs coding 
                 protein constitutes the soluble domain. The DNA sequences can be used for preparing 
               
               
                   
                   
                 for them 
                 recombinant DNA molecules in order to produce TNF-binding protein and TNF receptor. 
               
               
                   
                   
                   
                 With the aid of the TNF receptor or fragments thereof or with the aid of suitable host 
               
               
                   
                   
                   
                 organisms transformed with recombinant DNA molecules containing the DNA which codes 
               
               
                   
                   
                   
                 for the TNF receptor or fragments or modifications thereof, it is possible to investigate 
               
               
                   
                   
                   
                 substances for their interaction with the TNF receptor and/or for their effect on the 
               
               
                   
                   
                   
                 biological activity of TNF. 
               
               
                 5,843,693 
                 Dec. 1, 
                 Assay method for screening 
                 Methods and materials are disclosed for the production of purified, active recombinant 
               
               
                   
                 1998 
                 for inhibitors of proTNF 
                 human neutrophil protease, PR-3, via activation of a pro-form herein referred to as proPR- 
               
               
                   
                   
                 conversion 
                 3. Human PR 3 is useful for discovering inhibitors of excessive release of mature, active 
               
               
                   
                   
                   
                 TNF alpha. Also disclosed are methods for the identification of inhibitors of the conversion 
               
               
                   
                   
                   
                 of the pro-form of TNF alpha to its mature active form. 
               
               
                 5,843,678 
                 Dec 1, 
                 Osteoprotegerin binding 
                 A novel polypeptide, osteoprotegerin binding protein, involved in osteolcast maturation 
               
               
                   
                 1998 
                 proteins 
                 has been identified based upon its affinity for osteoprotegerin. Nucleic acid sequences 
               
               
                   
                   
                   
                 encoding the polypeptide, or a fragment, analog or derivative thereof, vectors and host 
               
               
                   
                   
                   
                 cells for production, methods of preparing osteoprotegerin binding protein, and binding 
               
               
                   
                   
                   
                 assays are also described. Compositions and methods for the treatment of bone diseases 
               
               
                   
                   
                   
                 such as osteoporosis, bone loss due to arthritis or metastasis, hypercalcemia, and Paget&#39;s 
               
               
                   
                   
                   
                 disease are also provided. 
               
               
                 5,843,675 
                 Dec. 1, 
                 TNF receptor death domain 
                 Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed. 
               
               
                   
                 1998 
                 ligand proteins and 
                 Polynucleotides encoding the TNF-R1-DD ligand protein are also disclosed, along with 
               
               
                   
                   
                 inhibitors of ligand binding 
                 vectors, host cells, and methods of making the TNF-R1-DD ligand protein. Pharmaceutical 
               
               
                   
                   
                   
                 compositions containing the TNF-R1-DD ligand protein, methods of treating inflammatory 
               
               
                   
                   
                   
                 conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. 
               
               
                   
                   
                   
                 Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by 
               
               
                   
                   
                   
                 such methods are also disclosed. 
               
               
                 5,843,452 
                 Dec. 1, 
                 Immunotherapy 
                 A composition for use in immunosuppression therapy is disclosed. The composition 
               
               
                   
                 1998 
                 composition and method 
                 includes an immunosuppressant drug, such as cyclosporin A, and an ethanol extract of the 
               
               
                   
                   
                   
                 root xylem of  Tripterygium wilfordii . The extract is effective alone, or in combination with 
               
               
                   
                   
                   
                 such an immunosuppressant, in the treatment of transplantation rejection. Also disclosed is 
               
               
                   
                   
                   
                 a method of immunosuppression that includes administering to a subject a 
               
               
                   
                   
                   
                 pharmaceutically effective amount of an immunosuppressant drug and an extract of the 
               
               
                   
                   
                   
                 type above, in an amount effective to potentiate the action of the drug. 
               
               
                 5,840,724 
                 Nov. 24, 
                 Compounds containing 
                 This invention is directed to the pharmaceutical use of phenyl compounds, which are 
               
               
                   
                 1998 
                 phenyl linked to aryl or 
                 linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The 
               
               
                   
                   
                 heteroaryl by an aliphatic- 
                 invention is also directed to the compounds, their preparation and pharmaceutica( 
               
               
                   
                   
                 or heteroatom-containing 
                 compositions containing these compounds. Furthermore, this invention is directed to the 
               
               
                   
                   
                 linking group 
                 pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase. 
               
               
                 5,840,277 
                 Nov. 24, 
                 Treatment of chronic 
                 A method and medicant for the inhibition of activation of the nuclear transcription NF- 
               
               
                   
                 1998 
                 pulmonary inflammation 
                 kappa B comprising administering an effective amount of a compound of the formula: [See 
               
               
                   
                   
                   
                 Original Patent for Chemical Structure Diagram] where R = ethylene, R′ = C4 to C14 
               
               
                   
                   
                   
                 straight chain or branched alkyl, x is greater than 1, and y = 8 to 18 is provided. The 
               
               
                   
                   
                   
                 medicant is preferably administered by aerosolization into the mammalian respiratory 
               
               
                   
                   
                   
                 system. The medicant may also be applied to the mammalian skin. Preferably the 
               
               
                   
                   
                   
                 medicant includes a physiologically acceptable carrier which may be selected from 
               
               
                   
                   
                   
                 buffered saline isotonic saline, normal saline petroleum-based ointments and U.S.P. cold 
               
               
                   
                   
                   
                 cream. There is further provided a method wherein said medicant includes an anti- 
               
               
                   
                   
                   
                 inflammatory steroid. In addition a method and medicant for treating cutaneous 
               
               
                   
                   
                   
                 inflammatory disorders, inhibiting the secretion of the pro-inflammatory cytokines TNF, IL- 
               
               
                   
                   
                   
                 1, IL6, IL-8 and the growth factor GM-CSF is provided. 
               
               
                 5,837,719 
                 Nov. 17, 
                 2,5-substituted aryl 
                 The present invention addresses 2,5-substituted aryl pyrroles of the formula: [See 
               
               
                   
                 1998 
                 pyrroles, compositions 
                 Original Patent for Chemical Structure Diagram] or a pharmaceutically acceptable salts 
               
               
                   
                   
                 containing such compounds 
                 thereof, as well as compositions containing such compounds and methods of treatment. 
               
               
                   
                   
                 and methods of use 
                 The compounds are useful for treating Cytokine mediated diseases, which refers to 
               
               
                   
                   
                   
                 diseases or conditions in which excessive or unregulated production or activity of one or 
               
               
                   
                   
                   
                 more cytokines occurs. Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8) and 
               
               
                   
                   
                   
                 Tumor Necrosis Factor (TNF) are cytokines which are involved in immunoregulation and 
               
               
                   
                   
                   
                 other physiological conditions, such as inflammation. The compounds also have glucagon 
               
               
                   
                   
                   
                 antagonist activity. 
               
               
                 5,837,293 
                 Nov. 17, 
                 Use of interleukin-10 
                 A method is provided for reducing an inflammatory response in a mammal comprising 
               
               
                   
                 1998 
                 analogs for antagonists to 
                 administering to a mammal at risk of developing or afflicted with an inflammatory response 
               
               
                   
                   
                 treat endotoxin- or 
                 characterized by substantially elevated levels of IL-1 alpha, IL-1 beta, IL-6, IL-8 and TNF 
               
               
                   
                   
                 superantigen-induced 
                 alpha, an amount of IL-10 effective to substantially lower the levels of such cytokines. 
               
               
                   
                   
                 toxicity 
               
               
                 5,837,342 
                 Nov. 17, 
                 Use of an interleukin-10 
                 A method is provided for toting a B cell mediated autoimmune disorder comprising 
               
               
                   
                 1998 
                 antagonist to treat a B cell 
                 administering an effective amount of an interleukin-10 antagonist. 
               
               
                   
                   
                 mediated autoimmune 
               
               
                   
                   
                 disorder 
               
               
                 5,837,340 
                 Nov. 17, 
                 Methods of treating 
                 This invention provides medical uses of a M-CSF, particularly a method and composition 
               
               
                   
                 1998 
                 allergies with M-CSF 
                 for treating inflammatory disease and allergy using natural M-CSF or recombinant M-CSF 
               
               
                   
                   
                   
                 or the derivatives thereof. 
               
               
                 5,834,435 
                 Nov. 10, 
                 Inhibition of TNF- alpha 
                 The pleiotropic effects of TNF alfa in a wide variety of mammalian cell types is decreased 
               
               
                   
                 1998 
                 pleiotropic and cytotoxic 
                 and treated by administering glucosaminylmuramyl peptides with D-amino acid residue in a 
               
               
                   
                   
                 effects 
                 second or third position from the proximal end. New methods for nonspecific oral, vaginal, 
               
               
                   
                   
                   
                 and topic inhibition is proposed. Inhibition of cytotoxicity of TNF alfa is also achieved. 
               
               
                 5,834,419 
                 Nov. 10, 
                 Chemokine binding protein 
                 The present invention provides a method of use for a novel type chemokine binding 
               
               
                   
                 1998 
                 and methods of use 
                 protein encoded by poxviruses and having amino acid sequence homology wth the 
               
               
                   
                   
                 therefor 
                 myxoma virus T7 interferon- gamma receptor homolog against disease syndromes 
               
               
                   
                   
                   
                 associated with acute or chronic dysregulated inflammatory responses. 
               
               
                 5,833,976 
                 Nov 10, 
                 Use of interleukin-10 (IL-10) 
                 A method is provided for treating septic shock or toxic shock that comprises administering 
               
               
                   
                 1998 
                 to treat endotoxin- or 
                 an effective amount of interleukin-10. 
               
               
                   
                   
                 superantigen-induced 
               
               
                   
                   
                 toxicity 
               
               
                 5,830,994 
                 Nov. 3, 
                 Peptide derivatives of 
                 Provided is a compound containing a peptide of at least 4 amino acids including the 
               
               
                   
                 1998 
                 alpha-MSH and their 
                 following sequence: His Phe* Arg, wherein Phe* represents phenylalanine or a 
               
               
                   
                   
                 application 
                 halogenated derivative of phenylalanine the said peptide being conjugated with thioctic 
               
               
                   
                   
                   
                 acid, dihydrolioic acid, or N-lipoyl-lysine, in the form of the corresponding salts, esters or 
               
               
                   
                   
                   
                 amides. In particular, compounds with anti-allergic and anti-inflammatory activities on the 
               
               
                   
                   
                   
                 one had, and melanogenesis-activating activities on the other, are described. 
               
               
                 5,830,742 
                 Nov. 3, 
                 TNF- alpha converting 
                 A metalloprotease that converts TNF- alpha from the 26 kD cell form to the 17 kD form 
               
               
                   
                 1998 
                 enzyme 
                 has been isolated and purified and the cDNA sequence known. In particular, the protease 
               
               
                   
                   
                   
                 has a molecular weight of approximately 80 kD. The isolated and purified protease is 
               
               
                   
                   
                   
                 useful for designing an inhibitor thereof, and may find use as a therapeutic agent. Assays 
               
               
                   
                   
                   
                 for detecting the protease-inhibiting activity of a molecule are also an aspect of the 
               
               
                   
                   
                   
                 invention. 
               
               
                 5,830,436 
                 Nov. 3, 
                 Method of mucociliary 
                 A method and medicament for the inhibition of oxidants comprising administering a 
               
               
                   
                 1998 
                 clearance in cystic fibrosis 
                 treatment effective amount of alkylaryl polyether alcohol polymers to a chemical or biologic 
               
               
                   
                   
                 patients using alkylaryl 
                 system in need thereof. Also, a method and medicament for mucociliary clearance, 
               
               
                   
                   
                 polyether alcohol polymers 
                 inhibition of cytokine production, and inhibition of interleukin-8 production in cystic fibrosis 
               
               
                   
                   
                   
                 patients. The method involves administering a treatment effective amount of alkylaryl 
               
               
                   
                   
                   
                 polyether alcohol polymers to a chemical or biologic system in need thereof. The 
               
               
                   
                   
                   
                 medicament is preferably administered by aerosolization into the mammalian respiratory 
               
               
                   
                   
                   
                 system. The medicament may also be applied to the mammalian skin. Preferably, the 
               
               
                   
                   
                   
                 medicament includes a physiologically acceptable carrier which may be selected from the 
               
               
                   
                   
                   
                 group consisting of physiologically buffered saline, isotonic saline, normal saline, 
               
               
                   
                   
                   
                 petrolatum based ointments and U.S.P. cold cream. 
               
               
                 5,824,551 
                 Oct. 20, 
                 Method for modulating cell 
                 The invention is based upon the newly recognized ability of beta chemokines to inhibit cell 
               
               
                   
                 1998 
                 apoptosis 
                 apoptosis. In particular, apoptosis of T cells is described. The known beta chemokines 
               
               
                   
                   
                   
                 309 and TCA-3 are examples of the beta chemokines which inhibit apoptosis. One aspect 
               
               
                   
                   
                   
                 of the invention is the use of these molecules to inhibit apoptosis. A second aspect of the 
               
               
                   
                   
                   
                 invention is the use of beta chemokine inhibitors or antagonists to provoke apoptosis. 
               
               
                 5,821,366 
                 Oct. 13, 
                 Xanthines and their 
                 1,3-Disubstituted-zanthines have therapeutic utility via TNF or phosphodiesterase 
               
               
                   
                 1998 
                 therapeutic use 
                 inhibition. 
               
               
                 5,821,262 
                 Oct. 13, 
                 Hydroxamic acid 
                 A compound of formula (I): [See Original Patent for Chemical Structure Diagram] (I) 
               
               
                   
                 1998 
                 derivatives as inhibitors of 
                 wherein: R&lt;1&gt; represents a (C1-C6) alkyl, phenyl, substituted phenyl, or heterocyclyl 
               
               
                   
                   
                 cytokine production 
                 group; R&lt;2&gt; represents a (C1-C6) alkyl group; R3&lt;3&gt; represents: 
               
               
                   
                   
                   
                 (i) the side chain of arginine, lysine, tryptophan, histidine, serine, threonine, or cysteine, 
               
               
                   
                   
                   
                 in which any polar amino, hydroxy, mercapto, guanidyl, imidazolyl or indolyl group is 
               
               
                   
                   
                   
                 rendered substantially non-polar by substitution at the polar N-, O- or S-atom; or 
               
               
                   
                   
                   
                 (ii) the side chain of aspartic or glutamic acid, in which side chain the carboxylic acid 
               
               
                   
                   
                   
                 group is amidated; 
               
               
                   
                   
                   
                 R&lt;4&gt; represents hydrogen or a (C1-C6) alkyl or phenyl (C1-C6) alkyl group; R&lt;5&gt; 
               
               
                   
                   
                   
                 represents hydrogen or and n is 0, 1 or 2; or substituted phenyl groups; or a salt solvate or 
               
               
                   
                   
                   
                 hydrate thereof. Compositions containing compound (I) and methods for treatment of 
               
               
                   
                   
                   
                 diseases or conditions mediated by TNF or MMPs in mammals. 
               
               
                 5,820,858 
                 Oct. 13, 
                 Methods and compositions 
                 This invention provides monoclonal antibodies that bind to the cell surface CD14 receptor 
               
               
                   
                 1998 
                 for inhibiting CD14 
                 and soluble CD14 receptor. The antibodies are useful for the detection of the presence of 
               
               
                   
                   
                 mediated cell activation 
                 cell surface and soluble CD14 in a sample. Chimeric and CDR grafted antibodies 
               
               
                   
                   
                   
                 generated from the above monoclonal antibodies are further provided. Pharmaceutical 
               
               
                   
                   
                   
                 compositions containing the above biological compositions are provided. These are useful 
               
               
                   
                   
                   
                 to treat and prevent LPS-associated disorders, such as sepsis. 
               
               
                 5,814,661 
                 Sep. 29, 
                 Use of Phthalidyliden esters 
                 A therapeutical method for treating endotoxic shock which comprises administering to a 
               
               
                   
                 1998 
                 of carnitine and alkanoyl 
                 patient in need thereof a (3-phthalidyliden) alkyl ester of carnitine or alkanoyl carnitine, is 
               
               
                   
                   
                 carnitines for the treatment 
                 disclosed. 
               
               
                   
                   
                 of endotoxic shock 
               
               
                 5,811,549 
                 Sep. 22, 
                 Process of preparing 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1998 
                 imidazole compounds 
                 cytokine inhibitors. 
               
