bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous iron in a primary‐care clinic
Authors: Maslovsky I.
Published: March 2005

The preferable route of iron delivery for most iron‐deficient patients is oral. Parenteral iron therapy is used in patients who cannot tolerate oral iron or in cases in which oral iron is not sufficiently effective. The most frequent indications for parenteral iron therapy are unbearable gastrointestinal side effects induced by oral iron itself, worsening of inflammatory bowel disease symptoms, insufficient intestinal absorption, renal failure‐caused anemia that is treated with erythropoietin, and unresolved ongoing bleeding, which would cause the acceptable oral doses of iron therapy to be exceeded. The serious adverse effects of iron dextran that was used in the past could explain the reluctance of medical personnel to prescribe this effective treatment. Patients with iron deficiency anemia were treated with intravenous iron in a primary care clinic. The iron gluconate was given in a dosage of 62.5 mg diluted in 150 mL of normal saline and was infused intravenously over 30 min, while iron sucrose was given in a dosage of 100 mg diluted in the same volume of normal saline and given at the same rate. In total, 724 infusions were administered to 57 patients. Iron sucrose was used in 628 infusions, and iron gluconate was used in the remaining 96. The frequency of the infusion treatments depended on the underlying disease and ranged from three times a week to once a month. Adverse effects were seldom observed and were minor in patients receiving iron gluconate, and were not registered at all in patients treated with iron sucrose. Two cases of flushing with paresthesias occurred. Slowing the infusion rate successfully eliminated these side effects. One case of hypotension was treated successfully with 500 cc of normal saline infusion. One case of dropout occurred, due to the patient's refusal to cooperate. No anaphylactic reactions were observed. Iron gluconate and iron sucrose are effective and safe for use in primary care clinics. The risk of adverse effects is low. Am. J. Hematol. 78:261–264, 2005. © 2005 Wiley‐Liss, Inc.
Primary plasma cell leukemia: Report of 17 new cases treated with autologous or allogeneic stem‐cell transplantation and review of the literature
Authors: Saccaro Steven , Fonseca Rafael , Veillon Diana M. , Cotelingam James , Nordberg Mary L. , Bredeson Christopher , Glass Jonathan , Munker Reinhold
Published: March 2005

Primary plasma cell leukemia (PPCL) is a rare hematologic malignancy characterized by the proliferation of plasma cells in blood, bone marrow, and other organs in the absence of established multiple myeloma. PPCL has a poor prognosis when treated with conventional therapy for multiple myeloma. We describe here 17 new cases of PPCL who underwent stem‐cell transplantation (SCT) (2 cases observed by the authors and 15 cases from the International Bone Marrow Transplant Registry [IBMTR]). The first case was diagnosed in a 21‐year‐old male who presented with leukocytosis and acute renal failure. He was treated with hyper‐CVAD, entered complete remission, and then proceeded to high‐dose chemotherapy with peripheral stem‐cell support. He is currently in complete remission 23 months after initial diagnosis and 19 months after autologous SCT. The second case was observed in a 31‐year‐old male who presented with leukocytosis and hepatic infiltration with plasma cells. He was treated with VAD chemotherapy and underwent allogeneic bone marrow transplantation from his HLA‐identical sister. He remained in complete remission for 3 years and then developed progressive refractory disease, dying 7 years after the initial diagnosis. In addition to these 2 cases, 15 further unpublished cases of PPCL from the IBMTR are reported here (treated between 1993 and 2001, 6 by autologous and 9 by allogeneic transplantation). Finally, the features of PPCL, the outcome, published data of SCT for PPCL, and indications for treatment are discussed. Am. J. Hematol. 78:288–294, 2005. © 2005 Wiley‐Liss, Inc.
Acute leukemia associated with valproic acid treatment: A novel mechanism for leukemogenesis?
Authors: Coyle Thomas E. , Bair Alicia K. , Stein Constance , Vajpayee Neerja , Mehdi Syed , Wright Jonathan
Published: March 2005

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia‐like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase. Am. J. Hematol. 78:256–260, 2005. © 2005 Wiley‐Liss, Inc.
Prognostic factors of chronic graft‐versus‐host disease after allogeneic blood stem‐cell transplantation
Authors: Pavletic Steven Z. , Smith Lynette M. , Bishop Michael R. , Lynch James C. , Tarantolo Stefano R. , Vose Julie M. , Bierman Philip J. , Hadi Abdul , Armitage James O. , Kessinger Anne
Published: March 2005

Allogeneic hematopoietic stem cells in peripheral blood transplantation (alloPBSCT) or bone marrow transplantation (alloBMT) have different biological characteristics which may affect differently prognostic factors for incidence and severity of chronic graft‐versus‐host disease (cGVHD). To determine the prognostic factors of cGVHD in patients receiving alloPBSCT, data on 87 patients who survived at least 100 days after matched related donor myeloablative transplantation were analyzed. Factors significantly associated with higher incidence of cGVHD after alloPBSCT included CMV‐positive donor, acute skin GVHD, and diagnoses other than lymphoma. Factors predictive for poor survival following cGVHD diagnosis included platelet count < 100,000/mm3 and history of acute liver GVHD. Acute liver GVHD and etoposide in the preparative regimen significantly increased risk of death due to cGVHD after alloPBSCT. All alloPBSCT multivariate models were fit to an independent cohort of comparable matched related donor alloBMT patients (n = 75). After alloBMT, only acute skin GVHD and diagnoses other than lymphoma retained prognostic significance for predicting cGVHD. Low platelet count was the only variable predictive for poor survival in cGVHD patients after alloBMT. Acute liver GVHD was the only factor that retained prognostic significance for risk of death due to cGVHD after alloBMT. These data suggest there are some cGVHD prognostic factors that may be unique to recipients of alloPBSCT. More studies are needed to determine whether cGVHD prognostic systems should be used interchangeably in patient populations receiving different stem‐cell products. Am. J. Hematol. 78:265–274, 2005. © 2005 Wiley‐Liss, Inc.
Successful treatment of Diamond‐Blackfan anemia with metoclopramide
Authors: Akiyama Masaharu , Yanagisawa Takaaki , Yuza Yuki , Yokoi Kentaro , Ariga Masamichi , Fujisawa Kohji , Hoshi Yasutaka , Eto Yoshikatsu
Published: March 2005

