bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth factors in the aqueous humor and their therapeutic implications in glaucoma and anterior segment disorders of the human eye
Authors: Tripathi Ramesh C. , Borisuth Navaneet S. C. , Tripathi Brenda J. 
Published: January 2005

AbstractThe presence of growth‐promoting substances in the aqueous humor has been suspected for the past decade, but it has been only during the last 2 years that the existence of growth factors such as basic fibroblast growth factor, epidermal growth factor, transforming growth factorp, transferrin, and insulin‐like growth factors in the aqueous humor has been demonstrated. The structures that border the anterior and posterior chambers of the eye syn‐ thesize some of these growth factors and release them into the aqueous humor. A breakdown of the blood‐aqueous‐barrier increases the amounts of growth factors and may also bring platelet‐derived growth factor, nerve growth factor, and interleukin‐6 into the aqueous humor. Growth factors maintain the normal function of ocular tissues in health and have a significant role in the pathogenesis and possible management of several disorders of the eye. The outcome of the pathogenetic process and its modulation are determined by a complex coordination and interactions of the growth factors in the aqueous humor and their eventual effect on the target tissues. We discuss the therapeutic implications of growth factors and their antagonists in the treatment of certain disorders of the anterior segment of the eye, including rubeosis iridis, neovascular glaucoma, primary open‐angle glaucoma, sand wound after filtration Surgery.
Topical capsaicin in the treatment of cutaneous disorders
Authors: Carter Richard B. 
Published: January 2005

AbstractCapsaicin, the primary pungent principle in hot peppers, produces marked alterations in the function of unmyelinated sensory afferent fibers, which are believed to signal pain and to initiate inflammatory responses. Capsaicin first excites and then desensitizes these nerves to subsequent stimulation both by itself and by a variety of physiocochemical stimuli. Accordingly, capsaicin is finding increasing use as a topical therapy for a variety of cutaneous disorders that involve pain and inflammation. Although topical capsaicin has shown therapeutic potential, the utility of capsaicin appears to be limited at present primarily by its irritant properties and secondarily by less than optimal therapeutic response, perhaps resulting from insufficient drug delivery. A capsaicin analogue with diminished irritant properties that retained the critical pharmacologic activities might present a reasonable alternative.
Gastric antisecretory activity of an acid stable H+/K+ ATPase inhibitor, WY‐26,769
Authors: DiJoseph John F. , Palumbo George J. , Crossley Roger , Santilli Arthur A. , Nielsen Susan T. 
Published: January 2005

AbstractWY‐26,769 (2‐3‐dihydro‐2‐(2‐pyridinyl) thiazolo‐[3,2‐a]benzimidazole) is a gastric antisecretory agent that acts by inhibiting the parietal cell proton pump. In vitro, WY‐26,769 was active against dbcAMP‐stimulated aminopyrine uptake in isolated parietal cells. Preincubating the drug with liver microsomal enzymes increased its potency 50 times, to an IC50 of 6.8 μM. Wy‐26,769 and its oxidative metabolite Wy‐26,876 each inhibited the H+/K+ ATPase (IC50 = 42 μM and 18 μM, respectively). In whole animal studies, Wy‐26,769 inhibited histaminestimulated gastric acid secretion (ID50 = 3 mg/kg) irrespective of whether Wy‐26,769 was administered orally or intravenously. Wy‐26,769 was not degraded in acid and also inhibited gastric acid secretion in the pylorus‐ligated rat. Wy‐26,769 was equiactive after oral or intravenous administration demonstrating that it is an acid stable proton pump inhibitor.
Biochemical, neurophysiological, and behavioral effects of Wy‐45,233 and other identified metabolites of the antidepressant venlafaxine
Authors: Muth Eric A. , Moyer John A. , Haskins J. Thomas , Andree Terrance H. , Husbands G. E. Morris 
Published: January 2005