               
                 5,811,455 
                 Sep. 22, 
                 Compounds useful for 
                 [See Original Patent for Chemical Strucutre Diagram] (I) [See Original Patent for Chemical 
               
               
                   
                 1998 
                 treating allergic or 
                 Structure Diagram] (II) Novel cyclohexanes of formulas (I) and (II) are described herein. 
               
               
                   
                   
                 inflammatory diseases 
                 They inhibit the production of Tumor Necrosis Factor and are useful in the treatment of 
               
               
                   
                   
                   
                 disease states mediated or exacerbated by TNF production; these compounds are also 
               
               
                   
                   
                   
                 useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase 
               
               
                   
                   
                   
                 IV. 
               
               
                 5,811,300 
                 Sep. 22, 
                 TNF- alpha ribozymes 
                 Enzymatic RNA molecules which cleave TNF- alpha mRNA. 
               
               
                   
                 1998 
               
               
                 5,811,118 
                 Sep. 22, 
                 Methods of treatment using 
                 This invention provides a method of adminstering an arachidonic acid metabolite, such 
               
               
                   
                 1998 
                 unilamellar liposomal 
                 as prostaglandin E1, to an animal. The metabolite is given to the animal, typically a human, 
               
               
                   
                   
                 arachidonic acid metabolite 
                 in asspcoatopm with a unilamellar liposome comprising a lipid and a release-inhibiting 
               
               
                   
                   
                 formulations 
                 aqueous buffer. This method can be used to treat animals afflicted with disorders 
               
               
                   
                   
                   
                 characterized by cell activation and adhesion, inflammation or toxemia. 
               
               
                 5,808,029 
                 Sep 15, 
                 DNA encoding a human 
                 The present invention is concerned with non-soluble proteins and soluble or insoluble 
               
               
                   
                 1998 
                 TNF binding protein 
                 fragments thereof, which bind TNF, in homogeneous form, as well as their physiologically 
               
               
                   
                   
                   
                 compatible salts, especially those proteins having a molecular weight of about 55 or 75 kD 
               
               
                   
                   
                   
                 (non-reducing SDS-PAGE conditions), a process for the isolation of such proteins, 
               
               
                   
                   
                   
                 antibodies against such proteins, DNA sequences which code for non-soluble proteins and 
               
               
                   
                   
                   
                 soluble or non-soluble fragments thereof, which bind TNF, as welI as those which code for 
               
               
                   
                   
                   
                 proteins comprising partly of a soluble fragment, which binds TNF, and partly of all 
               
               
                   
                   
                   
                 domains except the first of the constant region of the heavy chain of human 
               
               
                   
                   
                   
                 immunoglobulins and the recombinant proteins coded thereby as well as a process for their 
               
               
                   
                   
                   
                 manufacture using transformed pro- and eukaryotic host cells. 
               
               
                 5,807,884 
                 Sep. 15, 
                 Treatment for 
                 A method for the treatment of cardiovascular diseases and noncardiovascular 
               
               
                   
                 1998 
                 atherosclerosis and other 
                 inflammatory diseases that are mediated by VCAM-1isprovided that includes the removal, 
               
               
                   
                   
                 cardiovascular and 
                 decrease in the concentration of, or prevention of the formation of oxidized polyunsaturated 
               
               
                   
                   
                 inflammatory diseases 
                 fatty acids, or interferes with a complex formed between a polyunsaturated fatty acid or an 
               
               
                   
                   
                   
                 oxidized polyunsaturated fatty acid and a protein or peptide that mediates the expression 
               
               
                   
                   
                   
                 of VCAM-1. A method is also provided for suppressing the expression of a redox-sensitive 
               
               
                   
                   
                   
                 gene or activating a gene that is suppressed through a redox-sensitive pathway, that 
               
               
                   
                   
                   
                 includes administering an effective amount of a substance that prevents the oxidation of 
               
               
                   
                   
                   
                 the oxidized signal, and typically, the oxidation of a polyunsaturated fatty acid, or interferes 
               
               
                   
                   
                   
                 with a complex formed between the oxidized signal and a protein or peptide that mediates 
               
               
                   
                   
                   
                 the expression of the redox gene. 
               
               
                 5,804,588 
                 Sep. 8, 
                 Quinoline carboxanides and 
                 The subject invention concerns novel compounds of the general formula (I) [See Original 
               
               
                   
                 1998 
                 their therapeutic use 
                 Patent for Chemical Structure Diagram] that are useful in treating disease states, such 
               
               
                   
                   
                   
                 as those states associated with proteins that mediate cellular activity. The compounds of 
               
               
                   
                   
                   
                 the subject invention can be used, for example, to inhibit tumor necrosis factor and/or 
               
               
                   
                   
                   
                 phosphodiesterase IV. The subject invention also concerns methods for treating disease 
               
               
                   
                   
                   
                 states using the compounds of the invention. 
               
               
                 5,801,195 
                 Sep. 1, 
                 Immunotherapeutic aryl 
                 Novel aryl amides are inhibitors of tumor necrosis factor alpha and can be used to combat 
               
               
                   
                 1998 
                 amides 
                 cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is N-benzoyl-3- 
               
               
                   
                   
                   
                 amino-3-(3′,4′-dimethoxyphenyl)propanamide. 
               
               
                 5,798,368 
                 Aug. 25, 
                 Tetrasubstituted 2-(2,6- 
                 Tetrasubstituted 1-oxo-2-(2,6-dioxopiperidin-3-yl)isoindolines reduce the levels of TNF 
               
               
                   
                 1998 
                 dioxopiperidin-3-yl)-1- 
                 alpha in a mammal. A typical embodiment is 1-oxo-2-(2,6-dioxopipendin-3-yl)-4,5,6,7- 
               
               
                   
                   
                 oxoisoindolines and method 
                 tetrafluoroisoindoline. 
               
               
                   
                   
                 of reducing TNF alpha 
               
               
                   
                   
                 levels 
               
               
                 5,795,975 
                 Aug 18, 
                 TNF receptor promoter 
                 A DNA molecule containing the endogenous first intron-located p55 TNF-R gene 
               
               
                   
                 1998 
                   
                 promoter/enhancer sequence is provided. Also provided is a DNA molecule which contains 
               
               
                   
                   
                   
                 a gene in operative association with a promoter sequence that includes the endogenous 
               
               
                   
                   
                   
                 first intron-located p55 TNF-R gene promoter/enhancer sequence. 
               
               
                 5,795,967 
                 Aug. 18, 
                 Tumor necrosis factor 
                 Tumor necrosis factor antagonists are administered in therapeutically effective doses to 
               
               
                   
                 1998 
                 antagonists and their use 
                 suppress inflammatory immune-potentiated events. The antagonists of this invention 
               
               
                   
                   
                   
                 typically are selected from among several classes but preferably are neutralizing 
               
               
                   
                   
                   
                 antibodies directed against tumor necrosis factor. The antagonists are useful in 
               
               
                   
                   
                   
                 suppressing transplantation immunity and in the treatment of autoimmune diseases. 
               
               
                 5,795,859 
                 Aug. 18, 
                 Peptide which abrogates 
                 The present invention provides peptides which have the ability to abrogate TNF toxicity 
               
               
                   
                 1998 
                 TNF and/or LPS toxicity 
                 and/or LPS toxicity. The present invention further relates to compositions induding these 
               
               
                   
                   
                   
                 peptides as the active ingredient and methods of anti-inflammatory treatment involving the 
               
               
                   
                   
                   
                 administration of this composition. The peptides of the present invention are based 
               
               
                   
                   
                   
                 primarily on residue 1 to 26 of human TNF. 
               
               
                 5,789,550 
                 Aug. 4, 
                 TRAF inhibitors 
                 The invention concerns novel inhibitors of tumor necrosis factor receptor associated 
               
               
                   
                 1998 
                   
                 factor-(TRAF) mediated signal transduction. The invention encompasses the novel inhibitor 
               
               
                   
                   
                   
                 proteins (I-TRAFs), nucleic acid encoding them, methods for their recombinant production, 
               
               
                   
                   
                   
                 and their use in screening assays and as pharmaceuticals. 
               
               
                 5,780,667 
                 Jul. 14, 
                 Compounds, compositions 
                 Novel cyclohexane derivatives of Formula (I) [See Original Patent for Chemical Structure 
               
               
                   
                 1998 
                 and treatment of allergies 
                 Diagram] are described herein. These compounds inhibit the production of Tumor 
               
               
                   
                   
                 and inflammation therewith 
                 Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated 
               
               
                   
                   
                   
                 by TNF production; they are also useful in the mediation or inhibition of enzymatic or 
               
               
                   
                   
                   
                 catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of 
               
               
                   
                   
                   
                 disease states in need of mediation or inhibition thereof. 
               
               
                 5,777,176 
                 Jul. 7, 
                 4,4- 
                 The present invention relates to novel dimers of 4,4-(disubstituted)cyclohexan-1-ol dimers 
               
               
                   
                 1998 
                 (disubstituted)cyclohexan- 
                 and delated compounds, pharmaceutical compositions containing these compounds, and 
               
               
                   
                   
                 1-ol dimers and related 
                 their use in treating allergic and inflammatory diseases and for inhibiting the production of 
               
               
                   
                   
                 compounds 
                 Tumor Necrosis Factor (TNF). 
               
               
                 5,777,160 
                 Jul. 7, 
                 1,4,4-(trisubstituted) 
                 This invention relates to certain 1,4,4-(trisubstituted)cyclohex-1-ene dimers and related 
               
               
                   
                 1998 
                 cyclohex-1-ene dimers and 
                 compounds which are useful in treating allergic and inflammatory diseases and for 
               
               
                   
                   
                 related compounds 
                 inhibiting the production of Tumor Necrosis Factor (TNF). 
               
               
                 5,776,954 
                 Jul. 7, 
                 Substituted pyridyl pyrroles, 
                 The present invention addresses substituted pyridyl pyrroles, as well as compositions 
               
               
                   
                 1998 
                 compositions containing 
                 containing such compounds and methods of treatment. The compounds in the present 
               
               
                   
                   
                 such compounds and 
                 invention are glucagon antagonists and inhibitors of the biosynthesis and action of TNF 
               
               
                   
                   
                 methods of use 
                 alpha and IL1. The compounds block the action of glucagon at its receptors and thereby 
               
               
                   
                   
                   
                 decrease the levels of plasma glucose. The instant pyrroles are also inhibitors of TNF 
               
               
                   
                   
                   
                 alpha and IL1 and may be used as antidiabetic agents as well as other cytokine mediated 
               
               
                   
                   
                   
                 diseases. Cytokine mediated diseases refers to diseases or conditions in which excessive 
               
               
                   
                   
                   
                 or unregulated production of one or more cytokines occurs. Interleukin-1 (IL-1) and Tumor 
               
               
                   
                   
                   
                 Necrosis Factor (TNF) are cytokines produced by a variety of cells, which are involved in 
               
               
                   
                   
                   
                 immunoregulation and other physiological conditions, such as inflammation. 
               
               
                 5,776,947 
                 Jul. 7, 
                 Use of quinoline-3- 
                 The use of a quinoline-3-carboxamide compound comprising structure (I), optionally with 
               
               
                   
                 1998 
                 carboxamide compounds 
                 substituents for the hydrogen atoms shown (H&lt;1-9&gt;), and a salt of compound (I) where (a) 
               
               
                   
                   
                 for inhibiting the production 
                 represents that there are two conjugated double bonds between the atoms comprised 
               
               
                   
                   
                 of tumor necrosis factor 
                 by the dashed line, (b) X1 and X2 are separately selected form an oxygen atom or an 
               
               
                   
                   
                 (TNF) and/or for the 
                 NH&lt;9&gt; group, said X1 and X2 being bound by a single bond to the ring when attached to 
               
               
                   
                   
                 treatment of septic shock 
                 H&lt;7&gt; or H&lt;8&gt; and by a double bond when not bound to H&lt;7&gt; or H&lt;8&gt;, (c) H&lt;1-9&gt;; 
               
               
                   
                   
                   
                 are hydrogens with the provision that H&lt;9&gt; is only present when at least one of X1 and X2 
               
               
                   
                   
                   
                 is the NH&lt;9&gt; group, (d) H&lt;7&gt; and H&lt;8&gt; are hydrogens that are attached to different 
               
               
                   
                   
                   
                 atoms selected among X1, X2 and the nitrogen atom (N) in the quinoline ring, for the 
               
               
                   
                   
                   
                 manufacture of a composition intended for inhibiting the production of tumor necrosis factor 
               
               
                   
                   
                   
                 TNF in a living body and/or the treatment of septic shock in a living body. 
               
               
                 5,776,915 
                 Jul. 7, 
                 Phosphocholines of 
                 Novel retinoid phosphocholines are disclosed having the general Formula (I): [See 
               
               
                   
                 1998 
                 retinoids 
                 Original Patent for Chemical Structure Diagram] wherein R represents a retinyl or 
               
               
                   
                   
                   
                 retinoyl moiety. The optical and geometric isomers of compounds of Formula (I) and the 
               
               
                   
                   
                   
                 pharmaceutically-acceptable salts thereof, are also disclosed. The subject compounds 
               
               
                   
                   
                   
                 exhibit anti-tumor, anti-psoriatic and anti-inflammatory activities in addition to their inherent 
               
               
                   
                   
                   
                 Vitamin A-like activities. The invention embraces the novel compounds, pharmaceutical 
               
               
                   
                   
                   
                 compositions thereof, and methods of using the same. 
               
               
                 5,773,582 
                 Jun. 30, 
                 Tumor necrosis factor 
                 Muteins of human tumor necrosis factor (hTNF), a process for production thereof, and 
               
               
                   
                 1998 
                 muteins 
                 DNAs encoding these muteins are found to have a superior antitumor activity and lower 
               
               
                   
                   
                   
                 acute lethal toxicity compared to the wild-type human tumor necrosis factor. 
               
               
                 5,773,467 
                 Jun. 30, 
                 Benzoluran 
                 Benzoluran carboxides and sulphonamides have therapeutic utility, e.g. in the treatment 
               
               
                   
                 1998 
                 sulphonanmides 
                 of inflammation and asthma, by virtue of their ability to inhibit phosphodiesterases and 
               
               
                   
                   
                   
                 tumor necrosis factor. 
               
               
                 5,772,997 
                 Jun. 30, 
                 Monoclonal antibodies 
                 A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or 
               
               
                   
                 1998 
                 directed to the HER2 
                 growth factor by treatment of the cells with antibodies which inhibit the growth factor 
               
               
                   
                   
                 receptor 
                 receptor function, is disclosed. A method of treatment tumor cells with antibodies which 
               
               
                   
                   
                   
                 inhibit growth factor receptor function, and with cylotoxic factor(s) such as tumor necrosis 
               
               
                   
                   
                   
                 factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are 
               
               
                   
                   
                   
                 rendered more susceptible to cytotoxic factors. 
               
               
                 5,770,694 
                 Jun. 23, 
                 Genetically engineered BPI 
                 The present invention provides a composition comprising a BPI Protein and an anionic 
               
               
                   
                 1998 
                 variant proteins 
                 compound which composition exhibits (1) no bactericidal activity and (2) endotoxin 
               
               
                   
                   
                   
                 neutralizing activity. Also, this invention provides methods for using BPI Proteins. 
               
               
                 5,770,624 
                 Jun. 23, 
                 Certain alpha-substituted 
                 Particularly the invention relates to the compounds of formula I [See Original Patent for 
               
               
                   
                 1998 
                 arylsulfonamido 
                 Chemical Structure Diagram](I) wherein Ar represents carbocyclic aryl, heterocyclic aryl 
               
               
                   
                   
                 acetohydroxamic acids 
                 or biaryl; 
               
               
                   
                   
                   
                 R1 represents lower alkyl, cycloalkyl, aryl-lower alkyl, lower alkoxy-lower alkyl, aryl, 
               
               
                   
                   
                   
                 cycloalkyl-lower alkyl, halo-lower alkyl; 
               
               
                   
                   
                   
                 R2 represents hydrogen or lower alkyl; 
               
               
                   
                   
                   
                 R3 and R4 represent independently hydrogen, lower alkyl, lower alkoxy, halo, hydroxy, 
               
               
                   
                   
                   
                 acyloxy, lower alkoxy-lower alkoxy, trifluoromethyl or cyano; or R3 and R4 together 
               
               
                   
                   
                   
                 represent lower allylenedioxy; 
               
               
                   
                   
                   
                 n represents an integer from 1 to 5; 
               
               
                   
                   
                   
                 pharmaceutically acceptable prodrug derivatives; and pharmaceutically acceptable salts 
               
               
                   
                   
                   
                 thereof; methods for preparation thereof; 
               
               
                   
                   
                   
                 pharmaceutical compositions comprising said compounds; and a method of inhibiting 
               
               
                   
                   
                   
                 TNF-alpha activity and matrix-degrading metalloproteinases in mammals using such 
               
               
                   
                   
                   
                 compounds. 
               