Diamond‐Blackfan anemia (DBA) is a congenital anemia characterized by a low reticulocyte count, the absence or severe reduction of hemoglobin‐containing cells in the bone marrow, and normal megakaryocytic and granulocytic differentiation. Although the anemia may initially respond to corticosteroid therapy, many patients require lifelong red blood cell (RBC) transfusion, leading to infectious complications and iron overload. Metoclopramide has recently been used to treat DBA. Treatment with metoclopramide induces the release of prolactin from the pituitary and stimulates erythropoiesis. For these reasons, we used metoclopramide to treat a 20‐year‐old man with DBA refractory to low and high doses of corticosteroids, cyclosporin A, and tacrolimus (FK506). The hemoglobin and hematocrit slowly increased, and he has remained asymptomatic and transfusion‐independent for 8 months. Metoclopramide therapy should be considered in patients with refractory DBA before treatment‐related complications develop. Am. J. Hematol. 78:295–298, 2005. © 2005 Wiley‐Liss, Inc.
T‐cell large granular lymphocytic leukemia and hereditary hemochromatosis: A fortuitous association?
Authors: Gaur S. , Mansoor S. , Aish L.
Published: March 2005

We describe a patient with hereditary hemochromatosis (homozygous for C282Y mutation) and neutropenia who was found to have underlying T‐cell large granular lymphocytic (T‐LGL) leukemia. The diagnosis was confirmed by demonstrating T‐cell receptor (TCR) gene rearrangement by polymerase chain reaction (PCR). Multiple quantitative and qualitative defects have been described for the T cells of patients with hemochromatosis. Although the association between the two may be fortuitous, this case report raises the possibility that the T cells in these patients may be susceptible to leukemic transformation as well. Am. J. Hematol. 78:299–301, 2005. © 2005 Wiley‐Liss, Inc.
Ubiquitination of red blood cell α‐spectrin does not affect heterodimer formation
Authors: Riahi Mahnoush H. , Kakhniashvili David G. , Goodman Steven R.
Published: March 2005

Erythrocyte α‐spectrin is ubiquitinated in repeats α20/α21, which also represents the nucleation site for contact with the β subunit which leads to heterodimer formation by a zippering mechanism. In this study we have determined the second‐order rate constant for association of ubiquitinated α′‐spectrin, nonubiquitinated α‐spectrin, and β‐spectrin into the α′β or αβ heterodimer. The rate constant for incorporation of monomers into heterodimers at 37°C were (5.181 ± 0.001) × 105 M−1 sec−1 for total α‐spectrin (α + α′), (5.121 ± 0.001) × 105 M−1 sec−1 for α′‐spectrin, and (5.178 ± 0.003) × 105 M−1 sec−1 for β‐spectrin. We conclude that ubiquitination of α‐spectrin does not regulate heterodimer formation. Am. J. Hematol. 78:281–287, 2005. © 2005 Wiley‐Liss, Inc.
Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena
Authors: Ocio Enrique M. , Sanchez‐Guijo Fermin M. , Diez‐Campelo Maria , Castilla Cristina , Blanco Oscar J. , Caballero Dolores , San Miguel Jesus F.
Published: March 2005

Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder for which the best therapeutic option is not yet well established. Immune‐related disorders are rare complications of MCD. We report on an MCD case in a 23‐year‐old patient with extensive abdominal involvement and associated immune hemolytic anemia and Raynaud phenomenon. He was negative for human immunodeficiency virus (HIV) and human herpesvirus‐8 (HHV‐8). After 8 courses of the anti‐CD20 monoclonal antibody (rituximab), the patient achieved complete remission. Interestingly, Raynaud phenomenon disappeared under treatment and no new hemolytic events occurred. Anti‐CD20 antibody treatment could be an attractive therapeutic approach for MCD, mainly when immune‐related disorders are associated. Am. J. Hematol. 78:302–305, 2005. © 2005 Wiley‐Liss, Inc.
Hydroxychloroquine causes severe vacuolar myopathy in a patient with chronic graft‐versus‐host disease
Authors: Bolaños‐Meade Javier , Zhou Lan , Hoke Ahmet , Corse Andrea , Vogelsang Georgia , Wagner Kathryn R.
Published: March 2005

A 51‐year‐old man developed progressive debilitating limb and respiratory muscle weakness while undergoing treatment for chronic graft‐versus‐host disease secondary to allogeneic bone marrow transplant for mantle cell lymphoma. He had a normal serum creatine kinase level and acetylcholine receptor antibodies were negative. Electromyography showed a severe, nonirritable myopathy and a sensory motor axonal polyneuropathy. A muscle biopsy showed a necrotizing, vacuolar myopathy with many fibers containing autophagic and red‐rimmed vacuoles, suggestive of an amphiphilic drug myopathy. The patient's strength and function improved significantly after discontinuation of hydroxychloroquine. Am. J. Hematol. 78:306–309, 2005. © 2005 Wiley‐Liss, Inc.
Dendritic cell counts in the peripheral blood of healthy adults
Authors: Haller Hasskamp Joanne , Zapas John Louis , Elias Elias George
Published: March 2005