AbstractSeven metabolites of venlafaxine, identified in several species, were examined for CNS pharmacological activity in rodents. The O‐desmethyl compound Wy‐45,233, which is the major metabolite in man, had the greatest preclinical activity. This metabolite exhibited an antidepressant profile (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal β‐adrenergic subsensitivity) comparable to the parent drug, venlafaxine. This compound also inhibited serotonergic and noradrenergic firing rates like the parent compound, but with less potency. The cyclohexyl ring‐hydroxylated metabolite Wy‐47,877 and the N‐desmethyl metabolite Wy‐45, 494 were also active in reserpine hypothermia, but Wy‐45,494 was a weaker inhibitor of serotonin uptake and both metabolites were weaker inhibitors of norepinephrine uptake than Wy‐45,233. None of the seven metabolites tested exhibited significated binding at dopamine‐2, muscarinic cholinergic, α‐1‐adrenergic, histamine‐1, or opiate (μ) receptors. These results suggest that Wy‐45,233, the O‐desmethyl metabolite of venlafaxine, is an active metabolite which retains the benign side‐effect profile of venlafaxine.
Preclinical anxiolytic versus antipsychotic profiles of the 5‐HT3 antagonists ondansetron, zacopride, 3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester, and 1αH, 3α, 5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate
Authors: Dunn Robert W. , Carlezon William A. , Corbett Roy 
Published: January 2005

AbstractIn preclinical studies, the behavioral effects of serotonin antagonists at 5‐HT3 receptor sites suggest potential efficacy in the treatment of anxiety and schizophrenia. The present study shows that 5‐HT3 antagonists were effective in disinhibiting behavior in non‐conditioned rodent models which elicit a behavioral state presumed to be analogous to anxiety, but were generally not effective in conditioned rodent anxiety models or in assays that are traditionally predictive of antipsychotic agents. Ondansetron (0.01–0.1 mg/kg), zacopride (0.1–1.0 mg/kg), ICS 205–930 (3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester; 0.5 and 1.0 mg/kg), and MDL 72222 (1αH, 3α, 5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate; 10.0 and 20.0 mg/kg) demonstrated anxiolytic effects in the social interaction and elevated plus maze procedures, while having little or no effect in a modified Cook and Davidson conflict procedure. Ondansetron, zacopride, and ICS 205–930 had no effect in neuroleptic screening procedures, such as the apomorphine climbing mouse assay (CMA), the pole climb avoidance (PCA) procedure, and the intracranial self‐stimulation of the medial forebrain bundle (ICSS‐MFB) assay. MDL 72222 had no effect on CMA but dose‐dependently antagonized PCA (ED50 = 10.9 mg/kg) and ICSS‐MFB (ED50 = 8.8 mg/kg). The results of the present study suggest that MDL 72222 possesses a profile of activity that is different from the other 5‐HT3 antagonists tested and that, in general, 5‐HT3 antagonists may prove to be efficacious in the treatment of certain forms of anxiety in man.
Long‐term follow‐up treatment with sabeluzole in elderly patients with pronounced memory problems of unknown origin
Authors: Clincke Gilbert , Tritsmans Luc , Peelmans Boudewijn 
Published: January 2005

AbstractIn an open follow‐up study, 31 elderly patients with real memory problems of unknown origin were treated for at least 10 months with sabeluzole 10 mg b.i.d. Not only were the same improvements seen as in the preceding double‐blind trial on the cued recall task (CRT) and the word fluency test (WF), but additionally, significantly better results were obtained for the selective reminding procedure after this long‐term treatment: all quantitative (total recall, long‐term storage [LTS], long‐term retrieval [LTR], consistent long‐term retrieval [cLTR]) and qualitative (LTR/total recall, cLTR/total recall) parameters improved in this task. The objective effects were again accompanied by a subjective improvement as reported by the patients and their physician.
U‐80816: A novel partial muscarinic agonist
Authors: Sethy Vimala H. , Francis Jonathan W. , Hyslop Deborah K. , Patrick Sage G. , Oien Timothy T. , Meyer Annette L. , Collins R. James , Russell Roland R. , Heier Richard F. , Hoffmann William E. , Piercey Montford F. , Nichols Nanette F. , Schreur Peggy J. D. , Moon Malcolm W. 
Published: January 2005

