Future Clinical Trials (future + clinical_trials)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Polyunsaturated fatty acids and epilepsy

EPILEPSIA, Issue 8 2010
Ameer Y. Taha
Summary Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are dietary fatty acids that are involved in a myriad of physiologic processes in the brain. There is some evidence suggesting that PUFAs,and particularly omega-3 PUFAs,may have anticonvulsant effects, both in humans and in animals. In the present review, we assess the evidence related to the antiseizure properties of the n-3 PUFAs, discuss their possible mechanism(s) of action, and make recommendations for future clinical trials. In general, the available data from cell cultures and whole animal studies support the idea that the n-3 PUFAs have antiseizure properties. Future clinical trials involving the n-3 PUFAs should involve higher doses and longer periods of administration in order to definitively assess their possible antiseizure effects. [source]


A phase II trial of arsenic trioxide in patients with metastatic melanoma

CANCER, Issue 8 2005
Kevin B. Kim M.D.
Abstract BACKGROUND Arsenic trioxide induces growth inhibition and apoptosis in human melanoma cell lines. Therefore, a Phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with Stage IV melanoma. METHODS Twenty patients, 10 with metastatic melanoma of cutaneous origin and 10 with metastatic melanoma of choroidal origin, received arsenic trioxide 0.25 mg/kg/day for 5 days, followed by a maintenance dose of 0.35 mg/kg/day twice a week. All patients with melanoma of cutaneous origin and four patients with melanoma of choroidal origin had received prior therapy. RESULTS Single-agent arsenic trioxide did not induce clinical response in this patient population. Eight patients (five with melanoma of cutaneous origin, and three with melanoma of choroidal origin) had disease stabilization for at least six weeks. The median overall survival duration for patients with melanoma of cutaneous origin was 7.9 months, and that of patients with melanoma of choroidal origin has not been reached at a median follow-up duration of 11.8 months. Grade 3 toxicity included neutropenia, fatigue, abdominal pain, and arthralgia. Grade 4 toxicity did not occur. CONCLUSIONS Single-agent arsenic trioxide was generally well tolerated; however, no tumor regression was observed in this patient population. Future clinical trials should evaluate arsenic trioxide in combination with other anticancer drugs that may improve its clinical activity in melanoma. Cancer 2005. © 2005 American Cancer Society. [source]


Volume Overload and Cardiorenal Syndromes

CONGESTIVE HEART FAILURE, Issue 2010
Claudio Ronco MD
To include the vast array of interrelated derangements and to stress the bidirectional nature of the heart-kidney interactions, the classification of the cardiorenal syndrome today includes 5 subtypes whose terminology reflects their primary and secondary pathology, time frame, and the presence of concomitant cardiac and renal dysfunction. Cardiorenal syndromes (CRSs) are pathophysiologic disorders of the heart and kidneys whereby acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other. Type 1 CRS reflects an abrupt worsening of cardiac function leading to acute kidney injury. Type 2 CRS describes chronic abnormalities in cardiac function causing progressive chronic kidney disease. Type 3 CRS consists in an abrupt worsening of renal function causing acute cardiac disorder. Type 4 CRS describes a state of chronic kidney disease contributing to decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events. Type 5 CRS reflects a systemic condition (eg, sepsis) simultaneously causing both cardiac and renal dysfunction. Biomarkers can help characterize the subtypes of CRS as well as suggest the timing of treatment initiation and its likely effectiveness. The identification of patients and the pathophysiologic mechanisms underlying each syndrome subtype, including fluid overload or, in general, altered conditions of fluid status, can help physicians understand clinical derangements, provide the rationale for management strategies, and allow the design of future clinical trials with more accurate selection and stratification of the population under investigation. Congest Heart Fail. 2010;16(4)(suppl 1):Si,Siv. ©2010 Wiley Periodicals, Inc. [source]


Antipsychotic combination therapy in schizophrenia.