The normal range for adult blood dendritic cells (DC) has not been established. Blood DC counts were assayed directly from blood for 16 female and 11 male healthy adults with an age range of 22–60 years old (median, 46 years). DC were defined as lineage 1‐negative/dim, CD34‐negative/dim, and HLA‐DR‐positive within the total peripheral blood leukocyte (PBL) population. Impedance counter complete blood counts were used with flow cytometry percentages to calculate the absolute DC count and DC percentage of mononuclear cells (MNC). The normal adult ranges for DC calculated as the mean ± 2SD were 0.16–0.68% PBL, 0.55–1.63% MNC, and 13–37 DC/μL of blood. Am. J. Hematol. 78:314–315, 2005. © 2005 Wiley‐Liss, Inc.
Primary mediastinal B‐cell lymphoma with sclerosis: Report of 11 cases treated with intensified‐CHOP plus radiotherapy
Authors: Siracusano Licia , Balzarotti Monica , Magagnoli Massimo , Castagna Luca , Rahal Daoud , Santoro Armando
Published: March 2005

Primary mediastinal B‐cell lymphoma (PMBCL) is a clinicopathological entity with aggressive behavior. Retrospective evaluation suggests the need for intensive chemotherapy programs. From 1997 to February 2003, a total of 11 cases of previously untreated PMBCL with sclerosis were treated at our institution with 5 courses of intensified CHOP (ICHOP) regimen and mediastinal irradiation. Three patients were submitted to high‐dose chemotherapy with peripheral‐blood stem‐cell support, followed by radiotherapy, because of intermediate‐risk age‐adjusted International Prognostic Index at diagnosis. After a median follow up of 30 months, all patients but one are in continuous complete remission (CR), and overall survival is 100%. Am. J. Hematol. 78:312–313, 2005. © 2005 Wiley‐Liss, Inc.
Design, synthesis, and application of azabicyclo[X.Y.0]alkanone amino acids as constrained dipeptide surrogates and peptide mimics
Authors: Cluzeau Jérôme , Lubell William D.
Published: March 2005

Azabicyclo[X.Y.0]alkanone amino acids are challenging synthetic targets and useful tools for studying structure–activity relationships of native peptide ligands. They have been employed to increase potency and stability in conformationally rigid enzyme inhibitors and receptor ligands. Since last reviewed in 1997, activity in their synthesis and application has increased significantly and access is now available to a wider diversity of these peptide mimics. This review focuses on recent syntheses of these heterocyclic amino acids and their application in the investigation of biologically active peptides and peptide mimics. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2005
Erratum: Crystal structures of collagen model peptides with Pro‐Hyp‐Gly repeating sequence at 1.26 Å resolution: Implications for proline ring puckering, Kenji Okuyama, Chizuru Hongo, Rie Fukushima, Guanghan Wu, Hirotaka Narita, Keiichi Noguchi, Yuji Tanaka, Norikazu Nishino, Biopolymers (Peptide Science)(2004)76(5) 367–377
Authors: Okuyama Kenji , Hongo Chizuru , Fukushima Rie , Wu Guanghan , Narita Hirotaka , Noguchi Keiichi , Tanaka Yuji , Nishino Norikazu
Published: March 2005

The original article to which this Erratum refers was published in Biopolymers (Peptide Science) (2004) 76(5) 367–377
Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure
Authors: Ossipov Michael H. , Lai Josephine , King Tamara , Vanderah Todd W. , Porreca Frank
Published: March 2005

The opioid analgesics, commonly exemplified by morphine, represent the best option for the treatment of severe pain and for the management of chronic pain states, of both malignant and nonmalignant origin. It is well recognized that the prolonged use of opioids is associated with a requirement for ever‐increasing doses in order to maintain pain relief at an acceptable and consistent level. This phenomenon is termed analgesic tolerance. While the concept that tolerance can develop as a result of cellular adaptations to the presence of the opioid has been proposed, it is now becoming abundantly clear that tolerance may also be related to a state of hyperalgesia that results from exposure to the opioid itself. Patients who receive long‐term opioid therapy sometimes develop unexpected, abnormal pain. Similar paradoxical opioid‐induced pain has been confirmed in a number of animal studies, even during the period of continuous opioid delivery. A number of recent studies have demonstrated that such pain may be secondary to neuroplastic changes that occur in the brain and spinal cord. One such change may be the activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM) elicited in part by increased activity of cholecystokinin (CCK) in the RVM. A cascade of pronociceptive events may follow, such as opioid‐induced upregulation of spinal dynorphin levels that promotes enhanced input from primary afferent nociceptors. This mechanism appears to depend on intact descending pathways from the RVM, since interrupting this pathway abolishes enhanced abnormal pain. Furthermore, extended opioid exposure also can elicit increased calcitonin gene related peptide (CGRP) and substance P expression in the dorsal root ganglia. It is probable that increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance because the same manipulations that block abnormal pain also block antinociceptive tolerance. Taken together, such studies show that opioids elicit systems‐level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin, and enhanced, evoked release of excitatory transmitters from primary afferents. These adaptive changes in response to sustained exposure to opioids indicate the need for the evaluation of the clinical consequences of long‐term opioid administration. Additionally, these findings suggest a need for novel chemistry involving design of agents that may counteract opiate‐induced neuroplastic adaptations resulting in pain relief without analgesic tolerance. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2005
Structural features of a central mismatch in oligonucleotide hybrid duplexes visualized via Raman spectroscopy: Model system for evaluation of potential “antisense” drugs
Authors: Nĕmec̆ek Daniel , Vaisocherová Hana , S̆tĕpánek Josef , Turpin Pierre‐Yves
Published: April 2005