               
                 5,770,402 
                 Jun. 23, 
                 DNA encoding macrophage 
                 Disclosed are novel nucleic acid and peptide compositions comprising a constitutively- 
               
               
                   
                 1998 
                 inflammatory protein-1 
                 expressed CC chemokine. Also disclosed are methods of use for MIP-1 gamma amino 
               
               
                   
                   
                 gamma 
                 acid sequences and the DNA segments which encode them in the stimulation of an 
               
               
                   
                   
                   
                 immune response, the production of limited pyrexia, the treatment of proliferative cell 
               
               
                   
                   
                   
                 disorders and T-cell mediated diseases, and the prophylaxis of bacterial sepsis in an 
               
               
                   
                   
                   
                 animal. 
               
               
                 5,770,401 
                 Jun. 23, 
                 Methods and compositions 
                 Methods and compositions for treating allergic reactions, including cutaneous, ocular, 
               
               
                   
                 1998 
                 for treating allergic 
                 nasal and Bronchial allergic disease, are disclosed. Interleukin-1 and Tumor Necrosis 
               
               
                   
                   
                 reactions 
                 Factor receptors, and analogues thereof, are employed which bind the respective effector 
               
               
                   
                   
                   
                 competitively and thereby suppress allergic reactions. 
               
               
                 5,770,195 
                 Jun 23, 
                 Monoclonal antibodies 
                 A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or 
               
               
                   
                 1998 
                 directed to the her2 
                 growth factor by treatment of the cetls with antibodies which inhibit the growth factor 
               
               
                   
                   
                 receptor 
                 receptor function, is disclosed A method of treating tumor cells with antibodies which 
               
               
                   
                   
                   
                 inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis 
               
               
                   
                   
                   
                 factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are 
               
               
                   
                   
                   
                 rendered more susceptible to cytotoxic factors. 
               
               
                 5,767,151 
                 Jun. 16, 
                 3,3-(disubstituted) 
                 The present invention relates to novel 3,3-(disubstituted)-cyclohexan-1-ylidene acetate 
               
               
                   
                 1998 
                 cyclohexan-1-ylidine 
                 dimers of Formula (I): [See Original Patent for Chemical Structure Diagram] I and related 
               
               
                   
                   
                 acetate dimers and related 
                 compounds, pharmaceutical compositions containing these compounds and their use in 
               
               
                   
                   
                 compounds 
                 treating allergic and inflammateory diseases and for inhibiting the production of Tumor 
               
               
                   
                   
                   
                 Necrosis Factor (TNF). 
               
               
                 5,767,120 
                 Jun. 16, 
                 Tricyclic derivatives, 
                 Disclosed are compounds of Formula I: [See Original Patent for Chemical Structure 
               
               
                   
                 1998 
                 compositions and methods 
                 Diagram] (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: R&lt;3&gt; is 
               
               
                   
                   
                 of use 
                 alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, cycloalkyl, acyloxymethyl, alkoxy, alkoxymethyl, 
               
               
                   
                   
                   
                 or alkyl substituted with cycloalkyl; 
               
               
                   
                   
                   
                 R&lt;4&gt; is H, alkyl, alkenyl, alkoxy, or —OH. 
               
               
                   
                   
                   
                 Also disclosed are pharmaceutical compositions containing compounds of Formula 
               
               
                   
                   
                   
                 methods for inhibiting tumor necrosis factor- alpha and methods for treating septic shock, 
               
               
                   
                   
                   
                 inflammation, or allergic disease by administering a compound of Formula I. 
               
               
                 5,767,097 
                 Jun. 16, 
                 Specific modulation of 
                 Ribavirin is administered to a patient in a dosage range which is effective to modulate 
               
               
                   
                 1998 
                 Th1/Th2 cytokine 
                 tymphokine expression in activated T cells. In particutar, ribavirin is used to suppress Th2- 
               
               
                   
                   
                 expression by ribavirin in 
                 mediated T cell responses and promote Th1-mediated T cell response. Thus, instead of 
               
               
                   
                   
                 activated T-lymphocytes 
                 administering ribavirin in its well-recognized role as an anti-viral agent, ribavirin is herein 
               
               
                   
                   
                   
                 used in the treatment of imbalances in lymphokine expression. Such imbalances may be 
               
               
                   
                   
                   
                 found to be concomitants of allergic atopic disorders such as allergic asthma and atopic 
               
               
                   
                   
                   
                 dermatitis, hetminth infection and leishmaniasis, and various primary and secondary 
               
               
                   
                   
                   
                 immunodeficiencies, which may or may not also be associated with viral infection. 
               
               
                 5,766,917 
                 Jun. 16, 
                 Method for identifying and 
                 Molecules which influence the shedding of the cell-bound p55 Tumor Necrosis Factor 
               
               
                   
                 1998 
                 producing a protease 
                 receptor (p55-TNF-R), are provided, together with methods of producing them. 
               
               
                   
                   
                 capable of cleaving the 
               
               
                   
                   
                 TNF receptor 
               
               
                 5,766,865 
                 Jun. 16, 
                 Cell lines capable of 
                 A method of genetically engineering a cell line capable of detecting bioactive cytokines or 
               
               
                   
                 1998 
                 detecting low levels of 
                 growth factors is provided. Cells lines produced by this method and methods of using these 
               
               
                   
                   
                 cytokines in biological fluids 
                 cell lines to detect bioactive cytokines or growth factors in a biological fluid are also 
               
               
                   
                   
                   
                 provided. 
               
               
                 5,763,621 
                 Jun 9, 
                 Metalloproteinase inhibitors 
                 A compound of formula (I): [See Original Patent for Chemical Structure Diagram] 
               
               
                   
                 1998 
                   
                 wherein R4 is an optionally substituted C3-C8 cycloalkenyl group. The compounds are 
               
               
                   
                   
                   
                 inhibitors of matrix metalloproteinases. 
               
               
                 5,763,567 
                 Jun. 9, 
                 Biologically active peptides 
                 The present invention provides peptides having an amino acid sequence that is the amino 
               
               
                   
                 1998 
                 from funcional domains of 
                 acid sequence of a human bactericidal/permeability-increasing protein (BPI) functional 
               
               
                   
                   
                 bactericidal/permeability- 
                 domain or a subsequence thereof, and variants of the sequence or subsequence thereof, 
               
               
                   
                   
                 increasing protein and uses 
                 having at least one of the BPI biological activities, such as heparin binding, heparin 
               
               
                   
                   
                 thereof 
                 neutralization, LPS binding, LPS neutralization or bactericidal activity. The invention 
               
               
                   
                   
                   
                 provides peptides and pharmaceutical compositions of such peptides for a variety of 
               
               
                   
                   
                   
                 therapeutic uses. 
               
               
                 5,763,423 
                 Jun. 9, 
                 Pharmaceutical 
                 alpha-tocopherolphosphocholine and salts thereof have been discovered to possess 
               
               
                   
                 1998 
                 compositions, novel uses, 
                 anti-viral, anti-fungal, anti-inflammatory and PAF-antagonist activities. The compound and 
               
               
                   
                   
                 and novel form of 
                 salts have also been discovered to be capable of forming liposomes. The present invention 
               
               
                   
                   
                 tocopherylphosphocholine 
                 thus provides methods of treating viral and fungal infections, inflammatory disorders and 
               
               
                   
                   
                   
                 pathophysiological conditions due to PAF activity in a mammal by administering to the 
               
               
                   
                   
                   
                 mammal alpha -tocopherolphosphocholine or a pharmaceutically acceptable salt thereof. 
               
               
                   
                   
                   
                 The invention also provides pharmaceutical compositions comprising alpha - 
               
               
                   
                   
                   
                 tocopherolphosphocholine or a pharmaceutically acceptable salt thereof and a 
               
               
                   
                   
                   
                 pharmaceutically acceptable carrier. Further, the invention provides liposomes which 
               
               
                   
                   
                   
                 comprise alpha -tocopherolphosphocholine or a salt thereof as a structural component of 
               
               
                   
                   
                   
                 the liposome bilayer. 
               
               
                 5,756,499 
                 May 26, 
                 Substituted imidazole 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1998 
                 compounds 
                 cytokine inhibitors. 
               
               
                 5,753,691 
                 May 19, 
                 Agents for inhibiting the 
                 The pharmaceutical use of 1-cinnamoyl-2-pyrrolidinone derivatives having the activities to 
               
               
                   
                 1998 
                 production of IL-1 beta and 
                 inhibit the production of IL-1 beta and the retease of TNF alpha. Those derivatives are 
               
               
                   
                   
                 the release of TNF alpha 
                 useful in the treatment or prophylaxis of the diseases such as chronic rheumatism and 
               
               
                   
                   
                   
                 sepsis. 
               
               
                 5,753,666 
                 May 19, 
                 Quinotones and their 
                 1-Alkyl-substituted-quinotone-3-carboxamides have therapeutic utility via inhibition of 
               
               
                   
                 1998 
                 therapeutic use 
                 Phosphodiesterase IV esterase and/or Tumor Necrosis Factor activity. 
               
               
                 5,753,653 
                 May 19, 
                 Metalloproteinase 
                 The invention relates to compounds of the formula [See Original Patent for Chemical 
               
               
                   
                 1998 
                 inhibitors, pharmaceutical 
                 Structure Diagram] I in which Q is a divalent radical having four ring atoms which 
               
               
                   
                   
                 compositions containing 
                 together with C* and N form a six-membered ring, each of these four ring atoms being 
               
               
                   
                   
                 them and their 
                 unsubstituted or substituted by a suitable substituent and at least one being a heteroatom 
               
               
                   
                   
                 pharmaceutical uses 
                 selected from O, N and S, with the remainder being carbon atoms; and Ar is an aryl or 
               
               
                   
                   
                   
                 heteroaryl group. The invention further relates to pharmaceutically acceptable prodrugs 
               
               
                   
                   
                   
                 and pharmaceutically acceptable salts of these compounds. The invention also relates to 
               
               
                   
                   
                   
                 methods of inhibiting the activity of metalloproteinases, especially MMPs or TNF alpha 
               
               
                   
                   
                   
                 by administering a compound of the formula I or a salt or prodrug thereof. The invention 
               
               
                   
                   
                   
                 further relates to pharmaceutical compositions comprising an effective amount of these 
               
               
                   
                   
                   
                 compounds, salts, and prodrugs. 
               
               
                 5,753,628 
                 May 19, 
                 Peptide inhibitors of TNF 
                 Peptides which consist of six to eight, predominately D-amino acids and which bind to 
               
               
                   
                 1998 
                 containing predominantly 
                 tumor necrosis factor-alpha, prevent tumor necrosis factor-alpha from binding to its 
               
               
                   
                   
                 D-amino acids 
                 receptors and inhibit tumor necrosis factor-alpha activity are disclosed. Methods of 
               
               
                   
                   
                   
                 inhibiting tumor necrosis factor-alpha activity and of treating individuals suffering from 
               
               
                   
                   
                   
                 tumor necrosis factor-alpha-mediated diseases and disorders are disclosed. 
               
               
                 5,747,514 
                 May 5, 
                 Metalloproteinase inhibitors 
                 The present invention relates to therapeutically active hydroxamic acid and carboxylic 
               
               
                   
                 1998 
                   
                 acid derivatives, to processes for their preparation, to pharmaceutical compositions 
               
               
                   
                   
                   
                 containing them, and to the use of such compounds in medicine. In particular, the 
               
               
                   
                   
                   
                 compounds are inhibitors of metalloproteinases involved in tissue degradation, and in 
               
               
                   
                   
                   
                 addition are inhibitors of the release of tumor necrosis factor from cells. 
               
               
                 5,747,474 
                 May 5, 
                 Immunosuppression by 
                 Methods for inducing immunosuppression in animals which need immunosuppressive 
               
               
                   
                 1998 
                 administration of N&lt;6&gt;, 
                 treatment involving administration to animals of a therapeutically effective amount of the 
               
               
                   
                   
                 N&lt;6&gt;-disubstituted 
                 cyclic AMP agent HE-33 or its nucleoside. 
               
               
                   
                   
                 cAMP&#39;s, analogues thereof, 
               
               
                   
                   
                 and related nucleosides 
               
               
                 5,744,304 
                 Apr. 28, 
                 Inflammation-induced 
                 The present invention describes methods of controlling and regulating the inflammatory 
               
               
                   
                 1998 
                 expression of a 
                 reaction generated in response to various toxins, immunogens, pathogens and 
               
               
                   
                   
                 recombinant gene 
                 autoimmune insults. The method employs a vector that includes an anti-cytokine protein or 
               
               
                   
                   
                   
                 antibacterial protein gene under the control of a cytokine responsive promoter. In animal 
               
               
                   
                   
                   
                 models, adenoviral vectors successfully delivered the vectors to hepatic cells and were 
               
               
                   
                   
                   
                 subsequently shown to respond only to stimulation by induced cytokines. 
               
               
                 5,741,667 
                 Apr. 21, 
                 Tumor necrosis factor 
                 The invention concerns new tumor necrosis factor receptor associated factors, 
               
               
                   
                 1998 
                 receptor-associated factors 
                 designated TRAFs. The new factors are capable of specific association with the 
               
               
                   
                   
                   
                 intracellular domain of the type 2 TNF receptor (TNF-R2) and CD40, and are involved in 
               
               
                   
                   
                   
                 the mediation of TNF and CD40 ligand biological activities. 
               
               
                 5,741,488 
                 Apr. 21, 
                 Treatment of rheumatoid 
                 A method for treating autoimmune or inflammatory diseases, through the administration of 
               
               
                   
                 1998 
                 arthritis with anti-CD4 
                 anti-CD4 antibody in conjunction with or sequentially to anti-TNF antibody, is disclosed. 
               
               
                   
                   
                 antibodies in conjunction 
                 The method can be used to aid in therapy for humans and other mammals with a wide 
               
               
                   
                   
                 with anti-TNF antibodies 
                 variety of autoimmune or inflammatory diseases. 
               
               
                 5,739,143 
                 Apr. 14, 
                 Imidazole compounds and 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1998 
                 compositions 
                 cytokine inhibitors. 
               
               
                 5,736,570 
                 Apr. 7, 
                 Immunotherapeutic aryl 
                 Novel aryl amides are inhibitors of tumor necrosis factor alpha and can be used to 
               
               
                   
                 1998 
                 amides 
                 combat cachexia, endotoxic shock, and retrovirus replication A typical embodiment is N- 
               
               
                   
                   
                   
                 benzoyl-3-amino-3-(3′,4′-dimethoxyphenyl)propanamide. 
               
               
                 5,736,138 
                 Apr. 7, 
                 Monoclonal antibodies with 
                 A monoclonal antibody, or fragments thereof, against human TNF receptor protein which 
               
               
                   
                 1998 
                 specific binding against 
                 antibody neutralizes the known actions of TNF alpha and/or TNF beta is disclosed. The 
               
               
                   
                   
                 membrane proteins on 
                 antibody may be chimeric or humanized. Furthermore, the present invention provides a 
               
               
                   
                   
                 human cells, and 
                 process for obtaining the above monoclonal antibody, as wetI as a pharmaceutical 
               
               
                   
                   
                 pharmaceutical 
                 composition containing the above monoclonal antibody and/or the above protein with 
               
               
                   
                   
                 compositions containing 
                 antibody properties. 
               