AbstractU‐80816 (1‐(4‐(5‐methyl‐1H‐imidazol‐1‐yl)‐2‐butynyl)‐2‐pyrrolidinone is an acetylenic amine which has been investigated as a partial agonist of muscarinic receptors. In vitro U‐80816 inhibited binding of (3H)‐N‐methylscopolamine [(3H)‐NMS] and (methyl‐3H) oxotremorine‐M acetate [3H)‐Oxo‐M] to the cortical membrance preparation with Ki's of 75 and 3.24 nM, respectively. In the M1 cell line, U‐80816 increased phosphatidylinositol (Pl) hydrolysis. However, the maximum increase in the Pl hydrolysis was significantly (P < 0.01) less than oxotremorine and RS 86. Intraperitoneal administration of U‐80816 dose‐dependently increased striatal acetylcholine (ACh) concentration, and the effect was significant (P < 0.01) at 30 mg/kg. In the presence of hemicholinium‐3 (HC‐3), U‐80816 inhibited the release of (3H)‐ACh from hippocampal slices. On the other hand, in the presence of eserine, U‐80816 increased the release of (3H)‐ACh. In in vivo pharmacological tests, U‐80816 produced hypothermia and tremors in mice. This compound failed to produce lacrimation or salivation in mice when administered up to 100 mg/kg. U‐80816 antagonized oxotremorine‐induced salivation. It is bioavailable to the brain in a significant amount after oral administration and has a sufficiently long duration of action. The in vitro and in vivo pharmacological investigations indicate that U‐80816 is a partial agonist of muscarinic receptors.
Ritanserin, a new therapeutic approach for drug abuse. Part 1: Effects on alcohol
Authors: Meert Theo F. , Janssen Paul A. J. 
Published: January 2005

AbstractAfter a period of forced exposure to alcohol, rats developed a preference for alcohol when given the choice to drink either an alcohol solution or water. The development of alcohol preference was dependent on the alcohol concentration but independent of the presence of an alcohol withdrawal phase. The highest alcohol consumption was found with a 3% solution. The serotonin 5‐HT2 antagonist ritanserin reduced alcohol intake and alcohol preference in a dose‐related manner. Changes in test procedures and injection schedules did not affect the effectiveness of ritanserin. The activity of ritanserin started at doses ≥0.04 mg/kg and in the active dose range ritanserin reduced alcohol intake by 46 to 67% and alcohol preference by 33 to 42%. At any time during treatment, the decrease in alcohol drinking was compensated by an increase in water consumption. As a consequence, total fluid intake remained constant. Body weight gain in ritanserin‐treated rats was not different from vehicle‐treated animals. Discontinuation of ritanserin treatment in animals with a very low alcohol intake during ritanserin treatment resulted within one week in a gradual increase in 3% alcohol solution drinking up to 50% of total intake. In rats with a high alcohol preference ritanserin initiated water drinking again. Additional experiments showed that ritanserin neither directly interacted with the discriminative stimulus properties of alcohol nor induced a direct alcohol aversion. The activity of ritanserin against alcohol is discussed in terms of a serotonin 5‐HT2 antagonism that reduces the need for alcohol after a chronic exposure to alcohol.
Binding and uptake studies with [3H]CP‐93, 129, a radiolabeled selective 5‐HT1B receptor ligand
Authors: Koe B. Kenneth , Lebel Lorraine A. , Fox Carol B. , Macor John E. 
Published: January 2005

Abstract3‐(1,2,5,6‐Tetrahydro‐4‐pyridyl)‐5‐pyrrolo[3,2‐b]pyridone, CP‐93, 129, is a selective agonist ligand for 5‐HT1B receptors. High affinity binding sites of [3H]CP‐93, 129 were found in rat whole brain membranes, which showed KD and Bmax values similar to those for 5‐HT1B sites labeled by [3H]5‐HT. Uptake of [3H]CP‐93, 129 in crude rat synaptosomes was also observed, which was potently inhibited by 5‐HT uptake blockers and 5‐HT but not by desipramine (NE uptake blocker) or tametraline (NE and DA uptake blocker). Because of this sensitivity to 5‐HT uptake inhibitors and the structural similarity of CP‐93, 129 to serotonin, [3H]CP‐93, 129 uptake probably occurred in 5‐HT neurons.
Ganglioside modulation of CD4 does not block T‐helper cell function as compared to antagonism by anti‐CD4 antibody
Authors: Morrison William J. , Offner Halina , Vandenbark Arthur A. 
Published: January 2005