Structural features of mismatched base pairs were studied on four nonamer hybrid duplexes formed between the 5′‐d(GTGATATGC)‐3′ complement and its 5′‐r(GCAUNUCAC)‐3′ (N = A, C, G, U) counterparts. This oligonucleotide set is considered a model molecular system for future systematic studies of various modifications of internucleotide linkages with respect to their impact on the structure of mismatched base pairs. Raman spectra, measured at 15°C, revealed the prevailing A‐like structure of the RNA strand and mixed A‐like and B‐like characteristics for the DNA strand. All three mismatches disturb only weakly the overall conformation of the hybrid duplex in contrast to analogous mismatched DNA duplexes. In particular, the dT · rG mismatch influences the global hybrid duplex geometry almost negligibly. The dT · rC and dT · rU mismatches induce somewhat more pronounced distortions of the backbone structure and of the thymine position, the latter being expressed by a change of the surrounding methylene group without effect on the carbonyl's vibrations. Structural effects of the mismatches correlate well with the duplex thermodynamic stabilities obtained by ultraviolet (UV) absorption, i.e., the dT · rG mismatch decreases the hybrid duplex stability very weakly while the effect of both pyrimidine–pyrimidine mismatches is considerable. © 2005 Wiley Periodicals, Inc. Biopolymers 79: 1–8, 2005

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Phosphorylcholine is favorable for antibody production from hybridoma cells
Authors: Montano Ximena , Lewis Andrew L. , Leppard Simon W. , Lichtenstein Conrad
Published: April 2005

Growth of antibody‐secreting hybridomas requires special conditions such as serum‐free defined media containing growth factors and vitamins. However, the surface on which these cells can proliferate has been shown to play an important role. Phosphorylcholine (PC)‐based polymers are zwitterionic compounds with nonbiofouling properties. These polymers are characterized by having reduced protein absorption properties. Our aim was to determine whether well‐established hybridoma cell lines were able to proliferate and produce measurable amounts of monoclonal antibodies when grown on PC‐polymer‐coated surfaces. Comparative experiments using four well‐known hybridoma cell lines (PAb421, PAb246, PAb1801 which recognize p53, and PAb280 which recognizes SV40 small t antigen) grown on PC‐polymer‐coated, uncoated, and two commercially available tissue culture plates showed that PC‐polymer‐coated plates were more efficient than uncoated plates in sustaining cell growth and monoclonal antibody production/secretion as defined by growth assays and ELISA. Also, results demonstrated that PC‐polymer‐coated plates were able to perform better than commercially available plates. These observations suggest that PC polymers could be used as an alternative, efficient surface coating to grow hybridoma cell lines and allow detectable antibody secretion. © 2005 Wiley Periodicals, Inc.
Isomeric Mono‐ and Bis[(phosphane)gold(I)] Thiocyanate Complexes
Authors: Berger Raphael J. F. , Patzschke Michael , Schneider Daniel , Schmidbaur Hubert , Sundholm Dage
Published: April 2005

The solid‐state IR spectrum of Me3PAuSCN shows two signals in the range of the C–N stretching vibrations at 2075 and 2113 cm−1. On the basis of thoroughly tested quantum chemical ab initio calculations (MP2 level of theory) these signals have been assigned to the two isomeric forms Me3PAuNCS and Me3PAuSCN. The molecular structures, the vibrational frequencies, and the relative energies of the two species have been calculated and the results compared with the experimental IR data. Treatment of Me3PAuSCN with equimolar quantities of [(Me3P)Au]+[SbF6]− in CH2Cl2 at −78 °C gives the dinuclear reaction product [C7H9Au2NP2S]+[SbF6]− in high yields. A comparison of results of ab initio calculations and IR data suggest that at least three isomeric cationic species [(R3PAu)2NCS]+, [(R3PAu)2SCN]+ and [(R3PAu)SCN(AuPR3)]+ are present, the second and third being the predominant components. The structures and vibrational frequencies of all three species have been calculated. The relative energies in the gas phase and in solution are discussed and compared with the corresponding data of the experimental IR spectra.
Marriage and ethnicity predict treatment in localized prostate carcinoma
Authors: Denberg Thomas D. , Beaty Brenda L. , Kim Fernando J. , Steiner John F.
Published: March 2005

BACKGROUND

Primary treatment for early‐stage prostate carcinoma includes expectant management or, for curative intent, radical prostatectomy or radiotherapy. Treatment recommendations are generally guided by clinical factors such as Gleason grade, prostate‐specific antigen level, comorbid illnesses, and patient age. Sociocultural factors may also have influences on patient and urologist treatment choices.

METHODS

The authors used bivariate and multinomial logistic regression to identify medical and sociodemographic predictors of prostatectomy (compared with radiotherapy) and curative therapy (compared with expectant management) in a cohort of 27,920 non‐Latino white, black, and Latino men without comorbidities in the latest linked Surveillance, Epidemiology and End Results–Medicare dataset (years 1995–1999). Predictors included tumor stage, patient age, marital status, race/ethnicity, and soscioeconomic status.