               
                   
                   
                 them 
               
               
                 5,731,343 
                 Mar. 24, 
                 Method of use of radicicol 
                 The present invention provides a method of treating an immunopathological disorder 
               
               
                   
                 1998 
                 for treatment of 
                 having an etiology associated with production of a proinflammatory agent, by administering 
               
               
                   
                   
                 immunopathological 
                 a compound of the formula: [See Original Patent for Chemical Structure Diagram] where 
               
               
                   
                   
                 disorders 
                 R1 and R2 are independentty H or —COR3; R3 is H, 1-50C alkyl, 1-20C alkoxy, 2-30C 
               
               
                   
                   
                   
                 alkenyl, 2-30C alkenyloxy, 2-10 alkynyl, 6-14C aryl or aryloxy, a 5-6 membered heterocycte 
               
               
                   
                   
                   
                 (containing 1-3 N, O and/or S heteroatoms and optionally fused to an aryl group), 3-8C 
               
               
                   
                   
                   
                 cycloalkyl (optionally fused to aryl) or 5-8C cycloalkenyl; and R4 is a halogen. Examples of 
               
               
                   
                   
                   
                 such proinflammatory agents include interteukin-1(IL-1), interteukin-6 (IL-6), interferon- 
               
               
                   
                   
                   
                 gamma (IFN- gamma ), tumor necrosis factor- alpha (TNF- alpha), granutocyle 
               
               
                   
                   
                   
                 macrophage-colony stimulating factor (GM-CSF), the growth related gene KC, 
               
               
                   
                   
                   
                 cyclooxygenase-1(COX-1), cyclooxygenase-2 (COX-2), macrophage chemotactic protein 
               
               
                   
                   
                   
                 (MCP), inducible nitric oxide synthetase (iNOS), macrophage inflammatory protein (MIP), 
               
               
                   
                   
                   
                 tissue factor (TF), phosphotyrosine phosphatase (PTPase), and endotoxin. 
               
               
                 5,730,975 
                 Mar. 24, 
                 Treatment of insulin 
                 An induction of TNF- alpha mRNA expression has been observed in adipose tissue from 
               
               
                   
                 1998 
                 resistance in obesity linked 
                 four different insulin resistant rodent models of obesity and diabetes. TNF- alpha protein 
               
               
                   
                   
                 type II diabetes using 
                 was also elevated locally and systemically. Neutralization of TNF- alpha in obese fa/fa rats 
               
               
                   
                   
                 antagonist to TNF-alpha 
                 caused a significant increase in the peripheral uptake of glucose in response to insulin. A 
               
               
                   
                   
                 function 
                 method of treating an animal suffering from insulin resistance in obesity linked Type II 
               
               
                   
                   
                   
                 diabetes mellitus is disclosed. The method includes providing a therapeutic agent that 
               
               
                   
                   
                   
                 includes an antagonist to TNF- alpha function in a pharmaceutically acceptable carrier 
               
               
                   
                   
                   
                 substance and administering a pharmacologically effective amount of the therapeutic agent 
               
               
                   
                   
                   
                 to the animal. 
               
               
                 5,728,845 
                 Mar. 17, 
                 Immunotherapeutic nitrites 
                 Novel nitrites are inhibitors of tumor necrosis factor alpha and phosphodiesterase and can 
               
               
                   
                 1998 
                   
                 be used to combat cachexia, endotoxic shock, retrovirus replication, asthma, and 
               
               
                   
                   
                   
                 inflammatory conditions. A typical embodiment is 3-Phthalimido-3-(3,4- 
               
               
                   
                   
                   
                 dimethoxyphenyl)propionitrile. 
               
               
                 5,728,844 
                 Mar. 17, 
                 Immunotherapeutic agents 
                 Novel amides are inhibitors of TNF alpha and phosphodiesterase and can be used to 
               
               
                   
                 1998 
                   
                 combat cachexia, endotoxic shock, retrovirus replication, asthma, and inflammatory 
               
               
                   
                   
                   
                 conditions. A typical embodiment is 3-phthalimido-3-(3-cyclopentyloxy-4- 
               
               
                   
                   
                   
                 methoxyphenyl)propionamide. 
               
               
                 5,728,712 
                 Mar. 17, 
                 3,4-disubstituted- 
                 3,4-Disubstituted-phenylsulphonamides have therapeutic utility via TNF or 
               
               
                   
                 1998 
                 phenylsulphonamides and 
                 phosphodiesterase inhibition. 
               
               
                   
                   
                 their therapeutic use 
               
               
                 5,726,166 
                 Mar. 10, 
                 Malaria treatments 
                 A method of treating or preventing clinical manifestations associated with diseases 
               
               
                   
                 1998 
                   
                 caused by infectious organisms which express antigens which in the patient stimulate 
               
               
                   
                   
                   
                 secretion of harmful levels of at least one cytokine, other than diseases caused by 
               
               
                   
                   
                   
                 organisms which stimulate secretion of cytokines only by expression of lipopolysaccharide, 
               
               
                   
                   
                   
                 which method comprises administering to a human in need thereof an effective non-toxic 
               
               
                   
                   
                   
                 amount of a material selected from the group consisting of inhibitors and immunogens 
               
               
                   
                   
                   
                 wherein said inhibitors are pharmacologically acceptable materials which, in vitro, reduce 
               
               
                   
                   
                   
                 or abolish secretion, by at least one of human monocytes and mouse peritoneal 
               
               
                   
                   
                   
                 macrophages, of tumour necrosis factor following stimulation with a phospholipid- 
               
               
                   
                   
                   
                 containing; tumour necrosis factor-inducing antigen other than lipopolysaccharide, and 
               
               
                   
                   
                   
                 wherein said immunogens are pharmacologically acceptable materials comprising at least 
               
               
                   
                   
                   
                 one B-celI epitope and which stimulate production of antibodies which, in vitro, reduce or 
               
               
                   
                   
                   
                 abolish secretion, by at least one of human monocytes and mouse peritoneal 
               
               
                   
                   
                   
                 macrophages, of tumour necrosis factor following stimulation with a phospoiipid-containing, 
               
               
                   
                   
                   
                 tumour necrosis factor-inducing antigen other than lipopolysaccharide. Examples of 
               
               
                   
                   
                   
                 inhibitors include inositol monophosphate and phosphatidyl inositol lipids. Immunogens 
               
               
                   
                   
                   
                 include these inhibitors optionally with carrier proteins. 
               
               
                 5,725,856 
                 Mar. 10, 
                 Monoclonal antibodies 
                 A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or 
               
               
                   
                 1998 
                 directed to the HER2 
                 growth factor by treatment of the cells with antibodies which inhibit the growth factor 
               
               
                   
                   
                 receptor 
                 receptor function, is disclosed. A method of treating tumor cells with antibodies which 
               
               
                   
                   
                   
                 inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis 
               
               
                   
                   
                   
                 factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are 
               
               
                   
                   
                   
                 rendered more susceptible to cytotoxic factors. 
               
               
                 5,723,681 
                 Mar. 3, 
                 3,3- 
                 The present invention relates to novel 3,3-(disubstituted)cyclohexan-1-ol dimers and 
               
               
                   
                 1998 
                 (disubstituted)cyclohexan- 
                 related compounds, pharmaceutical compositions containing these compounds, and their 
               
               
                   
                   
                 1-01 dimers and related 
                 use in treating allergic and inflammatory diseases and for inhibiting the production of 
               
               
                   
                   
                 compounds 
                 Tumor Necrosis Factor (TNF). 
               
               
                 5,723,116 
                 Mar. 3, 
                 Decreased mortality of 
                 A method for treating acute pancreatitis is disclosed. The method comprises 
               
               
                   
                 1998 
                 severe acute pancreatitis 
                 administering to a patient with acute pancreatitis an effective amount of a suitable tumor 
               
               
                   
                   
                 following proximal cytokine 
                 necrosis factor (TNF) antagonist such as a TNF soluble receptor or a pharmaceutically 
               
               
                   
                   
                 blockade 
                 acceptable salt thereof. 
               
               
                 5,721,121 
                 Feb. 24, 
                 Mammalian cell culture 
                 The present invention relates to novel process for the preparation of glycoproteins by 
               
               
                   
                 1998 
                 process for producing a 
                 mammalian cell culture wherein the sialic acid content of the glycoprotein produced is 
               
               
                   
                   
                 tumor necrosis factor 
                 controlled over a broad range of values by manipulating the ceIl culture environment. The 
               
               
                   
                   
                 receptor immunoglobulin 
                 invention provides for processes in which the sialic acid content of the glycoprotein is 
               
               
                   
                   
                 chimeric protein 
                 modified by changes in cell culture parameters which affect cell specific productivity. 
               
               
                   
                   
                   
                 Preferred embodiments of the invention include cell culture processes in the osmolality of 
               
               
                   
                   
                   
                 the cell culture is controlled as welI as the concentration of a transcription enhancer during 
               
               
                   
                   
                   
                 the production phase of the cell culture. The invention further provides for novel 
               
               
                   
                   
                   
                 preparations of soluble type 1 tumor necrosis factor immunoglobulin G1 and their uses in 
               
               
                   
                   
                   
                 the treatment of inflammatory or immune related disorders. 
               
               
                 5,720,954 
                 Feb. 24, 
                 Monoclonal antibodies 
                 A method of inhibiting growth of tumor cells which overexpress a growth factor receptor or 
               
               
                   
                 1998 
                 directed to the HER2 
                 growth factor by treatment of the cells with antibodies which inhibit the growth factor 
               
               
                   
                   
                 receptor 
                 receptor function, is disclosed. A method of treating tumor cells with antibodies which 
               
               
                   
                   
                   
                 inhibit growth factor receptor function, and with cytotoxic factor(s) such as tumor necrosis 
               
               
                   
                   
                   
                 factor, is also disclosed. By inhibiting growth factor receptor functions tumor cells are 
               
               
                   
                   
                   
                 rendered more susceptible to cytotoxic factors. 
               
               
                 5,720,937 
                 Feb. 24, 
                 In vivo tumor detection 
                 In vivo assay methods for detecting tumors having amplified expression of the HER2 
               
               
                   
                 1998 
                 assay 
                 receptor are disclosed. In the assay, cells within the body of a mammal are exposed to an 
               
               
                   
                   
                   
                 antibody which specifically binds to the extracellular domain of the HER2 receptor and 
               
               
                   
                   
                   
                 inhibits growth in vitro of SK-BR-3 breast tumor cells which overexpress p185&lt;HER2&gt; 
               
               
                   
                   
                   
                 The antibody is generally tagged with a radioactive isotope to permit the extent of binding 
               
               
                   
                   
                   
                 of the antibody to the cells to be quantified. 
               
               
                 5,719,184 
                 Feb. 17, 
                 3,3- 
                 The present invention relates to novel 3,3-(disubstituted)cyclohexan-1-carboxylate dimers 
               
               
                   
                 1998 
                 (disubstituted)cyclohexan- 
                 and related compounds, pharmaceutical compositions containing these compounds, and 
               
               
                   
                   
                 1-carboxylate dimers and 
                 their use in treating allergic and inflammatory diseases and for inhibiting the production of 
               
               
                   
                   
                 related compounds 
                 Tumor Necrosis Factor (TNF). 
               
               
                 5,716,981 
                 Feb. 10, 
                 Anti-anglogenic 
                 The present invention provides compositions comprising an anti-anglogenic factor, and a 
               
               
                   
                 1998 
                 compositions and methods 
                 polymeric carrier. Representative examples of anti-anglogenic factors include Anti-Invasive 
               
               
                   
                   
                 of use 
                 Factor, Retinoic acids and derivatives thereof, and paclitaxel. Also provided are methods 
               
               
                   
                   
                   
                 for embolizing blood vessels, and eliminating biliary, urethral, esophageal, and 
               
               
                   
                   
                   
                 tracheal/bronchial obstructions. 
               
               
                 5,716,972 
                 Feb 10, 
                 Pyridyl substituted 
                 The novel compounds of Formula (I) have been found to be useful cytokine suppressive 
               
               
                   
                 1998 
                 imidazoles 
                 agents and therefore useful in the treatment and prophylaxis of disease states mediated 
               
               
                   
                   
                   
                 thereby. 
               
               
                 5,716,955 
                 Feb. 10, 
                 Substituted imidazole 
                 Novel 1,4,5-substituted imidazoe compounds and compositions for use in therapy as 
               
               
                   
                 1998 
                 compounds 
                 cytokine inhibitors. 
               
               
                 5,714,147 
                 Feb. 3, 
                 Hybrid immunoglobulins 
                 Novel polypeptides are provided, together with methods for making and using them, and 
               
               
                   
                 1998 
                   
                 nucleic acids encoding them. These polypeptides are useful as cell surface adhesion 
               
               
                   
                   
                   
                 molecules and ligands, and are useful in therapeutic or diagnostic compositions and 
               
               
                   
                   
                   
                 methods. 
               
               
                 5,714,140 
                 Feb. 3, 
                 Method for inhibiting the 
                 This invention provides medical uses of a M-CSF, particularly a method and composition 
               
               
                   
                 1998 
                 production of bioactive IL-1 
                 for treating inflammatory disease and allergy using natural M-CSF or recombinant M-CSF 
               
               
                   
                   
                 by administering M-CSF 
                 or the derivatives thereof. 
               
               
                 5,712,381 
                 Jan. 27, 
                 MADD, a TNF receptor 
                 Novel TNF receptor death domain (“TNF-R1-DD”) ligand proteins are disclosed. 
               
               
                   
                 1998 
                 death domain ligand protein 
                 Polynucleotides encoding the TNF-R1-DD ligand protein are also disclosed, along with 
               
               
                   
                   
                   
                 vectors, host cells, and methods of making the TNF-R1-DD ligand protein. Pharmaceutical 
               
               
                   
                   
                   
                 compositions containing the TNF-R1-DD ligand protein, methods of treating inflammatory 
               
               
                   
                   
                   
                 conditions, and methods of inhibiting TNF-R death domain binding are also disclosed. 
               
               
                   
                   
                   
                 Methods of identifying inhibitors of TNF-R death domain binding and inhibitors identified by 
               
               
                   
                   
                   
                 such methods are also disclosed. 
               
               
                 5,712,286 
                 Jan. 27, 
                 Naphthyridine derivatives 
                 Compounds of formula (I) including pharmaceutically acceptable salts thereof in which R1 
               
               
                   
                 1998 
                   
                 represents a C1-6 akyl group; R2 represents a group of the formula COOR4 in which R4 
               
               
                   
                   
                   
                 represents a C1-5 akyl group; and R3 represents a group of formula COOR5 in which RS 
               
               
                   
                   
                   
                 represents a C1-5 alkyl group are disclosed, which are anti-rheumatic agents and are 
               
               
                   
                   
                   
                 useful as modulators of cytokine synthesis, immunomodulatory agents, anti-inflammatory 
               
               
                   
                   
                   
                 agents and anti-allergic agents. Compositions containing these compounds and processes 
               
               
                   
                   
                   
                 to make these compounds are also disclosed. 
               
               
                 5,712,155 
                 Jan. 27, 
                 DNA encoding tumor 
                 Tumor necrosis factor receptor DNAs and expression vectors encoding TNF receptors, 
               
               
                   
                 1998 
                 necrosis factor- alpha and - 
                 and processes for producing TNF receptors as products of recombinant cell culture, are 
               
               
                   
                   
                 beta receptors 
                 disclosed. 
               
               
                 5,708,142 
                 Jan. 13, 
                 Tumor necrosis factor 
                 The invention concerns new tumor necrosis factor receptor associated factors, 
               
               
                   
                 1998 
                 receptor-associated factors 
                 designated TRAF. The new factors are capable of specific association with the intracellular 
               
               
                   
                   
                   
                 domain of the type 2 TNF receptor (TNF-R2), and are involved in the mediation of TNF 
               
               
                   
                   
                   
                 biological activities 
               
               
                 5,705,389 
                 Jan 6, 
                 Oligonucleotides that inhibit 
                 A sequence of anti-direction, anti-messenger RNA oligonucleotides of alpha -TNF 
               
               
                   
                 1998 
                 production of alpha -tumor 
                 characterized in that it possesses the structure of the formula [See Original Patent for 
               
               
                   
                   
                 necrosis factor 
                 Chemical Structure Diagram] I wherein X is hydrogen, or a sequence of 1 to 17 
               
               
                   
                   
                   
                 oligonucleotides in free form, in alkylated form, in sulfurated form or in the form of a poly L- 
               
               
                   
                   
                   
                 lysine derivative useful for stopping the production of alpha -TNF. 
               