ACTA PSYCHIATRICA SCANDINAVICA, Issue 5 2002
A review of efficacy, risks of current combinations
Objective:, To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials. Method:, A computerized Medline search supplemented by an examination of cross-references and reviews was performed. Results:, Empirical evidence for the efficacy of combining antipsychotics is too limited to draw firm conclusions. The practice of augmenting clozapine with more ,tightly bound' D2 receptor antagonists as exemplified by risperidone augmentation of clozapine has some empirical and theoretical support. The risks of augmentation strategies have not been studied systematically. No study has examined the economic impact of combination treatment. Conclusion:, Further trials of antipsychotic combination therapies are needed before this currently unsupported practice can be recommended. Rationales for combination treatment include a broadening of the range of receptor activity or an increase in D2 receptor occupancy with certain atypical agents. Trial methodology needs to take into account subject characteristics, duration of treatment, optimization of monotherapy comparators, and appropriate outcome measures. [source]


Polyunsaturated fatty acids and epilepsy

EPILEPSIA, Issue 8 2010
Ameer Y. Taha
Summary Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are dietary fatty acids that are involved in a myriad of physiologic processes in the brain. There is some evidence suggesting that PUFAs,and particularly omega-3 PUFAs,may have anticonvulsant effects, both in humans and in animals. In the present review, we assess the evidence related to the antiseizure properties of the n-3 PUFAs, discuss their possible mechanism(s) of action, and make recommendations for future clinical trials. In general, the available data from cell cultures and whole animal studies support the idea that the n-3 PUFAs have antiseizure properties. Future clinical trials involving the n-3 PUFAs should involve higher doses and longer periods of administration in order to definitively assess their possible antiseizure effects. [source]


Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2004
Philippe Rousselot
Abstract: Objectives :,Pharmacological concentrations of arsenic trioxide (ATO) and organic arsenic melarsoprol induce apoptosis in malignant plasma cells. In an attempt to further document the interest of the arsenic in vivo, we treated severe combined immunodeficient (SCID) mice transplanted with human myeloma cells by ATO or melarsoprol. Methods :,Fifty-two SCID mice were irradiated before intraperitoneal (i.p.) injection of plasma cells from five myeloma patients. Engraftment was assessed by serial measurement of the human monoclonal immunoglobulin G (HuMIgG) concentration in mouse serum. Treatment with ATO (10 ,g/g i.p. 5 d a week), melarsoprol (30 ,g/g i.p. 5 d a week) or phosphate buffer saline was started when a sustained growth of the tumor cells was demonstrated. Results :,Seventeen mice developed the human tumor. A significant decrease in HuMIgG amounts was observed in three of five mice of the ATO group, including two that achieved an apparent complete remission persisting up to 5 months after ATO discontinuation. In these mice, no human plasma cells were detected in tissue samples collected postmortem. Soluble human interleukin-6 receptor amount, measured in mice sera as a surrogate marker of the plasma cell proliferation, varied in parallel with HuMIgG concentration. A significant difference in survival was observed between control and ATO treated mice (113 and 158 d, respectively; P = 0.01) whereas no difference could be evidenced in control and melarsoprol groups. Conclusion :,Present study confirms in vivo the in vitro effects of ATO on myeloma cells. Delayed relapses were observed suggesting that prolonged or maintenance therapy has to be considered in future clinical trials. Whether or not this will translate into clinically relevant effect of the drug in myeloma patients deserves further consideration. [source]


Tests of Muscle Strength and Physical Function: Reliability and Discrimination of Performance in Younger and Older Men and Older Men with Mobility Limitations