RESULTS

Younger age and higher tumor grade were robust predictors of curative treatment compared with expectant management and of prostatectomy compared with radiotherapy. Sociodemographic factors had an additive role in treatment choice. Marriage predicted curative treatment compared with expectant management (adjusted risk ratio [RR] = 1.28 [1.25–1.30]) and prostatectomy compared with radiotherapy (adjusted RR = 1.24 [1.20–1.28]). Although blacks and Latinos were just as likely as whites to receive curative treatment, blacks were significantly less likely, whereas Latinos were more likely, to receive prostatectomy compared with radiotherapy (adjusted RRs = 0.77 [0.72–83]) and 1.24 [1.18–1.30], respectively).

CONCLUSIONS

Marriage was positively associated with curative treatment in general, and with prostatectomy specifically. Blacks received prostatectomy less often than whites, although they did not receive less curative treatment overall. Latinos received prostatectomy more often than whites. Clinicians should recognize the importance of cultural and social forces as well as biomedical factors in decisions regarding the treatment of patients with early‐stage prostate carcinoma. Cancer 2005. © 2005 American Cancer Society.
National survival trends of young adults with sarcoma
Authors: Bleyer Archie , Montello Michael , Budd Troy , Saxman Scott
Published: March 2005

BACKGROUND

Young adults with cancer in the U.S. have had less improvement in survival than either younger patients or older patients. The authors attempted to determine whether similar deficits have occurred in young adults with sarcomas and, if so, then why.

METHODS

In 38,144 young adults with sarcoma who were diagnosed during 1975–1998 and were followed by the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results Program, the average annual percent change in 5‐year survival was derived as a function of patient age. National sarcoma treatment trial data were obtained on 3242 patients who were entered onto NCI‐sponsored trials during 1997–2002.

RESULTS

1) For patients with bone and soft‐tissue sarcomas, except Kaposi sarcoma (KS), the least survival improvement occurred between age 15 years and age 45 years. For patients with KS, the pattern was reversed, with the greatest survival increase occurring among patients ages 30–44 years. 2) The lowest participation rate in NCI‐sponsored sarcoma treatment trials occurred in patients ages 20–44 years. For patients with KS, the highest accrual rate occurred in patients ages 35–44 years. 3) The age‐dependent survival improvement and clinical‐trial accrual patterns were correlated directly (soft‐tissue sarcomas, P < 0.005; bone sarcomas, P < 0.05; KS, P = 0.06), regardless of whether the accrual profile demonstrated a decline or a peak (KS) during early adulthood.

CONCLUSIONS

The lack of survival prolongation in patients age 15–44 years in the U.S. with non‐KS sarcomas may have been a result of their relative lack of participation in clinical trials. If this is true, then reversing the shortfall in survival among young adults with sarcomas, as was accomplished among patients with KS, should benefit from increased clinical trial availability, access, and participation. Cancer 2005. Published 2005 by the American Cancer Society.
Effects of 2‐(1‐hydroxypentyl)‐benzoate on platelet aggregation and thrombus formation in rats
Authors: Zhang Yi , Wang Ling , Zhang Liying , Wang Xiaoliang
Published: March 2005

2‐(1‐hydroxypentyl)‐benzoate (dl‐PHPB), a derivate of 3‐n‐butylphthalide (NBP), is a novel therapeutic agent for treatment of cerebral ischemia. In the present study, the antiplatelet and antithrombotic activities of dl‐PHPB were evaluated in ex vivo platelet aggregation and in vivo arteriovenous (A‐V) shunt models. dl‐PHPB inhibited platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), and collagen (COL) in a dose‐dependent manner when given orally (12.9–129.5 mg/kg). The inhibitory potency was similar to 3‐n‐butylphthalide (NBP) and aspirin (ASP). Inhibition on platelet aggregation was also observed after iv administration of dl‐PHPB (1.29–12.9 mg/kg). The time‐course of these effects showed the maximal inhibition on platelet aggregation at 1 h after oral administration and 30 min after iv injection. dl‐PHPB (12.9–129.5 mg/kg, p.o.) caused dose‐dependent inhibition of thrombus formation in the rat A‐V shunt thrombosis model. These results show that dl‐PHPB is an orally and iv antiplatelet and antithrombotic agent and may be useful for treatment of ischemia stroke. Drug Dev Res 63:174–180, (2004). © 2004 Wiley‐Liss, Inc.
The airways pharmacology of DNK333, a potent, selective, non‐peptide dual NK1/NK2 receptor antagonist
Authors: Lewis C.A. , El‐Hashim A.Z. , Gerspacher M. , Hoshiko K. , Mazzoni L. , Pfannkuche H.‐J. , Subramanian N. , Fozard J.R.
Published: March 2005