               
                 5,705,364 
                 Jan. 6, 
                 Mammalian cell culture 
                 The present invention relates to novel process for the preparation of glycoproteins by 
               
               
                   
                 1998 
                 process 
                 mammalian cell culture wherein the sialic acid content of the glycoprotein produced is 
               
               
                   
                   
                   
                 controlled over a broad range of values by manipulating the cell culture environment. The 
               
               
                   
                   
                   
                 invention provides for processes in which the sialic acid content of the glycoprotein is 
               
               
                   
                   
                   
                 modified by changes in cell culture parameters which affect cell specific productivity. 
               
               
                   
                   
                   
                 Preferred embodiments of the invention include cell culture processes in the osmolality of 
               
               
                   
                   
                   
                 the cell culture is controlled as well as the concentration of a transcription enhancer during 
               
               
                   
                   
                   
                 the production phase of the cell culture. The invention further provides for novel 
               
               
                   
                   
                   
                 preparations of soluble type 1tumor necrosis factor immunoglobulin G1and their uses in 
               
               
                   
                   
                   
                 the treatment of inflammatory or immune related disorders. 
               
               
                 5,703,098 
                 Dec. 30, 
                 Immunotherapeutic 
                 Imide/amide ethers and alcohols are inhibitors of cytokines including tumor necrosis 
               
               
                   
                 1997 
                 imideslamides 
                 factor alpha and can be used to combat cachexia, endotoxic shock, arthritis, asthma, and 
               
               
                   
                   
                   
                 retrovirus replication. A typical embodiment is 3-Phthalimido-3-(3′, 4′- 
               
               
                   
                   
                   
                 dimethoxyphenyl)propan-1-ol. 
               
               
                 5,703,092 
                 Dec. 30, 
                 Hydroxamic acid 
                 The present invention provides novel hydroxamic acids and carbocyclic acids and 
               
               
                   
                 1997 
                 compounds as 
                 derivatives thereof and to pharmaceutical compositions and methods of use of these novel 
               
               
                   
                   
                 metalloprotease and TNF 
                 compounds for the inhibition of matrixmetalloproteinases, such as stromelysin and other 
               
               
                   
                   
                 inhibitors 
                 matrix metalloproteinases, and also inhibit the production of tumor necrosis factor (TNF), 
               
               
                   
                   
                   
                 and are therefore useful for the treatment of arthritis and other related inflammatory 
               
               
                   
                   
                   
                 diseases. These novel compounds are represented by Formula betow: [See Original 
               
               
                   
                   
                   
                 Patent for Chemical Structure Diagram] Formula I 
               
               
                 5,703,038 
                 Dec. 30, 
                 Therapeutic uses of 
                 Improved therapeutic uses of bactericidal/permeability-increasing protein (BPI) involve 
               
               
                   
                 1997 
                 bactericidal-permeability- 
                 use of BPI protein product formulations in the form of physiologically stable dimeric 
               
               
                   
                   
                 increasing protein dimer 
                 associations of BPI protein product monomers characterized by enhanced in vivo biological 
               
               
                   
                   
                 products 
                 activity. Preferred formulations include 50 percent or more by weight dimeric product. 
               
               
                 5,702,705 
                 Dec. 30, 
                 Antibody methods for the 
                 Cleavage site blocking antibody that binds to prohormones, preferable Tumor Necrosis 
               
               
                   
                 1997 
                 treatment of a hormone- 
                 Factor, thereby preventing the formation of prohormone fragment(s) by proteolysis of the 
               
               
                   
                   
                 mediated disease 
                 prohormone, and uses of the antibody including prophylactic and therapeutic methods to 
               
               
                   
                   
                   
                 treat disease, and diagnostic assays for determining the amount of the prohormone and 
               
               
                   
                   
                   
                 prohormone fragments present in a patients body. 
               
               
                 5,700,909 
                 Dec 23, 
                 Prosaposin and cytokine- 
                 Prosaposin and peptide derivatives derived therefrom will promote neurite outgrowth in 
               
               
                   
                 1997 
                 derived peptides 
                 vitro. A peptide consensus sequence was determined by comparing the active neurite 
               
               
                   
                   
                   
                 outgrowth-inducing saposin C peptide sequence with that of various hematopoietic and 
               
               
                   
                   
                   
                 neuropoietic cytokines. These cytokine-derived peptides will promote the same processes 
               
               
                   
                   
                   
                 as their corresponding cytokines. In addition, prosaposin and saposin C promote increased 
               
               
                   
                   
                   
                 nerve cell myelination ex vivo. 
               
               
                 5,700,788 
                 Dec. 23, 
                 Ureido derivatives of 
                 Subject of the present invention are new ureido derivatives of naphthalenephosphonic 
               
               
                   
                 1997 
                 naphthalenephosphonic 
                 acids having the following formula (I) [See Original Patent for Chemical Structure Diagram] 
               
               
                   
                   
                 acids 
                 (I) [See Original Patent for Chemical Structure Diagram] wherein each of m and n, which 
               
               
                   
                   
                   
                 are the same, is an integer of 1 to 4; each of p and q, which are the same, is an integer of 
               
               
                   
                   
                   
                 1 gto 3; and each of the R groups, which are the same, is a free or esterified phosphonic 
               
               
                   
                   
                   
                 acid group; and the pharmaceutically acceptable salts thereof. 
               
               
                 5,698,711 
                 Dec. 16, 
                 Compounds containing 
                 This invention is directed to the pharmaceutical use of phenyl compounds, which are 
               
               
                   
                 1997 
                 phenyl linked to aryl or 
                 linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The 
               
               
                   
                   
                 heteroaryl by an aliphatic- 
                 invention is also directed to the compounds, their preparation and pharmaceutical 
               
               
                   
                   
                 or heteroatom-containing 
                 compositions containing these compounds. Furthermore, this invention is directed to the 
               
               
                   
                   
                 linking group 
                 pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase. 
               
               
                 5,698,706 
                 Dec. 16, 
                 Heterocyclic amides and 
                 Peptidyl derivatives having a SH or acyl S group and which are amides, primary amides or 
               
               
                   
                 1997 
                 methods of use 
                 thioamides, have therapeutic utility via MMP or TNF inhibition. 
               
               
                 5,698,579 
                 Dec. 16, 
                 Cyclic amides 
                 Cyclic amides are inhibitors of tumor necrosis factor and can be used to combat cachexia, 
               
               
                   
                 1997 
                   
                 endotoxic shock, and retrovirus replication. A typical embodiment is 3-phenyl-3-(1- 
               
               
                   
                   
                   
                 oxoisoindolin-2-yl)propionamide. 
               
               
                 5,698,564 
                 Dec. 16, 
                 Diphenyl disulfide 
                 Diphenyl disulfide compounds having an inhibiting activity against the production of 
               
               
                   
                 1997 
                 compounds 
                 Interleukin-1 beta (IL-1 beta) or the release of Tumor Necrosis Factor alpha (TNF alpha), 
               
               
                   
                   
                   
                 which are useful in the treatment or prophylaxis of the diseases such as chronic 
               
               
                   
                   
                   
                 rheumatism and sepsis are described. 
               
               
                 5,698,518 
                 Dec. 16, 
                 Method for regulating 
                 A method of treating patients to inhibit inflammation is disclosed. In the method, an 
               
               
                   
                 1997 
                 inflammation and tumor 
                 effective amount of calmodulin, a calmodulin analogue or calmodulin receptor agonist is 
               
               
                   
                   
                 growth with calmodulin, 
                 administered to a patient to inhibit production of tumor necrosis factor and/or augment 
               
               
                   
                   
                 calmodulin analogues or 
                 elastase. In another method, an effective amount of calmodulin antagonist is administered 
               
               
                   
                   
                 calmodulin antagonists 
                 to a patient to stimulate immune response or inhibit elastase release. In another 
               
               
                   
                   
                   
                 embodiment, a diagnostic test is disclosed to be used on patient blood samples to 
               
               
                   
                   
                   
                 determine individual propensity to regulate tumor necrosis factor and/or elastase by 
               
               
                   
                   
                   
                 calmodulin, its analogues or receptor agonists. 
               
               
                 5,698,391 
                 Dec 16, 
                 Methods for synthetic 
                 Methods useful for the determination of oligomers which have specific activity for a target 
               
               
                   
                 1997 
                 unrandomization of 
                 molecule from a pool of primarily randomly assembled oligomers are provided. The 
               
               
                   
                   
                 oligomer fragments 
                 disclosed methods involve repeated syntheses of increasingly simplified sets of oligomers 
               
               
                   
                   
                   
                 coupled with selection procedures for determining oligomers having the highest activity. 
               
               
                   
                   
                   
                 Freedom from the use of enzymes allows the application of these methods to any 
               
               
                   
                   
                   
                 molecules which can be oligomerized in a controlled fashion. 
               
               
                 5,698,195 
                 Dec. 16, 
                 Methods of treating 
                 Anti-TNF antibodies, fragments and regions thereof which are specific for human tumor 
               
               
                   
                 1997 
                 rheumatoid arthritis using 
                 necrosis factor- alpha (TNF alpha ) and are useful in vivo for diagnosis and therapy of a 
               
               
                   
                   
                 chimeric anti-TNF 
                 number of TNF alpha -mediated pathologies and conditions, including rheumatoid arthritis 
               
               
                   
                   
                 antibodies 
                 as well as polynucleotides coding for murine and chimeric antibodies, methods of 
               
               
                   
                   
                   
                 producing the antibody, methods of use of the anti-TNF antibody, or fragment, region or 
               
               
                   
                   
                   
                 derivative thereof, in immunoassays and immunotherapeutic approaches are provided. 
               
               
                 5,695,993 
                 Dec. 9, 
                 Cloning and regulation of 
                 Human protein C and activated protein C were shown to bind to endothelium specifically, 
               
               
                   
                 1997 
                 an endothelial cell protein 
                 selectively and saturably (Kd = 30 nM, 7000 sites per cell) in a Ca&lt;2 +&gt; dependent 
               
               
                   
                   
                 C/activated protein C 
                 fashion. Expression cloning revealed a 1.3 kb CDNA that coded for a novel type 
               
               
                   
                   
                 receptor 
                 transmembrane glycoprotein capable of binding protein C. This protein appears to be a 
               
               
                   
                   
                   
                 member of the CD1/MHC superfamily. Like thrombomodulin, the receptor involved in 
               
               
                   
                   
                   
                 protein C activation, the endothelial cell protein C receptor (EPCR) function and message 
               
               
                   
                   
                   
                 are both down regulated by exposure of endothelium to TNF. Identification of EPCR as a 
               
               
                   
                   
                   
                 member of the CD1/MHC superfamily provides insights into the role of protein C in 
               
               
                   
                   
                   
                 regulating the inflammatory response, and determination of methods for pharmaceutical 
               
               
                   
                   
                   
                 use in manipulating the inflammatory response. 
               
               
                 5,695,953 
                 Dec. 9, 
                 DNA that encodes a tumor 
                 Tumor Necrosis Factor (TNF) Inhibitory Protein is isolated and substantially purified and 
               
               
                   
                 1997 
                 necrosis factor inhibitory 
                 the DNA that encodes the TNF inhibitory protein, vectors, host cells, and a recombinant 
               
               
                   
                   
                 protein and a recombinant 
                 method for producing the encoded protein are also set forth. It has the ability to inhibit: (a) 
               
               
                   
                   
                 method of production 
                 the binding of TNF to its receptors, and (b) the cytotoxic effect of TNF. TNF Inhibitory 
               
               
                   
                   
                   
                 Protein and salts, functional derivatives and active fractions thereof can be used to 
               
               
                   
                   
                   
                 antagonize the deleterious effects of TNF. 
               
               
                 5,691,382 
                 Nov. 25, 
                 Inhibition of TNF production 
                 The present invention is directed to the method of inhibiting the release of tumor necrosis 
               
               
                   
                 1997 
                 with matrix 
                 factor (TNF) in a condition mediated by TNF by administration of certain hydroxamic add 
               
               
                   
                   
                 metaloproteinase inhibitors 
                 derivatives, also known as matrix metalloproteinase inhibitors, and thus the method of this 
               
               
                   
                   
                   
                 invention is useful in the management of diseases or conditions mediated by TNF. 
               
               
                 5,691,381 
                 Nov. 25, 
                 Hydroxamic and 
                 The present invention provides novel hydroxamic acids and carbocyclic acids and 
               
               
                   
                 1997 
                 carbocyclic acids as 
                 derivatives thereof and to pharmaceutical compositions and methods of use of these novel 
               
               
                   
                   
                 metalloprotease inhibitors 
                 compounds for the inhibition of matrix metalloproteinases, such as stromelysin, and inhibit 
               
               
                   
                   
                   
                 the production of tumor necrosis factor alpha, and for the treatment of arthritis and other 
               
               
                   
                   
                   
                 related inflammatory diseases. these novel compounds are represented by Formula I 
               
               
                   
                   
                   
                 below [See Original Patent for Chemical Structure Diagram] Formula I 
               
               
                 5,688,805 
                 Nov. 18, 
                 Tricyclic derivatives, 
                 Disclosed are compounds of Formula [See Original Patent for Chemical Structure 
               
               
                   
                 1997 
                 compositions and methods 
                 Diagram] (I) or a pharmaceutically acceptable salt or solvate thereof. Also disclosed are 
               
               
                   
                   
                 of use 
                 pharmaceutical compositions containing compounds of Formula I, methods for inhibiting 
               
               
                   
                   
                   
                 tumor necrosis factor- alpha and methods for treating septic shock, inflammation, or 
               
               
                   
                   
                   
                 allergic disease. 
               
               
                 5,686,455 
                 Nov. 11, 
                 Imidazole derivatives and 
                 As cytokine inhibitors 2,4,5-triarylimidazole compounds and compositions for use as 
               
               
                   
                 1997 
                 their use as cytokine 
                 cytokine inhibitors. 
               
               
                   
                   
                 inhibitors 
               
               
                 5,686,431 
                 Nov. 11, 
                 Methods of using low 
                 The present invention relates to methods for the prevention and/or treatment of 
               
               
                   
                 1997 
                 molecular weight heparins 
                 pathological processes involving the induction of TNF- alpha secretion comprising a 
               
               
                   
                   
                 for treatment of pathological 
                 pharmaceutically acceptable carrier and a low molecular Weight heparin (LMWH). In the 
               
               
                   
                   
                 processes 
                 pharmaceutical compositions of the present invention, the LMWH present in a low effective 
               
               
                   
                   
                   
                 dose and is administered at intervals of about 5-8 days. Furthermore, the LMWH is 
               
               
                   
                   
                   
                 capable of inhibiting in vitro TNF- alpha secretion by resting T cells and/or macrophages in 
               
               
                   
                   
                   
                 response to T cell-specific antigens, mitogens, macrophage activators, disrupted 
               
               
                   
                   
                   
                 extracellular matrix (dECM), laminin, fibronectin, and the like. 
               
               
                 5,686,259 
                 Nov. 11, 
                 Assay method for the 
                 Cleavage site blocking antibody that binds to prohormones, preferable Tumor Necrosis 
               
               
                   
                 1997 
                 detection of 26 kd TNF 
                 Factor, thereby preventing the formation of prohormone fragment(s) by proteolysis of the 
               
               
                   
                   
                 prohormone 
                 prohormone, and uses of the antibody including prophylactic and therapeutic methods to 
               
               
                   
                   
                   
                 treat disease, and diagnostic assays for determining the amount of the prohormone and 
               
               
                   
                   
                   
                 prohormone fragments present in a patients body. 
               
               
                 5,684,222 
                 Nov. 4, 
                 Mutant mouse having a 
                 The multiple biological activities of tumor necrosis factor (TNF) are mediated by two 
               
               
                   
                 1997 
                 disrupted TNFRp55 
                 distinct cell surface receptors of 55 and 75 kDa. Mutant mice of the invention lacking tumor 
               
               
                   
                   
                   
                 necrosis factor receptor (TNFR) p55 still express functional TNFRp75 molecules at the cell 
               
               
                   
                   
                   
                 surface. Normal weight and size of the mutant mice are not altered. Thymocyle 
               
               
                   
                   
                   
                 development and Iymphocyle populations are normal, and clonal deletion of potentially 
               
               
                   
                   
                   
                 self-reactive T cells is not impaired. Activation of the nuclear transcription factor kappa B 
               
               
                   
                   
                   
                 (NF- kappa B), however, is completely abrogated after stimulation with TNF. Moreover, 
               
               
                   
                   
                   
                 TNFRp55 mutant mice are protected from septic shock induced by bacterial endotoxin or 
               
               
                   
                   
                   
                 superantigen, but Listeria clearance is severely impaired and mutant mice easily succumb 
               
               
                   
                   
                   
                 to Listeria infection. Thus, the two TNF receptors are not redundant, are independently 
               
               
                   
                   
                   
                 controlled, and piay different roles in normal and pathological physiology. 
               