AbstractGangliosides (GM1) modulate CD4 from the surface of T‐helper lymphocytes and have been shown to block CD4‐mediated HIV‐1 infection in vitro. However, the effects of GM1 on CD4 are neutralized in the presence of serum. We sought to make a GM1 derivative which would resist serum neutralization and to determine whether modulation of CD4 by GM1 would affect T‐helper lymphocyte function. Study of GM1 and GM1‐derivatives in the presence of serum indicated that the active conformation involves intact sialic acid hydroxyl groups and intermolecular ganglioside interactions. All chemical modifications directed toward the sialic acid moiety reduced the ability of GM1 to modulate CD4. Elution profiles of GM1 in the presence and absence of albumin indicate that the active form of GM1 is represented by micelles that are disrupted by albumin. Function studies show that CD4 T‐helper cells made CD− by GM1 treatment continued to proliferate in culture and recognize antigen (Ag) through the T cell receptor (TcR). Moreover, T‐helper cell mediated inflammation assessed by Ag‐specific, delayed type hypersensitivity (DTH) was enhanced after passive transfer of GMl‐treated T‐helper cells to naive animals. In comparison, CD4 blockade by anti‐CD4 antibody decreased Ag‐stimulated T‐helper cell proliferation and DTH reactions. These results demonstrate that (1) CD4 modulation involves an active conformation that arises from sialic acid effector molecules organized by micellar GM1 conformations; and (2) the mechanism by which GM1 modulates CD4 is different from CD4 antagonism seen with anti‐CD4 antibody treatment. © 1992 Wiley‐Liss, Inc.
Ethopharmacological studies differentiate the effects of various serotonergic compounds on aggression in rats
Authors: Mos J. , Olivier B. , Tulp M. T. H. M. 
Published: January 2005

AbstractA series of experiments was performed to investigate the effects on aggression of various drugs affecting serotonergic transmission in rats. Using ethologically derived behavioural categories, the behaviour of treated animals was described. Drug effects were observed in two aggression models: resident–intruder aggression (RI) in male rats, and maternal aggression in lactating females during the postpartum period (MA). The 5‐HT1A agonists, buspirone, iosapirone, and 8‐OH‐DPAT, decreased aggression in RI and MA but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific anti‐aggressive profile. Nonselective 5‐HT agonists, such as RU 24969, eltoprazine (DU 28853), and TEMPP, reduced aggression quite specifically and did not decrease social interest or exploration, but sometimes even increased these behaviours. In RI and MA, the behavioural effects of these drugs were roughly similar. By contrast, MA was more sensitive to the treatment with the 5‐HT reuptake blocker fluvoxamine, which blocked RI aggression only nonspecifically at the highest dose. DOI, a 5‐HT2 and 5‐HT1C agonist, decreased aggressive behaviour and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by “wet dog shaking,” characteristic of 5‐HT2‐receptor stimulation. The nonspecific 5‐HT agonist (and 5‐HT3 antagonist) quipazine also induced “wet dog shaking” at doses that suppressed aggression, social interest and exploration but increased inactive behaviours (sitting and lying). The discussion attempts to delineate a role for 5‐HT receptor subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs stressing the consistent role of 5‐HT in different forms of aggression. © 1992 wiley‐Liss, Inc.
Endothelin mechanisms in the central nervous system: A target for drug development
Authors: Gulati Anil , Srimal Rikhab C. 
Published: January 2005

AbstractEndothelin (ET), a vasoconstrictor peptide, was isolated and characterized in 1988. Since then extensive studies have been done in different animal species to identify its receptors in central nervous system (CNS) and peripheral tissues. Three forms of ETs have been identified: ET‐1, ET‐2, and ET‐3. Their distribution pattern and pharmacological functions have been defined. ET‐1 and ET‐2 are mainly distributed in the CNS, including spinal cord and the peripheral tissues, while ET‐3 although present in other tissues is mainly concentrated in the pituitary. ET receptors have been found to be coupled to intracellular pathways involving stimulation of Ca++ fluxes, through phospholipase C and inhibition of adenyl cyclase. The literature concerning central actions of ET has been reviewed. The bulk of the evidence shows that it may be a regulator of regional cerebral blood flow, and a modulator of the release of posterior pituitary hormones (oxytocin and vasopressin). It may also regulate the release of prolactin, growth, thyroid stimulating, or luteinizing hormones. The regulatory role of ET on cardiovascular system can be exerted by central as well as peripheral actions. Besides direct regulation, ET modulates the release of endothelium derived relaxing factor/nitric oxide (EDRF/NO) and increases the sensitivity of peripheral α‐adreno‐ceptors. Thus ET appears to establish a balance between vasodilatation induced by EDRF/NO release and vasoconstriction due to increased sensitivity of vascular a‐adrenoceptors. The level of ET was found to be raised in several pathological conditions like subarachnoid hemorrhage, myocardial infarction, cardiogenic and septic shock, Raynaud's disease, and pulmonary hypertension. Its level was also raised in patients undergoing chronic hemodialysis. On the other hand, the level of ET was significantly lower in the cerebrospinal fluid (CSF) of patients of depression. The available data suggest that ET has a neuromodulatory role in the CNS and may be involved in the pathophysiological processes of several diseases. ET mechanisms in the CNS could provide potential targets for the development of newer drugs. © 1992 Wiley‐Liss, Inc.
Effects of serotonergic agonists on micturition and sexual function in the rat
Authors: Steers William D. , Albo Michael , van Asselt Els 
Published: January 2005