The airways' pharmacology of DNK333 ((1R,3R,2E)‐N‐[3,4‐dichlorobenzyl)]‐4‐[(hexahydro‐2‐oxo‐1H‐azepin‐3‐yl)amino]‐N‐methyl‐3,5bis(trifluoromethyl) benzamide), a potent and selective dual NK1/NK2 neurokinin receptor antagonist is described in the present paper. DNK333 bound with high and similar affinities to human NK1 and NK2 receptors. In guinea‐pig isolated trachea, DNK333 induced concentration‐dependent blockade of the contractile responses to NK1‐ or NK2‐receptor agonists. In anaesthetized guinea‐pigs, DNK333 shifted the bronchoconstrictor dose‐response curves induced by NK1‐ and NK2‐receptor agonists by 21.8‐ (3 mg/kg) and 6.8‐fold (10 mg/kg), respectively. At 10 mg/kg, a 12‐h duration of action was observed. Nasal perfusion of substance P and capsaicin to anaesthetized guinea‐pigs induced extravasation, which was inhibited dose‐dependently by DNK333 (ED50 values 72 and 70 µg/kg, respectively). Exposure of conscious guinea‐pigs to 0.6 M citric acid resulted in cough and an increase in enhanced pause of respiratory function (Penh). Oral administration of DNK333 (0.3, 3, or 10 mg/kg, −2 h) inhibited cough by 62, 63, and 82%, respectively and the increase in Penh by 85.5 and 77.2% (3 and 10 mg/kg, respectively). Bronchoconstrictor responses in anaesthetized guinea‐pigs to intravenous injections of methacholine and substance P were increased 60 min after LPS challenge (1 mg/kg, i.v.). DNK333 (1 and 10 mg/kg) dosed intraduodenally 30 min prior to LPS challenge inhibited airway hyperreactivity in a dose‐dependent manner. In conclusion, DNK333 is a potent, orally bioavailable, dual NK1/NK2 receptor antagonist with a long duration of action. It inhibits bronchoconstriction, extravasation, cough, and airway hyperreactivity induced by endogenous release of neuropeptides, which renders DNK333 suitable for exploring the role of tachykinins in respiratory disease. Drug Dev Res 63:161–173, 2004. © 2004 Wiley‐Liss, Inc.
Ethical Issues in the Biotechnology and Pharmaceutical Industries
Authors: Aronson Debra , Best Simon G. , Werner Michael J. , Moos Walter H.
Published: March 2005

Ethical topics come in many shapes and forms. When we set out to identify potential areas for the present special issue of this journal, we considered many areas that fit within a theme of “future challenges in bioethics.” We were interested in the impact of new technologies, how society will cope, how institutions will change to deal with the issues, and how different parts of the world will view the same issues differently. In this preface, we briefly describe selected issues, including scientific openness, genetics and related areas, informed consent and privacy, and human rights in the third world. We also mention corporate ethics, an area of much recent attention in the media, at corporations, with auditors, and on Wall Street. Finally, we describe the areas covered by the specific articles that follow. Drug Dev Res 63:89–92, 2004. © 2005 Wiley‐Liss, Inc.
Patenting the sun: Enclosing the scientific commons and transforming the university—ethical concerns
Authors: Triggle David J.
Published: March 2005

University and corporate interests have grown increasingly close during the past quarter century, particularly, but not exclusively so, in the life science areas. Legislation passed in 1980 specifically encouraged universities to seek patents on their basic science discoveries and to develop and license such patents. Universities are now significant players in the life sciences area, although the rewards are confined to a very small number of institutions. Questions arise concerning the influence of such commercial activities on the character of the universities, on their roles as public institutions, on the integrity of science and scientists, and on the progressive enclosing of the basic science commons, to which universities have traditionally been major contributors. Drug Dev Res 63:139–149, 2004. © 2005 Wiley‐Liss, Inc.
Closing the public health gap in Africa: Are we losing sight of our priorities?
Authors: Wasunna Angela Amondi
Published: March 2005

Given a plethora of data and information that show high mortality and morbidity in Africa from preventable diseases, it appears that the public health agenda in Africa is not being given the prominence and attention it deserves. This article provides background to the problem, and calls on communities, governments, and international stakeholders to refocus their health plans and funding priorities to ensure that primary care and public health are not relegated to the rear in the pursuit of better health in Africa. Drug Dev Res 63:134–138, 2004. © 2005 Wiley‐Liss, Inc.
Bioterrorism and the Responsible Conduct of Biomedical Research
Authors: Resnik David B. , Shamoo Adil E.
Published: March 2005

This article discusses the ethical responsibilities of biomedical researchers to prevent bioterrorism, including duties related to research, publication, editorial review, public education, expert opinion, advocacy, and reporting suspicious activity. Since actions taken to avert bioterrorism may also undermine important scientific norms, such as openness, freedom, and collegiality, and individual rights, such as privacy, biomedical scientists may encounter ethical dilemmas and problems when they consider taking steps against terrorism. This article proposes some policies and recommendations that attempt to strike a fair and reasonable balance between protecting scientific norms and individual rights and promoting national and international security. This article articulates policies and recommendations that will help ensure that the norms that govern biomedical research and individual rights are not casualties in the struggle against terrorism. Drug Dev Res 63:121–133, 2004. © 2005 Wiley‐Liss, Inc.
The Ethics of the F Word: Faith‐Based Science in a Faith‐Based World
Authors: Triggle David J.
Published: March 2005

“And you never ask questions when god's on your side,”—Bob Dylan (1963). Science demands organized skepticism and the acknowledgement that science is a product of nature and not of a particular religion, culture, or political system. Faith‐based science that demands an unquestioning acceptance of a particular view or opinion is thus an oxymoronic discipline. Nonetheless, the incursion of faith‐based religious or political values into scientific disciplines and science‐based decision‐making is a persistent and increasing challenge. Religious values have always been a major part of American public and political life, but have assumed increased significance over the past two decades. In particular, the Presidency of George W. Bush has brought such issues to the forefront in many areas where science and science‐based decision‐making impacts the political decision‐making process. The current role of religion in impacting science‐based decision‐making in the United States is discussed. Drug Dev Res 63:112–120, 2004. © 2005 Wiley‐Liss, Inc.
Sponsored research and the public's right to know
Authors: Fersko Raymond S. , Merabet Hind
Published: March 2005