               
                 5,679,696 
                 Oct 21, 
                 Compounds containing 
                 This invention is directed to the pharmaceutical use of phenyl compounds, which are 
               
               
                   
                 1997 
                 phenyl linked to aryl or 
                 linked to an aryl moiety by vanous linkages, for inhibiting tumor necrosis factor. The 
               
               
                   
                   
                 heteroaryl by an aliphatic-or 
                 invention is also directed to the compounds, their preparation and pharmaceutical 
               
               
                   
                   
                 heteroatom-containing 
                 compositions containing these compounds. Furthermore, this invention is directed to the 
               
               
                   
                   
                 linking group 
                 pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase. 
               
               
                 5,679,684 
                 Oct. 21, 
                 Hydroxyalkylammonium- 
                 Novel hydroxyalkylammonium-pyrimidine of the formula [See Original Patent for Chemical 
               
               
                   
                 1997 
                 pyrimidines and nucleoside 
                 Structure Diagram] (I) and nucieoside derivatives have been found to be useful as 
               
               
                   
                   
                 derivatives, useful as 
                 inhibitors of inflammatory cytokines. They can be used, inter alia, in the therapy of septic 
               
               
                   
                   
                 inhibitors of inflammatory 
                 shock, cachexia, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and 
               
               
                   
                   
                 cytokines 
                 AIDS. The compounds are typically prepared by reaction of an iodo substituted nucleoside 
               
               
                   
                   
                   
                 with the appropriately substituted hydroxyalkylamine. 
               
               
                 5,679,338 
                 Oct. 21, 
                 Use of IL-4 for inhibition of 
                 Applicants&#39; invention discloses therapeutic compositions and methods for treating 
               
               
                   
                 1997 
                 the breakdown of articular 
                 articular cartilage breakdown associated with osteoarthritis and rheumatoid arthritis. The 
               
               
                   
                   
                 cartiiage and other tissues 
                 compositions comprise a therapeutically effective amount of IL-4 to reduce or inhibit 
               
               
                   
                   
                   
                 breakdown of articular cartilage, optionally in the presence of a pharmaceutically 
               
               
                   
                   
                   
                 acceptable carrier or excipient. Methods for treating articular cartilage breakdown comprise 
               
               
                   
                   
                   
                 administering a therapeutically effective amount of IL-4 to reduce or inhibit breakdown of 
               
               
                   
                   
                   
                 articular cartilage, optionally in the presence of a pharmaceutically acceptable carrier to a 
               
               
                   
                   
                   
                 subject in need of such treatment. The invention also relates to compositions and methods 
               
               
                   
                   
                   
                 for treating tumor metastases, periodontal disease, emphysema and osteoporosis. 
               
               
                 5,677,182 
                 Oct. 14, 
                 Cleavage site blocking 
                 Cleavage site blocking antibody that binds to prohormones, preferable Tumor Necrosis 
               
               
                   
                 1997 
                 antibody to prohormone 
                 Factor, thereby preventing the formation of prohormone fragment(s) by proteolysis of the 
               
               
                   
                   
                 proteins and uses thereof 
                 prohormone, and uses of the antibody including prophylactic and therapeutic methods to 
               
               
                   
                   
                   
                 treat disease, and diagnostic assays for determining the amount of the prohormone and 
               
               
                   
                   
                   
                 prohormone fragments present in a patients body. 
               
               
                 5,672,347 
                 Sep. 30, 
                 Tumor necrosis factor 
                 Tumor necrosis factor antagonists are administered in therapeutically effective doses to 
               
               
                   
                 1997 
                 antagonists and their use 
                 suppress inflammatory immune-potentiated events. The antagonists of this invention 
               
               
                   
                   
                   
                 typically are selected from among several classes but preferably are neutralizing 
               
               
                   
                   
                   
                 antibodies directed against tumor necrosis factor. The antagonists are useful in 
               
               
                   
                   
                   
                 suppressing transplantation immunity and in the treatment of autoimmune diseases. 
               
               
                 5,670,527 
                 Sep. 23, 
                 Pyridyl imidazole 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1997 
                 compounds and 
                 cytokine inhibitors. 
               
               
                   
                   
                 compositions 
               
               
                 5,670,526 
                 Sep 23, 
                 1,3,4-oxadiazoles 
                 1,3,4-oxadiazole compounds are disdosed. The subject compounds suppress immune 
               
               
                   
                 1997 
                   
                 function and have hepatoprotection activity. 
               
               
                 5,670,506 
                 Sep 23, 
                 Halogen, isothiocyanate or 
                 There is disclosed a compound having the formula [See Original Patent for Chemical 
               
               
                   
                 1997 
                 azide substituted xanthines 
                 Structure Diagram] wherein n is an integer from 5 to 9, wherein the core moiety is a 
               
               
                   
                   
                   
                 heterocylic moiety wherein C[a], C[b], and C[c] are an R or S enantiomer or racemic 
               
               
                   
                   
                   
                 mixture and the C[a], C[b], and C[c] carbon atoms are bonded together by a single bond, 
               
               
                   
                   
                   
                 double bond, ether or ester linkages, wherein R1, R2 and R3 are independently halo, 
               
               
                   
                   
                   
                 hydroxy, hydrogen, keto, isothiocyano, azide or haloacetoxy with the proviso that at least 
               
               
                   
                   
                   
                 one of R1, R2 or R3 must be a halo, isothiocyano, azide or haloacetoxy group, wherein R4 
               
               
                   
                   
                   
                 is hydrogen, C1-6 alkyl, C1-6 alkenyl, cyclo C4-6 alkyl, or phenyl, and wherein halo refers 
               
               
                   
                   
                   
                 to fluoro, chloro, bromo and iodo and salts thereof and pharmaceutical compositions 
               
               
                   
                   
                   
                 thereof. 
               
               
                 5,670,319 
                 Sep. 23, 
                 Assay for tumor necrosis 
                 The invention concerns new tumor necrosis factor receptor associated factors, 
               
               
                   
                 1997 
                 factor receptor-associated 
                 designated TRAF. The new factors are capable of specific association with the intracellular 
               
               
                   
                   
                 factors 
                 domain of the type 2 TNF receptor (TNF-R2), and are involved in the mediation of TNF 
               
               
                   
                   
                   
                 biological activities. 
               
               
                 5,670,149 
                 Sep. 23, 
                 Lymphotoxin- beta, 
                 This invention relates to lymphotoxin- beta, a lymphocyle membrane type protein. This 
               
               
                   
                 1997 
                 Lymphotoxin- beta 
                 protein is found on the surface of a number of cells, including phorbol ester (PNA) 
               
               
                   
                   
                 complexes, pharmaceutical 
                 stimulated T cell hybridoma II-23.D7 cells. This invention also relates to complexes formed 
               
               
                   
                   
                 preparations and 
                 between lymphotoxin- beta and other peptides such as lymphotoxin- alpha and to 
               
               
                   
                   
                 therapeutic uses thereof 
                 complexes comprising multiple subunits of lymphotoxin- beta. These proteins and 
               
               
                   
                   
                   
                 complexes are useful in holding LT- alpha formed within the cell on the cell surface where 
               
               
                   
                   
                   
                 the LT- alpha /LT- beta complex may act as an inflammation regulating agent, a tumor 
               
               
                   
                   
                   
                 growth inhibiting agent, a T cell inhibiting agent, a T cell activating agent, an autoimmune 
               
               
                   
                   
                   
                 disease regulating agent, or an HIV inhibiting agent. Furthermore, the antitumor activity of 
               
               
                   
                   
                   
                 the LT- alpha /LT- beta complex may be delivered to tumor cells by tumor infiltrating 
               
               
                   
                   
                   
                 lymphocyles (TILs) transfected with the gene for LT- beta. 
               
               
                 5,668,143 
                 Sep. 16, 
                 Heterocyclic 
                 The present invention relates to heterocyclic benzenesulfonylimine derivatives and their 
               
               
                   
                 1997 
                 benzenesulfonylimine 
                 use as inhibitors of Interleukin-1 (IL-1) action. Such inhibitors are useful in the treatment of 
               
               
                   
                   
                 derivatives as inhibitors of 
                 various disease states as disclosed herein including rheumatoid arthritis, multiple sclerosis, 
               
               
                   
                   
                 IL-1 action 
                 diabetes mellitus, atherosclerosis, septic shock and pulmonary fibrosis. 
               
               
                 5,667,967 
                 Sep. 16, 
                 T-cell receptor varible 
                 Methods are provided for determining relations between autoimmune degenerative 
               
               
                   
                 1997 
                 transcnpts as disease 
                 diseases and specific variable regions of T-cell receptors as associated with the host HLA 
               
               
                   
                   
                 related markers 
                 or T-cells associated with umbatting neoprofilerative diseases. By identifying the particular 
               
               
                   
                   
                   
                 T-cell receptors which cause or are the disease in mammals, various prophylactic and 
               
               
                   
                   
                   
                 therapeutic techniques may be employed for inhibiting the attack of the T-cell receptors on 
               
               
                   
                   
                   
                 the native protein or tissue enhance the defense. In addition, individuals may be diagnosed 
               
               
                   
                   
                   
                 as to their propensity for a particular autoimmune disease or the occurrence of such a 
               
               
                   
                   
                   
                 disease. 
               
               
                 5,667,776 
                 Sep. 16, 
                 Treatment for biological 
                 Damage to cells, tissue and other bocly parts in a mammalian host may be treated by 
               
               
                   
                 1997 
                 damage using tumor 
                 using a tumor necrosis factor in conjunction with at least one biological modifier, which may 
               
               
                   
                   
                 necrosis factor and a free- 
                 be a free radical scavenger or a metabolic inhibitor. The biological modifier is preferably 
               
               
                   
                   
                 radical scavenger 
                 uric acid, buthionine sulphoximine, vitamin C, aspirin, or nordihydrogualaretic acid. Such a 
               
               
                   
                   
                   
                 combination may be used to treat, for example, cancer, infectious diseases, and damage 
               
               
                   
                   
                   
                 caused by radiation therapy, high oxygen tension, and chemotherapy. 
               
               
                 5,665,859 
                 Sep. 9, 
                 Molecules influencing the 
                 Molecules which influence the shedding of the cell-bound p55 Tumor Necrosis Factor 
               
               
                   
                 1997 
                 shedding of the TNF 
                 receptor (p55-TNF-R), are provided, together with methods of producing them. 
               
               
                   
                   
                 receptor, their preparation 
               
               
                   
                   
                 and their use 
               
               
                 5,665,777 
                 Sep. 9, 
                 Biphenyl hydroxamate 
                 Compounds of formula [See Original Patent for Chemical Structure Diagram] or a 
               
               
                   
                 1997 
                 inhibitors of matrix 
                 pharmaceutically acceptable salt thereof inhibit matrix metalloproteinases and TNF alpha 
               
               
                   
                   
                 metalloproteinases 
                 secretion and are useful in the treatment of inflammatory disease states. Also disclosed 
               
               
                   
                   
                   
                 are matrix metalloproteinases and TNF alpha secretion inhibiting compositions and a 
               
               
                   
                   
                   
                 method for inhibiting matrix metalloproteinases and TNF alpha secretion. 
               
               
                 5,665,754 
                 Sep. 9, 
                 Substituted pyrrolidines 
                 Novel pyrrolidine compounds which are useful for inhibiting the function of Type IV 
               
               
                   
                 1997 
                   
                 phosphodiesterase (PDE-IV) as well as methods for making the same are disdosed. 
               
               
                   
                   
                   
                 Applications in treating inflammatory diseases and other diseases involving elevated levels 
               
               
                   
                   
                   
                 of cytokines, as well as central nervous system (CNS) disorders, are also disclosed. 
               
               
                 5,665,714 
                 Sep. 9, 
                 N-substituted 
                 The present invention relates to novel, therapeutically active fatty alkyl and alkenyl ether 
               
               
                   
                 1997 
                 glycerophosphoethanolami 
                 glycerophospholipids bearing a 3-(2-imidazolinyl)-2-imidazolinyl or 2-imidazolinyl 
               
               
                   
                   
                 nes 
                 substituent on the ethanolamine nitrogen, methods of using the compounds and 
               
               
                   
                   
                   
                 pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing 
               
               
                   
                   
                   
                 same. The novel, therapeutically active compounds and salts of the invention possess anti- 
               
               
                   
                   
                   
                 tumor, anti-psoriatic, anti-inflammatory, and anti-asthma activities. 
               
               
                 5,663,334 
                 Sep. 2, 
                 Process for preparing 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1997 
                 pyrimidyl imidazoles 
                 cytokine inhibitors. 
               
               
                 5,658,949 
                 Aug. 19, 
                 Inhibition of tumor necrosis 
                 A novel method of inhibiting production of two important mediators of cellular function, 
               
               
                   
                 1997 
                 factor by retinoic acid 
                 tumor necrosis factor and nitric oxide; and treating a pathophysiological state characterized 
               
               
                   
                   
                   
                 by an undesirable production or level of tumor necrosis factor or nitric acid. The methods of 
               
               
                   
                   
                   
                 the present invention employ retinoic acid compounds. The most preferred retinoic acid is 
               
               
                   
                   
                   
                 all-trans-retinoic acid. Also provided is a method of inhibiting tumor necrosis factor 
               
               
                   
                   
                   
                 receptors using retinoic acid-like compounds. 
               
               
                 5,658,940 
                 Aug. 19, 
                 Succinimide and maleimide 
                 Novel succinimides and maleimides are inhibitors of tumor necrosis factor alpha and 
               
               
                   
                 1997 
                 cytokine inhibitors 
                 phosphodiesterase and can be used to combat cachexia, endotoxic shock, retrovirus 
               
               
                   
                   
                   
                 replication, asthma, and inflammatory conditions. A typical embodiment is methyl 3- 
               
               
                   
                   
                   
                 (3′,4′,5′,6′-tetrahydrophthalimido)-3-(3″,4″-dimethoxyphenyl)propionate. 
               
               
                 5,658,903 
                 Aug. 19, 
                 Imidazole compounds, 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1997 
                 compositions and use 
                 cytokine inhibitors. 
               
               
                 5,658,581 
                 Aug. 19, 
                 Histamine antagonist, an 
                 The invention relates to the use of a histamine antagonist, an interleukin-1 antagonist 
               
               
                   
                 1997 
                 interleukin-1 antagonist 
                 and/or a TNF alpha anlagonist in a cosmetic, pharmaceutical or dermatological 
               
               
                   
                   
                 and/or a TNF alpha 
                 composition for treating sensitive skins. It relates especially to the use of a histamine 
               
               
                   
                   
                 antagonist in a cosmetic, 
                 antagonist, an interleukin-1 antagonist and/or a TNF alpha antagonist for preventing and/or 
               
               
                   
                   
                 pharmaceutical or 
                 combating skin irritations and/or sores and/or erylhema and/or dysaesthetic sensations 
               
               
                   
                   
                 dermatological composition 
                 and/or sensations of inflammation and/or pruritus and/or prickling and/or tingling and/or 
               
               
                   
                   
                 and composition obtained 
                 discomfort and/or tightness of the skin and/or mucosae. It also relates to a composition 
               
               
                   
                   
                   
                 containing a histamine antagonist, an interleukin-1 antagonist and/or a TNF alpha 
               
               
                   
                   
                   
                 antagonist which limits or eliminates the irritant side-effects of certain products, and in 
               
               
                   
                   
                   
                 particular of certain cosmetic, dermatological or pharmaceutical active agents. 
               
               
                 5,656,644 
                 Aug. 12, 
                 Pyridyl imidazoles 
                 Novel 2,4,5-triaryl imidazole compounds and compositions for use in therapy. 
               