AbstractBehavioral and electrophysiological methods were used to study the role of 5‐hydroxytryptamine (5‐HT) receptors on bladder and erectile function in the male rat. Postulated 5‐HT1A [p‐aminophenylethyl‐m‐trifluoromethylphenylpiperazine (PAPP), 5‐methoxydimethyltyramine (5‐MeODMT)] and 5‐HT1C/2 [MK212, m‐trifluoromethylphenylpiperazine (TFMPP)] agonists did not consistently alter sensitivity voiding frequency (VF) in awake rats or affect micturition threshold (0.4 vs. 0.3 cc) in anesthetized rats. The 5‐HT1B agonist Organon 6997 (ORG 6997) had no effect on pelvic nerve‐induced detrusor contraction or evoked responses in bladder nerves. 5‐HT1C/2 agonists abolished reflexly evoked bladder contractions by inhibiting efferent firing in the pelvic nerve. 5‐HT1C/2 agonists also produced penile erections (2–5/30 min) via firing in cavernous nerves mediated by preganglionics in the pelvic nerve. Neural activity in the cavernous nerves following administration of MK212 and TFMPP was abolished by the 5‐HT1C/2 antagonist mianserin. 5‐HT1A, 5‐HT1B, 5‐HT1C/2 agonists failed to influence synaptic transmission in the pelvic ganglion. These data support a functional diversity of 5‐HT receptor subtypes with selective excitation or inhibition of central autonomic pathways regulating pelvic visceral function. These observations suggest that 5‐HT1C/2 agonists could be clinically useful for managing impotence or urinary incontinence. © 1992 Wiley‐Liss, Inc.
Role of GABA during the multiple consolidation of memory
Authors: Brioni Jorge D. 
Published: January 2005

AbstractAlzheimer's disease (AD) is the most common form of senile dementia and it is a neurodegenerative disorder associated with a progressive deterioration of memory and cognitive capacity. Although one of the most characteristic abnormalities in AD patients is the reduced cholinergic input to the cortex, AD is a disorder that affects different neuronal populations in the brain, including the GABAergic neurons. The data regarding the participation of the central GABAergic system on memory indicate that: (1) drugs that facilitate GABA‐A and GABA‐B neurotransmission impair memory in experimental animals and in humans; (2) drugs that reduce GABA‐A neurotransmission facilitate memory in rodents; (3) the facilitatory effect of thee drugs has not been corroborated at the clinical level, as they show a small therapeutic window, but new drugs are presently being evaluated in clinical studies; (4) the cognitive effects of the GABAergic agents are dose‐ and time‐related, and cannot be explained by state‐dependency; (5) the effects of the GABAergic antagonists are centrally mediated, as peripherally acting drugs are ineffective in memory tests; (6) GABA and endogenous benzodiazepines are released in different brain areas during learning of different tasks and after the induction of long‐term potentiation (LTP); (7) GABA‐A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices; and (8) the amygdala, the basal forebrain, the septo‐hippocampal pathway, the trisynaptic circuit and the entorhinal cortex are likely candidate regions for the central actions of GABAergic drugs. The consolidation process of memory storage can be presently envisioned as multiple consolidation process that takes place in different brain circuits and at different times after the learning experience. The anatomical evidence on the presence of GABAergic neurons in brain areas relevant to memory (and affected in Alzheimer's patients) like the cortex, amygdala, septum, hippocampus and NBM, together with the electrophysiological and biochemical changes induced by the learning experience, suggest that the GABAergic neurons can critically modulate the electrical activity of these brain areas during the “multiple consolidation” process of memory storage. © 1993 Wiley‐Liss, Inc. © 1993 Wiley‐Liss, Inc.