Technology transfer provides various protections and incentives for universities and federal research laboratories to develop and profit from their discoveries. However, the government, academic and private sectors may have conflicting, yet interrelated, values, interests, and practices when it comes to the gathering, recording, reporting, use, interpretation, and ownership of research data. The increasing commercialization of biomedical research has blurred some of these seeming divisions, and individuals and institutions occasionally find themselves succumbing to the financial pressures generated by their sponsors. This article discusses the ethical duty towards the public, and patients particularly, to present research results as accurately and objectively as possible, including in the specific context of human embryonic stem cell research. Drug Dev Res 63:103–111, 2004. © 2005 Wiley‐Liss, Inc.
Bioethics in biotechnology: from pain to gain
Authors: Dhanda Rahul K.
Published: March 2005

As the biotechnology industry grows, it will continually rely on the development of new technologies and the innovative use of mature scientific discoveries. These technologies will undoubtedly raise ethical issues challenging both their mode of development and intended use. Biotechnology companies are affected by the public debates and regulatory decisions that will ensure, but the ability of individual companies to address these challenges is, on the whole, insubstantial. Many companies are aware and appreciate the gravity of bioethics issues, but they lack the infrastructure and guidance to approach them. In this essay, a brief analysis is offered to help assess the impact of these issues on biotechnology firms, which is followed by suggested strategies for acting responsibly in the face of these important moral challenges. Drug. Dev Res 63:93–102, 2004. © 2005 Wily‐Liss, Inc.
Enhancement of dissolution rate of rofecoxib using solid dispersions with urea
Authors: Liu Chengsheng , Desai Kashappa Goud H. , Liu Chenguang , Park Hyun J.
Published: March 2005

The aim of this study was to enhance the dissolution rate of rofecoxib using solid dispersions (SDs) with urea. In preliminary studies, the solubility behavior of rofecoxib in the presence of polyethylene glycol (PEG)‐4000, polyvinylpyrrolidone (PVP) K30, mannitol, and urea in water was obtained at 37°C to choose an effective carrier for preparing its SDs. A systematic increase in the solubility behavior of rofecoxib was observed with increasing concentrations of these carriers in water except mannitol. The Gibbs free energy (ΔG) values were negative indicating the spontaneous nature of rofecoxib solubilization, and it decreased with increases in concentration, demonstrating that the reaction became more favorable as the concentration of these carriers increased. Since, urea exhibited higher solubilizing power than the other carriers, SDs of rofecoxib with urea were prepared at 1:1, 1:2, 1:5, and 1:10 (rofecoxib:urea) ratios by the fusion method. Evaluation of the properties of the SDs was performed using dissolution studies, fourier‐transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X‐Ray diffraction (XRD), and scanning electron microscopy (SEM). The dissolution rate of rofecoxib was enhanced rapid by its SDs with urea and increased with increasing concentrations of urea in SDs. The mean dissolution time (MDT) of rofecoxib decreased after preparation of SDs and physical mixtures with urea. FTIR spectroscopic studies showed the stability of rofecoxib and the absence of a well‐defined rofecoxib‐urea interaction. DSC and XRD studies confirmed the amorphous state of rofecoxib in SDs of rofecoxib with urea. SEM pictures showed the formation of effective SDs of rofecoxib with urea since well‐defined changes in the surface nature of rofecoxib, SDs, and physical mixture were observed. Drug Dev Res 63:181–189, (2004). © 2004 Wiley‐Liss, Inc.
Epidermal lipids: thermotropic behavior and role in transcutaneous permeation of levodopa
Authors: Babita Kumar , Rana Vikas , Tiwary Ashok Kumar
Published: March 2005

Skin lipids play a pivotal role in maintaining the barrier properties of skin. The present investigation aimed at studying the effect of skin lipid synthesis inhibitors on the transcutaneous delivery of levodopa (LD). Skin perturbation with ethanol was found to reduce the content of cholesterol, fatty acid, and sphingosine. Subsequent treatment with various doses of their respective synthesis inhibitors atorvastatin, cerulenin, and β‐chloroalanine sustained the reduced content of these lipids in viable rat skin. A maximum synthesis inhibition of approximately 80, 60, and 55% for cholesterol, triglycerides (an indicator of fatty acid), and sphingosine (a precursor of ceramide) was observed at 2, 2, and 8 h, respectively, after topical application of optimized dose of the inhibitors. Differential scanning calorimetric (DSC) analysis of treated rat epidermis revealed approximately 70, 52, and 50% reduction in enthalpy (ΔH) of the lipid endothermic transition peak by the corresponding doses of inhibitors. The effective plasma concentration (Ceff) of LD in rats was achieved by treatment with atorvastatin, cerulenin, and β‐chloroalanine within 2, 4, and 6 h, respectively. After application of a combination of these inhibitors, the lag time was reduced to 1 h and Ceff was maintained over 48 h. The inhibition of lipid synthesis in epidermis and concomitant decrease in enthalpy of lipid endothermic transition were directly correlated with enhanced in vitro and in vivo permeation of LD. These findings suggest that lipid synthesis inhibition can be exploited to enhance transcutaneous delivery of a polar drug, levodopa. Drug Dev Res 63:190–199, 2004. © 2004 Wiley‐Liss, Inc.
Effect of ascorbic acid, dihydrolipoic acid, t‐Butylhydroquinone, and phenylbutylnitrone on mortality and neurological impairment induced by sequential common carotid artery sectioning in mice
Authors: Santiago‐Mejia Jacinto , Fuentes‐Vargas Monica , Rios Camilo , Vidrio Horacio , Rodriguez Rodolfo
Published: March 2005