               
                   
                 1997 
               
               
                 5,656,272 
                 Aug. 12, 
                 Methods of treating TNF- 
                 Anti-TNF antibodies, fragments and regions thereof which are specific for human tumor 
               
               
                   
                 1997 
                 alpha -mediated Crohn&#39;s 
                 necrosis factor- alpha (TNF alpha) and are useful in vivo for diagnosis and therapy of a 
               
               
                   
                   
                 disease using chimeric anti- 
                 number of TNF alpha -mediated pathologies and conditions, including Crohn&#39;s disease, as 
               
               
                   
                   
                 TNF antibodies 
                 well as polynucleotides coding for murine and chimeric antibodies, methods of producing 
               
               
                   
                   
                   
                 the antibody, methods of use of the anti-TNF antibody, or fragment, region or derivative 
               
               
                   
                   
                   
                 thereof, in immunoassays and immunotherapeutic approaches are provided. 
               
               
                 5,654,407 
                 Aug. 5, 
                 Human anti-TNF antibodies 
                 Human monoclonal antibodies (mAbs) which bind to human TNF alpha are disclosed 
               
               
                   
                 1997 
                   
                 Autoantibodies of both the IgM and IgG isotypes are disclosed. A preferred human 
               
               
                   
                   
                   
                 monoclonal antibody is known as BS (F78-1A10-B5 mAb) and it binds to recombinant 
               
               
                   
                   
                   
                 human TNF alpha (rhTNF alpha) in ELISA format with a titer comparable to three high 
               
               
                   
                   
                   
                 affinity neutralizing mouse mAbs. It also binds to cell surface TNF alpha and prevents TNF 
               
               
                   
                   
                   
                 alpha secretion by human monocyle cell lines. 
               
               
                 5,654,323 
                 Aug. 5, 
                 Heterocyclic compounds 
                 A compound of formula (I): [See Original Patent for Chemical Structure Diagram] (I) in 
               
               
                   
                 1997 
                   
                 which X, n, B and Y are as defined in the description useful as cytokine inhibitors. 
               
               
                 5,654,312 
                 Aug 5, 
                 Treatment of inflammatory 
                 Methods of treatment for inflammatory and autoimmune dermatoses which comprises 
               
               
                   
                 1997 
                 and/or autoimmune 
                 topical and/or systemic administration of a therapeutically-effective amount of thalidomide 
               
               
                   
                   
                 dermatoses with 
                 alone or in combination with other dermatological agents. 
               
               
                   
                   
                 thalidomide alone or in 
               
               
                   
                   
                 combination with other 
               
               
                   
                   
                 agents 
               
               
                 5,652,353 
                 Jul. 29, 
                 DNAs encoding tumor 
                 It is an object of this invention to provide a human Tumor Necrosis Factor mutein or a 
               
               
                   
                 1997 
                 necrosis factor- alpha 
                 pharmaceutically acceptable salt thereof characterized in that the TNF sequence is 
               
               
                   
                   
                 muteins 
                 changed by a deletion, insertion, substitution or combinations thereof, of one or more 
               
               
                   
                   
                   
                 amino acids so that the mutein shows a significant difference between its binding affinity to 
               
               
                   
                   
                   
                 the human p75-Tumor-Necrosis-Factor-Receptor and to the human p55-Tumor-Necrosis- 
               
               
                   
                   
                   
                 Factor-Receptor. The invention also includes DNA sequences coding for such muteins, 
               
               
                   
                   
                   
                 vectors comprising such DNA sequences, host cells transformed with such vectors and a 
               
               
                   
                   
                   
                 process for the production of such muteins employing such transformed host cells and 
               
               
                   
                   
                   
                 pharmaceutical compositions containing such muteins and theiruse for the treatment of 
               
               
                   
                   
                   
                 illnesses, for example cancer. 
               
               
                 5,652,243 
                 Jul. 29, 
                 Methods of using 
                 There is disclosed compounds and pharmaceutical compositions that are a resolved R or 
               
               
                   
                 1997 
                 enantiomerically pure 
                 S (preferably R) enantiomer of an omega -1 alcohol of a straight chain alkyl (C5-8) 
               
               
                   
                   
                 hydroxylated xanthine 
                 substituted at the 1-position of 3,7-disubstituted xanthine. The inventive compounds are 
               
               
                   
                   
                 compounds 
                 effective in modulating cellular response to external or in situ primary stimuli, as well as to 
               
               
                   
                   
                   
                 specific modes of administration of such compounds in effective amounts. 
               
               
                 5,650,396 
                 Jul. 22, 
                 Methods of modulating 
                 Methods for modulating the expression of inflammatory cytokines in the central nervous 
               
               
                   
                 1997 
                 inflammatory cytokines in 
                 system comprising administering an effective amount of TGF- beta are disclosed. The 
               
               
                   
                   
                 the CNS using TGF- beta 
                 methods include suppressing pro-inflammatory cytokines in the central nervous system by 
               
               
                   
                   
                   
                 administering an effective amount of TGF- beta and inducing anti-inflammatory cytokines in d 
               
               
                   
                   
                   
                 the central nervous system by administering an effective amount of TGF- beta. 
               
               
                 5,650,316 
                 Jul. 22, 
                 Uses of triplex forming 
                 The present invention provides novel methods of treating anti-neopastic and non- 
               
               
                   
                 1997 
                 oligonucleotides for the 
                 neoplastic cell proliferative diseases. The present methods involve administration of triplex 
               
               
                   
                   
                 treatment of human 
                 forming oligonucleotides to humans to inhibit the biological activity of tumor necrosis factor. 
               
               
                   
                   
                 diseases 
                 Also provided are methods of treating neuro-oncologic states and renal cancer. 
               
               
                 5,648,359 
                 Jul. 15, 
                 Tumor necrosis factor 
                 There is provided a composition for inhibiting the production or secretion of tumor 
               
               
                   
                 1997 
                 production inhibitors 
                 necrosis factor effective for the treatment of cachexia, septic shock, multiple organ failure, 
               
               
                   
                   
                   
                 rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, osteoarthritis, Behcet 
               
               
                   
                   
                   
                 disease, systemic lupus erythematosus (SLE), graft versus host disease (GvHD), malaria, 
               
               
                   
                   
                   
                 acquired immune deficiency syndrome (AIDS), meningitis, hepatitis and Type II diabetes 
               
               
                   
                   
                   
                 mellitus. The composition comprises a pharmaceutically effective amount of a compound 
               
               
                   
                   
                   
                 of formula (1). 
               
               
                 5,646,158 
                 Jul. 8, 
                 1,3,3- 
                 This invention relates to certain 1,3,3-(trisubstituted)cyclohex-1-ene monomers and 
               
               
                   
                 1997 
                 (trisubstituted)cyclohex-1- 
                 related compounds which are useful in treating allergic and inflammatory diseases and for 
               
               
                   
                   
                 ene monomers and related 
                 inhibiting the production of Tumor Necrosis Factor (TNF). 
               
               
                   
                   
                 compounds 
               
               
                 5,646,154 
                 Jul. 8, 
                 Pharmaceutical 
                 Quinazoline compounds represented by general formula (1) or (2) possess an activity of 
               
               
                   
                 1997 
                 compositions for inhibiting 
                 significantly inhibiting the production or secretion of a tumor necrosis factor and are useful 
               
               
                   
                   
                 the formation of tumor 
                 as drugs for the treatment of diseases wherein a tumor necrosis factor is considered to be 
               
               
                   
                   
                 necrosis factor 
                 involved in causing those diseases: [See Original Patent for Chemical Structure Diagram] 
               
               
                   
                   
                   
                 (1) [See Original Patent for Chemical Structure Diagram] (2) wherein R&lt;1&gt; through R&lt;7 
               
               
                   
                   
                   
                 &gt; and A represent specific functional groups. 
               
               
                 5,646,128 
                 Jul. 8, 
                 Methods for treating 
                 Novel compounds which selectively inhibit adenosine kinase and methods of preparing 
               
               
                   
                 1997 
                 adenosine kinase related 
                 adenosine kinase inhibitors are provided. Also provided are methods of treating various 
               
               
                   
                   
                 conditions 
                 inflammatory conditions, including arthritis and SIRS, which may be ameliorated by 
               
               
                   
                   
                   
                 increased ocal concentrations of adenosine using adenosine kinase inhibitors. 
               
               
                 5,644,034 
                 Jul. 1, 
                 Tumour necrosis factor 
                 The present invention relates to ligands which bind to human tumour necrosis factor 
               
               
                   
                 1997 
                 binding ligands 
                 alpha (TNF) in a manner such that upon binding of these ligands to TNF the biological 
               
               
                   
                   
                   
                 activity of TNF is modified. In preferred forms the ligand binds to TNF in a manner such 
               
               
                   
                   
                   
                 that the induction of endothelial procoagulant activity of the TNF is inhibited; the binding of  
               
               
                   
                   
                   
                 TNF to receptors on endothelial cells is inhibited; the induction of fibrin deposition in the 
               
               
                   
                   
                   
                 tumor and tumor regression activities of the TNF are enhanced; and the cytotoxicity and 
               
               
                   
                   
                   
                 receptor binding activities of the TNF are unaffected or enhanced on tumor cells. The 
               
               
                   
                   
                   
                 ligand is preferably an antibody, F(ab) fragment, single domain antibody (dABs) single 
               
               
                   
                   
                   
                 chain antibody or a serum binding protein. It is preferred, however, that the ligand is a 
               
               
                   
                   
                   
                 monoclonal antibody or F(ab) fragment thereof. 
               
               
                 5,643,946 
                 Jul. 1, 
                 Compounds useful for 
                 Compounds of the formula [See Original Patent for Chemical Structure Diagram] 
               
               
                   
                 1997 
                 treating allergic and 
                 wherein the substituents are as defined herein, are disclosed. Pharmaceutical 
               
               
                   
                   
                 inflammatory diseases 
                 compositions and methods of treating allergic and inflammatory diseases are also taught. 
               
               
                 5,643,915 
                 Jul. 1, 
                 Treatment of  
                 In accordance with the present invention, a method is provided for treating reperfusion 
               
               
                   
                 1997 
                 ischemia/reperfusion injury 
                 injury, ischemia and runaway inflammatory conditions with thalidomide alone or in 
               
               
                   
                   
                 with thalidomide alone or in 
                 combination with other drugs selected from the group consisting of nitrates, beta- 
               
               
                   
                   
                 combination with other 
                 adrenoceptor blocking agents, anti-platelet/thrombolytic drugs, drugs acting as the 
               
               
                   
                   
                 therapies 
                 arachindonic acid cascade and calcium antagonists. Pharmaceutical compositions 
               
               
                   
                   
                   
                 comprising thalidomide alone or in combination with other drugs are also provided. 
               
               
                 5 643,893 
                 Jul. 1, 
                 N-substituted- 
                 Novel N-substituted-(dihydroxyboryl)alkyl purine, indole and pyrimidine derivatives have 
               
               
                   
                 1997 
                 (Dihydroxyboryl)alkyl 
                 been found to be useful as inhibitors of inflammatory cytokines. They can be used inter 
               
               
                   
                   
                 purine, indole and 
                 alia, in the therapy of septic shock, cachexia, rheumatoid arthritis, inflammatory bowel 
               
               
                   
                   
                 pyrimidine derivatives, 
                 disease, multiple sclerosis and AIDS. The compounds are typically prepared by reaction of  
               
               
                   
                   
                 useful as inhibitors of  
                 an bromoalkyl boronic acid with the purine, indole or pyrimidine base. 
               
               
                   
                   
                 inflammatory cytokines 
               
               
                 5,643,570 
                 Jul. 1, 
                 BPI-immunoglobulin fusion 
                 Disclosed are novel hybrid fusion proteins comprising at their amino terminus, 
               
               
                   
                 1997 
                 proteins 
                 bactericidal/permeability-increasing protein or a biologically active fragment thereof and, at 
               
               
                   
                   
                   
                 their carboxy terminus, at least one immunoglobulin heavy chain constant domain useful in 
               
               
                   
                   
                   
                 treating bacterial infection. Also disclosed are DNA sequences encoding such proteins, 
               
               
                   
                   
                   
                 recombinant methods for production of the proteins, and pharmaceutical preparations 
               
               
                   
                   
                   
                 containing the recombinant products. 
               
               
                 5,641,783 
                 Jun. 24, 
                 Substituted amino alcohol 
                 Disclosed are compounds having a straight or branched aliphatic hydrocarbon structure 
               
               
                   
                 1997 
                 compounds 
                 of formula [See Original Patent for Chemical Structure Diagram] I In formula I, n is an 
               
               
                   
                   
                   
                 integer from one to four and m is an integer from four to twenty. Independently, R1 and R2 
               
               
                   
                   
                   
                 are hydrogen, a straight or branched chain alkyl, alkenyl or alkynyl of up to twenty carbon 
               
               
                   
                   
                   
                 atoms in length or —(CH2)[w]R5. If R1 or R2 is —(CH2)[w]R5, w may be an integer from one 
               
               
                   
                   
                   
                 to twenty and R5 may be an hydroxyl, halo, C1-8 alkoxyl group or a substituted or 
               
               
                   
                   
                   
                 unsubstituted carbocycle or heterocycle. Alternatively, R1 and R2 may jointly form a 
               
               
                   
                   
                   
                 substituted or unsubstituted, saturated or unsaturated heterocycle having from four to eight 
               
               
                   
                   
                   
                 carbon atoms, N being a hetero atom of the resulting heterocycle. R3 may be either 
               
               
                   
                   
                   
                 hydrogen or C1-3. In the compounds, a total sum of carbon atoms comprising R1 or R2, 
               
               
                   
                   
                   
                 (CH2)[n] and (CH2)[m] does not exceed forty. R4 is a terminal moiety comprising a 
               
               
                   
                   
                   
                 substituted or unsubstituted, oxidized or reduced ring system, the ring system having a 
               
               
                   
                   
                   
                 single ring or two to three fused rings, a ring comprising from three to seven ring atoms. 
               
               
                   
                   
                   
                 The disclosed compounds are effective agents to inhibit undesirable responses to cell 
               
               
                   
                   
                   
                 stimuli. 
               
               
                 5,641,751 
                 Jun. 24, 
                 Tumor necrosis factor 
                 Peptides which consist of 4-25 amino acids and which bind to tumor necrosis factor- 
               
               
                   
                 1997 
                 inhibitors 
                 alpha, prevent tumor necrosis factor-alpha from binding to its receptors and inhibit tumor 
               
               
                   
                   
                   
                 necrosis factor-alpha activity are disclosed. Methods of inhibiting tumor necrosis factor- 
               
               
                   
                   
                   
                 alpha activity and of treating individuals suffering from tumor necrosis factor-alpha- 
               
               
                   
                   
                   
                 mediated diseases and disorders are disclosed. 
               
               
                 5,639,597 
                 Jun. 17, 
                 Cell-free receptor binding 
                 The invention reates to cell-free receptor binding assays which permit the binding 
               
               
                   
                 1997 
                 assays, the production and 
                 behavior of receptor proteins in the cell membrane toward natural or artificial ligands to be 
               
               
                   
                   
                 use thereof  
                 investigated. This entails the particular receptor being linked to a suitable carrier molecule, 
               
               
                   
                   
                   
                 preferably the heavy chain of an immunoglobulin, and being bound via the carrier, with 
               
               
                   
                   
                   
                 retention of its biological property, to a suitable solid phase. 
               
               
                 5,639,593 
                 Jun. 17, 
                 Method for determining 
                 Compositions and methods are described for identifying inhibitors of mature protein 
               
               
                   
                 1997 
                 TNF 
                 hormone formation from a prohormone, and prophylactic and therapeutic uses of the 
               
               
                   
                   
                   
                 inhibitors for treating diseases associated with elevated levels of the mature hormones, 
               
               
                   
                   
                   
                 particulary sepsis, AIDS and autoimmune diseases. 
               
               
                 5,635,517 
                 Jun. 3, 
                 Method of reducing TNF 
                 1-Oxo- and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the 
               
               
                   
                 1997 
                 alpha levels with amino 
                 benzo ring reduce the levels of TNF alpha in a mammal. A typical embodiment is 1,3- 
               
               
                   
                   
                 substituted 2-(2,6- 
                 dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. 
               
               
                   
                   
                 dioxopiperidin-3-yl)-1-oxo- 
               
               
                   
                   
                 and 1,3-dioxoisoindolines 
               
               
                 5,633,145 
                 May 27, 
                 TNF alpha receptor-derived 
                 A polypeptide is provided which is capable of binding human TNF alpha and which has 
               
               
                   
                 1997 
                 binding protein 
                 the first three cysteine-rich subdomains, but not the fourth cysteine-rich subdomain, of the 
               
               
                   
                   
                   
                 extracellular binding domain of a receptor selected from the group consisting of the 55 kD 
               
               
                   
                   
                   
                 and 75 kD receptors for human TNF alpha. The ability of the polypeptide to bind TNF 
               
               
                   
                   
                   
                 alpha means that it can be used for treating diseases mediated by TNF alpha activity, such 
               
               
                   
                   
                   
                 as rheumatoid arthritis. 
               
               
                 5,632,982 
                 May 27, 
                 Cytotoxic enhancement of  
                 Copper chelates serve as cytotoxic agents in conjunction with a surface membrane 
               
               
                   
                 1997 
                 TNF with copper 
                 protein receptor internalizing agent, particularly TNF, which has independent cytotoxic 
               
               
                   
                   
                   
                 activity, for use against target cells. By employing concentrations of the two agents, where 
               
               
                   
                   
                   
                 the agents have substantially reduced adverse side effects, the combination is shown to 
               
               
                   
                   
                   
                 have effective cytotoxic activity. 
               
               
                 5,631,286 
                 May 20, 
                 Compounds useful for 
                 Novel cyclohexanes of formulas (I) and (II) are described herein. They inhibit the 
               
               
                   
                 1997 
                 treating allergic or 
                 production of Tumor Necrosis Factor and are useful in the treatment of disease states 
               
               
                   
                   
                 inflammatory diseases 
                 mediated or exacerbated by TNF production: these compounds are also useful in the 
               
               
                   
                   
                   
                 mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV. [See 
               
               
                   
                   
                   
                 Original Patent for Chemical Structure Diagram] (I) [See Original Patent for Chemical 
               
               
                   
                   
                   
                 Structure Diagram] (II) 
               
               
                 5,631,258 
                 May 20, 
                 Method of effecting 
                 This invention relates to methods of effecting immunosuppression and inhibiting tumor 
               
               
                   
                 1997 
                 immunosuppression by 
                 necrosis factor alpha in a patient in need thereof comprising administering to said patient 
               
               
                   
                   
                 administering carbocyclic 
                 an effective immunosuppressive amount of a compound of the formula [See Original 
               
               
                   
                   
                 adenosine analogs 
                 Patent for Chemical Structure Diagram] wherein the hydroxy substituent on the 
               
               
                   
                   
                   
                 cydopentanyl ring is in the CIS configuration relative to the bicyclic substituent, 
               
               
                   
                   
                   
                 Y3 is N, Y7, Y8 and Y9 are each independently nitrogen or a CH group, 
               
               
                   
                   
                   
                 Q is NH2, halogen or hydrogen, and 
               
               
                   
                   
                   
                 Z is hydrogen, halogen, or NH2; 
               
               
                   
                   
                   
                 or a pharmaceutically-acceptable salt thereof. Also presented are pharmaceutical 
               
               
                   
                   
                   
                 compositions comprising compounds of the same formula. 
               
               
                 5,629,315 
                 May 13, 
                 Treatment of diseases 
                 There is disclosed compounds and pharmaceutical compositions that are a resolved R or 
               
               
                   
                 1997 
                 using enantiomerically pure 
                 S (preferably R) enantiomer of an omega -1 alcohol of a straight chain alkyl (C5-8) 
               
               
                   
                   
                 hydroxylated xanthine 
                 substituted at the 1-position of 3,7-disubstituted xanthine. The inventive compounds are 
               
               
                   
                   
                 compounds 
                 effective in modulating cellular response to external or in situ primary stimuli, as well as to 
               
               
                   
                   
                   
                 specific modes of administration of such compounds in effective amounts. 
               
               
                 5,629,285 
                 May 13, 
                 Inhibitors of TNF- alpha 
                 Compounds and methods are disclosed that are useful in inhibiting the TNF- alpha 
               
               
                   
                 1997 
                 secretion 
                 converting enzyme (TACE) responsible for cleavage of TNF- alpha precursor to provide 
               
               
                   
                   
                   
                 biologically active TNF- alpha. The compounds employed in the invention are peptidyl 
               
               
                   
                   
                   
                 derivatives having active groups capable of inhibiting TACE such as, hydroxamates, thiols, 
               
               
                   
                   
                   
                 phosphoryls and carboxyls. 
               
               
                 5,627,262 
                 May 6, 
                 Method and composition for 
                 The present invention contemplates a composition and method for treating septic shock 
               
               
                   
                 1997 
                 the treatment of septic 
                 in a mammal or as a prophylactic treatment prior to a surgical procedure, comprising 
               
               
                   
                   
                 shock 
                 administering a therapeutically effective amount of a bacterial lipopolysaccharide binding 
               
               
                   
                   
                   
                 peptide derived from CAP37 protein. In a preferred version, the composition and method of  
               
               
                   
                   
                   
                 use may comprise a peptide comprising amino acids 20-44 or 120-146 of CAP37 or 
               
               
                   
                   
                   
                 subunits thereof. 
               
               
                 5,625,085 
                 Apr. 29, 
                 Esters of acyl L-carnitines 
                 Esters of alkanoyl L-carnilines wherein the alkanoyl is a saturated or unsaturated, straight 
               
               
                   
                 1997 
                 and pharmaceutical 
                 or branched alkanoyl having 2-26 carbon atoms, optionally omega -substituted with 
               
               
                   
                   
                 compositons containing 
                 trialkylammonium, dialkylsulfonium, hydroxyl, carboxyl, halogen, methanesulfonyl and 
               
               
                   
                   
                 same for treating endotoxic 
                 hydroxysulfonyl, are useful for preparing pharmaceutical compositions for the treatment of  
               
               
                   
                   
                 shock 
                 endotoxic shock. 
               
               
                 5,624,913 
                 Apr. 29, 
                 Method reducing TNF- 
                 A method for reducing the TNF-alpha in mammals with cerebral malaria comprising the 
               
               
                   
                 1997 
                 alpha in mammals with 
                 administration of 2-methylthio-ATP or 2-chloro-ATP. 
               
               
                   
                   
                 cerebral malaria 
               
               
                 5,616,490 
                 Apr. 1, 
                 Ribozymes targeted to 
                 An enzymatic RNA molecule which cleaves mRNA associated with development or 
               
               
                   
                 1997 
                 TNF- alpha RNA 
                 maintenance of an inflammatory disease. 
               
               
                 5,614,540 
                 Mar. 25, 
                 Compounds useful for 
                 Novel compounds of Formula (I) [See Original Patent for Chemical Structure Diagram] 
               
               
                   
                 1997 
                 treating allergic and 
                 where X4 is a substituted cyclohexane or cyclohexane group and the other radicals are 
               
               
                   
                   
                 inflammatory diseases 
                 defined herein. These compounds inhibit the production of Tumor Necrosis Factor and are 
               
               
                   
                   
                   
                 useful in the treatment of disease states mediated or exacerbated by TNF production. The 
               
               
                   
                   
                   
                 compounds of the present invention are also useful in the mediation or inhibition of  
               
               
                   
                   
                   
                 enzymatic or catalyyic activity of phosphodiesterase IV and are therefore useful in the 
               
               
                   
                   
                   
                 treatment of disease states in need of mediation or inhibition thereof. 
               
               
                 5,612,476 
                 Mar. 18, 
                 Anti-endotoxin compounds 
                 Disclosed are lipid A analogs useful for the treatment of septic shock and LPS-mediated 
               
               
                   
                 1997 
                   
                 activation of viral infection. 
               
               
                 5,612,349 
                 Mar. 18, 
                 Enantiomerically pure 
                 There is disclosed compounds and pharmaceutical compositions that are a resolved R or 
               
               
                   
                 1997 
                 hydroxylated xanthine 
                 S (preferably R) enantiomer of an omega -1alcohol of a straight chain alkyl (C[5-8]) 
               
               
                   
                   
                 compounds to treat shock 
                 substituted at the 1-position of 3,7-disubstituted xanthine. The inventive compounds are 
               
               
                   
                   
                 symptoms 
                 effective in modulating cellular response to external or in situ primary stimuli, as welI as to 
               
               
                   
                   
                   
                 specific modes of administration of such compounds in effective amounts. 
               
               
                 5,610,279 
                 Mar. 11, 
                 Human TNF receptor 
                 The present invention is concerned with non-soluble proteins and soluble or insoluble 
               
               
                   
                 1997 
                   
                 fragments thereof, which bind TNF, in homogeneous form, as welI as their physiologically 
               
               
                   
                   
                   
                 compatible salts, especially those proteins having a molecular weight of about 55 or 75 kD 
               
               
                   
                   
                   
                 (non-reducing SDS-PAGE conditions), a process for the isolation of such proteins, 
               
               
                   
                   
                   
                 antibodies against such proteins, DNA sequences which code for non-soluble proteins and 
               
               
                   
                   
                   
                 soiuble or non-soluble fragments thereof, which bind TNF, as well as those which code for 
               
               
                   
                   
                   
                 proteins comprising partly of a soluble fragment, which binds TNF, and partly of all 
               
               
                   
                   
                   
                 domains except the first of the constant region of the heavy chain of human 
               
               
                   
                   
                   
                 immunoglobulins and the recombinant proteins coded thereby as weIl as a process for their 
               
               
                   
                   
                   
                 manufacture using transformed pro- and eukaryotic host cells. 
               
               
                 5,606,023 
                 Feb. 25, 
                 Mutant tumor necrosis 
                 Mutant tumor necrosis factor proteins which retain full or near full capability to bind to a 
               
               
                   
                 1997 
                 factor proteins 
                 TNFR-p75 receptor while retaining only a limited capability to bind a TNFR-p55 receptor 
               
               
                   
                   
                   
                 are provided. Methods of inhibiting toxicity induced by tumor necrosis factor by treating 
               
               
                   
                   
                   
                 cells or tissues having a tumor necrosis factor receptor with these mutant human tumor 
               
               
                   
                   
                   
                 necrosis factor proteins are also provided. Pharmaceutical compositions and methods of  
               
               
                   
                   
                   
                 inhibiting systemic tumor necrosis factor induced toxicity in a p atient undergoing antitumor 
               
               
                   
                   
                   
                 TNF- alpha therapy with these compositions are also provided. 
               
               
                 5,605,923 
                 Feb. 25, 
                 Compounds useful for 
                 Novel cyclohexene-ylidene derivatives of formula (I) are described herein. These 
               
               
                   
                 1997 
                 treating inflammatory 
                 compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment 
               
               
                   
                   
                 diseases and inhibiting 
                 of disease states mediated or exacerbated by TNF production; they are also useful in the 
               
               
                   
                   
                 production of tumor 
                 mediation or inhibition of enzymatic or catalylic activity of phosphodiesterase IV and are 
               
               
                   
                   
                 necrosis factor 
                 therefore useful in the treatment of disease states in need of mediation or inhibition thereof. 
               
               
                   
                   
                   
                 [See Original Patent for Chemical Structure Diagram] (I) 
               
               
                 5,605,914 
                 Feb. 25, 
                 Imides 
                 Cyclic imides are inhibitors of tumor necrosis factor alpha and can be used to combat 
               
               
                   
                 1997 
                   
                 cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is 2-(2,6-dioxo- 
               
               
                   
                   
                   
                 3-piperidinyl)-4-azalsoindoline-1,3-dione. 
               
               
                 5,605,826 
                 Feb. 25, 
                 24 kilodalton cyloplasmic 
                 An apoptosis-associated protease having a relative mass of 24 kilodaltons and a defined 
               
               
                   
                 1997 
                 protease activating DNA 
                 amino acid composition is disclosed, togetherwith a method for its purification from a 
               
               
                   
                   
                 fragmentation in apoptosis 
                 cyloplasmic extract of mammalian cells treated with an apoptosis-inducing agent, such as 
               
               
                   
                   
                   
                 tumor necrosis factor- alpha or UV irradiation, that comprises affinity chromatography with 
               
               
                   
                   
                   
                 the serine protease inhibitor DK120 followed by heparin-sepharose chromatography. The 
               
               
                   
                   
                   
                 protease has activity against the elastase-like substrate MAAPV and is capable of inducing 
               
               
                   
                   
                   
                 apoptosis in isolated U937 cell target nuclei. 
               
               
                 5,605,690 
                 Feb. 25, 
                 Methods of lowering active 
                 A method for treating TNF-dependent inflammatory diseases in a mammal by 
               
               
                   
                 1997 
                 TNF- alpha levels in 
                 administering a TNF antagonist, such as soluble TNFR. 
               
               
                   
                   
                 mammals using tumor 
               
               
                   
                   
                 necrosis factor receptor 
               
               
                 5,602,173 
                 Feb. 11, 
                 Compounds useful for 
                 Novel cyclohexane-ylidene derivatives of formula (I) are described. These compounds 
               
               
                   
                 1997 
                 treating allergic and 
                 inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease 
               
               
                   
                   
                 inflammatory diseases 
                 states mediated or exacerbated by TNF production. These compounds are also useful in 
               
               
                   
                   
                   
                 the mediation or inhibition of enzymatic or catalylic activity of phosphodiesterase IV and 
               
               
                   
                   
                   
                 are therefore useful in the treatment of disease states in need of mediation or inhibition 
               
               
                   
                   
                   
                 thereof. [See Original Patent for Chemical Structure Diagram] (I) 
               
               
                 5,602,166 
                 Feb. 11, 
                 Cytokine inhibitors 
                 Invented are methods of inhibiting the production of cytokines, particularly inhibiting the 
               
               
                   
                 1997 
                   
                 production of interleukin-1 and inhibiting the production of tumor necrosis factor in a 
               
               
                   
                   
                   
                 mammal in need thereof which comprises administering to such mammal an effective 
               
               
                   
                   
                   
                 amount of an azaspirane derivative. 
               
               
                 5,602,157 
                 Feb. 11, 
                 Compounds useful for 
                 Novel compounds or formula (I) are described herein. These compounds inhibit the 
               
               
                   
                 1997 
                 treating allergic and 
                 production of Tumor Necrosis Factor and are useful in the treatment of disease states 
               
               
                   
                   
                 inflammatory diseases 
                 mediated or exacerbated by TNF production. The compounds or the present invention are 
               
               
                   
                   
                   
                 also useful in the mediation or inhibition of enzymatic or catalytic activity of 
               
               
                   
                   
                   
                 phosphodiesterase IV and are therefore useful in the treatment of disease states in need of  
               
               
                   
                   
                   
                 mediation or inhibition therefore. [See Original Patent for Chemical Structure Diagram] (I) 
               
               
                 5,597,899 
                 Jan. 28, 
                 Tumor necrosis factor 
                 Human TNF muteins having higher binding affinity for human p75-TNF receptor than for 
               
               
                   
                 1997 
                 muteins 
                 human p55-TNF receptor indude muteins having at least one different amino acid relative 
               
               
                   
                   
                   
                 to wild-type human TNF at a position corresponding to position 33, 65, 67, 75, 87, 143, 145 
               
               
                   
                   
                   
                 or 147 of the wild-type amino acid sequence. 
               
               
                 5,594,106 
                 Jan. 14, 
                 Inhibitors of TNF- alpha 
                 Compounds and methods are disclosed that are useful in inhibiting the TNF- alpha 
               
               
                   
                 1997 
                 secretion 
                 converting enzyme (TACE) responsible for cleavage of TNF- alpha precursor to provide 
               
               
                   
                   
                   
                 biologically active TNF- alpha. The compounds employed in the invention are peptidyl 
               
               
                   
                   
                   
                 derivatives having active groups capable of inhibiting TACE such as, hydroxamates, thiols, 
               
               
                   
                   
                   
                 phosphoryls and carboxyls. 
               
               
                 5,593,992 
                 Jan. 14, 
                 Compounds 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1997 
                   
                 cytokine inhibitors. 
               
               
                 5,593,991 
                 Jan. 14, 
                 Imidazole compounds, use 
                 Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as 
               
               
                   
                 1997 
                 and process of making 
                 cytokine inhibitors. 
               
               
                   
               
             
          
         
       
     
     Throughout the present specification, reference has been made to various patent and non-patent publications, including the patents listed in Table 2. The entire disclosure of each such reference is incorporated herein by reference. The disclosure of U.S. patent application Ser. No. 60/084,668, filed on May 7, 1998, is also incorporated herein by reference. 
     Although the invention has been described with reference to the presently preferred embodiment, it should be understood that various modifications will become apparent to those of skill in the art upon review of the present disclosure. Such modifications are intended to be within the scope of the present invention.