The efficacy of four antioxidant agents to reduce neurological deficits and mortality produced by sequential common carotid artery sectioning (SCAS) in mice was evaluated. Ascorbic acid (AA, 500 mg/kg), dihydrolipoic acid (DHLA, 100 mg/kg), tert‐butylhydroquinone (t‐BHQ, 100 mg/kg) or phenylbutylnitrone (PBN, 100 mg/kg) were injected ip 15 min after the second artery sectioning. Animals were evaluated at 24, 48, and 72 h after antioxidant or saline injection using two procedures: neurological examination and spontaneous motility. Based on neurological examination, a disability status scale was used to determine the degree of functional incapacity after brain ischemia for each animal. The scale comprised 10 progressive steps beyond 0 (normal) extending to status 10 (death due to SCAS). In this scale, the highest scores reflect greater neurological dysfunction. AA and DHLA but neither t‐BHQ nor PBN decreased mortality and reduced neurobehavioral deficits caused by SCAS in mice. The observed 24‐, 48‐, and 72‐h survival rates for AA were 86, 71, and 48% and for DHLA were 75, 65, and 65%, representing a significant prolongation of lifespan as compared with vehicle‐treated animals (60, 35, 35%). The 24‐, 48‐, and 72‐h neurological scores for AA of 5.2, 6.2, and 7.5 and for DHLA of 4.6, 5.3, and 5.8 as compared with the scores observed for the saline‐treated control group (7.6, 8.6, and 8.6) indicate that administration of these antioxidants is beneficial for the neurological output of surviving animals. These antioxidants may have important neuroprotective properties, and indicate that a clinical trial, mainly of DHLA, in stroke patients should be considered. Drug Dev. Res. 63:212–218, 2004. © 2004 Wiley‐Liss, Inc.
Cardiotoxin III induces apoptosis in T24 cells via reactive oxygen species‐independent mitochondrial death pathway
Authors: Chien Ching‐Ming , Yang Sheng‐Huei , Lu Mei‐Chin , Chang Long‐Sen , Lin Shinne‐Ren
Published: March 2005

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. CTX III inhibited the growth of T24 cells in a time‐ and dose‐dependent manner with an IC50value of 1.7 µg/mL and displayed several features of apoptosis including apoptotic body formation, increase of sub G1 population, DNA fragmentation, and poly (ADP‐ribose) polymerase (PARP) cleavage. Using apoptosis analysis, measurement of reactive oxygen species (ROS) and assessment of mitochondrial membrane potentials (ΔΨm), CTX III was found to be a potent inducer of apoptosis, transducing apoptotic signals via a decrease in mitochondrial membrane potential (ΔΨm) and release of cytochrome c from mitochondria into cytosol. However, CTX III did not generate reactive oxygen species (ROS). Taken together, the present data indicate that CTX III induces apoptosis in T24 cells through an ROS‐independent mitochondrial dysfunction pathway and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of CTX III on T24 cells. Drug Dev. Res. 63:219–224, 2004. © 2004 Wiley‐Liss, Inc.
Flavonoid compounds: a review of anticancer properties and interactions with cis‐diamminedichloroplatinum(II)
Authors: Kosmider Beata , Osiecka Regina
Published: March 2005

Flavonoid compounds, especially quercetin and genistein, have antitumor activity. These compounds are cytotoxic to cancer cells but have no or insignificant activity in normal cells. These beneficial properties prompted synthesis of flavonoid synthetic derivatives, e.g., flavopiridol; 5‐amino‐2,3‐fluorophenyl)‐6,8‐difluoro‐7‐methyl‐4H‐1‐benzopyran‐4‐one; B43‐genistein and EGF‐genistein). cis‐DDP (cis‐diamminedichloroplatinum(II)) is one of the most effective drugs used for chemotherapy, but its actions are limited by many side effects. Beneficial synergistic effects of flavonoids (e.g., quercetin, genistein, butein, tannic acid) and cis‐DDP were found in cis‐DDP‐sensitive and resistant cancer cells that resulted in a lower toxicity for cis‐DDP. Further studies focused on the synthesis of complexes of compounds belonging to different groups, e.g., cis‐bis(3‐aminoflavone)dichloroplatinum(II) where introduction of the flavone ligand altered the DNA‐binding properties of the complex as compared to cis‐DDP alone. The beneficial anticancer and antioxidant properties of flavonoids and their synthetic derivatives have prompted further research on the synergistic interactions of these compounds with routinely applied chemotherapeutic drugs, e.g. cis‐DDP. Drug Dev. Res. 63:200–211, 2004. © 2004 Wiley‐Liss, Inc.
Recent strategies and methods for improving insulin delivery
Authors: Lin Congrong , Gokhale Rajeev , Trivedi Jay S. , Ranade Vasant
Published: March 2005

Subcutaneous insulin has been used to treat diabetes since the discovery of insulin itself. However, despite a number of different formulations and routes of administration, intensive insulin therapy without limitations, such as too low bioavailability, has not enjoyed widespread clinical acceptance. Attempts to find effective, well‐tolerated routes for delivering insulin began in the late 1920s and as of today, an ideal insulin delivery is still formidable. The most recent advances in insulin delivery are focused on using the inhalation route. The recent European filing of inhaled insulin (Exubera) is providing hope for alternative delivery routes, for example. This article reviews recent advances and approaches that hold promise toward the successful development of insulin delivery for the management of diabetes. Drug Dev. Res. 63:151–160, 2004. © 2004 Wiley‐Liss, Inc.