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 11 2008
Nathan K. LeBrasseur PT
OBJECTIVES: To compare the reliability of muscle strength and physical function measures in younger and older men. DESIGN: Cross-sectional. SETTING: Academic research center. PARTICIPANTS: Thirty younger men, 31 older men, and 39 older men with mobility limitations. MEASUREMENTS: Test,retest measures of one repetition maximum (1 RM), unloaded and loaded 50-m walk and stair climb, and a lift-and-lower task. Reliability was assessed using intraclass correlation (ICC) analysis and the Bland-Altman method. RESULTS: Leg and chest press 1 RM measures identified significant differences between the groups, exhibited excellent test,retest reliability in younger men, older men, and older men with mobility limitations (ICCs=0.946,0.994) and minimal bias between Trials 1 and 2 (Bland-Altman=improvement of 21.1 and 1.1 N for leg and chest press, respectively). Test,retest measures of the time to walk 50 m and climb 12 steps also demonstrated excellent agreement (ICCs=0.980,0.988 and 0.942,992, respectively) and minimal bias (Bland-Altman=0.755,1.007 and 0.141,0.361 seconds faster, respectively). When a subject repeated these measures carrying a modest load, ICCs remained greater than 0.940, bias was similar, and the tests better discriminated between the groups. The lift-and-lower measure demonstrated excellent agreement (ICCs=0.925,0.947) and minimal bias (1.4,2.9 more shelves) and revealed significant differences between groups. CONCLUSION: Measures of muscle strength and physical function can be performed in younger men, older men, and older men with mobility limitations with high reliability. In future clinical trials, more-challenging measures of performance may better discriminate between higher-functioning study participants. [source]


Emerging targets and novel strategies in the treatment of AIDS-related Kaposi's sarcoma: Bidirectional translational science

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006
Bruce J. Dezube
Through the mentorship process, Dr. Arthur Pardee emphasized the critical importance of bidirectional translational research,not only advancing drug development from bench to bedside, but also bringing back precious clinical material to the laboratory to assess the biologic effects of therapeutic agents on their targets. This mini-review focuses on the signal transduction pathways of Kaposi's sarcoma (KS) and on how the knowledge of such pathways has led to the rational development of molecularly targeted pathogenesis-driven therapies. Acquired immune deficiency syndrome (AIDS) related-KS results from co-infection with human immunodeficiency virus and KS herpesvirus/human herpesvirus-8 (KSHV/HHV8), which leads to the development of an angiogenic-inflammatory state that is critical in the pathogenesis of KS. KS is driven by KSHV/HHV8-specific pathways, which include viral G protein-coupled receptor (vGPCR), viral interleukin-6 (vIL-6), and viral chemokine homologues. In addition, cellular growth/angiogenic pathways, such as vascular endothelial growth factor (VEGF), insulin-like growth factor, platelet-derived growth factor (PDGF), angiopoietin and matrix metalloproteinases (MMPs) are "pirated" by KSHV/HHV8. As a very tangible example of how translational research has led to a marked improvement in patient outcome, the signal transduction inhibitor imatinib (a tyrosine kinase inhibitor of c-kit and PDGF) was administered to patients with KS whose tumors were serially biopsied. Not only did the patients' tumors regress, but also the regression was correlated with the inhibition of PDGF receptor (PDGFR) in the biopsy samples. Recent and future clinical trials of molecularly targeted therapy for the treatment of KS are a prelude to a shift in the paradigm of how KS is managed. J. Cell. Physiol. 209: 659,662, 2006. © 2006 Wiley-Liss, Inc. [source]


Prognostic factors in patients with small hepatocellular carcinoma treated by percutaneous ethanol injection

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2002
Hitoshi Kuriyama
Abstract Background: Percutaneous ethanol injection (PEI) has been widely performed and is now accepted as a viable alternative to hepatic resection in patients with small hepatocellular carcinomas (HCC). However, only a few extensive investigations have been conducted regarding the prognostic factors for HCC patients treated with PEI. Methods: We investigated the prognostic factors in 100 patients with small HCC who had undergone PEI. Univariate analysis and multivariate analysis with Cox's proportional hazards model were used to determine the factors potentially related to survival. For clinical application, a prognostic index was calculated based on the regression coefficients of the independent variables identified from the multivariate analysis. Results: Median survival time and 1, 3 and 5 year survival rates were 71 months and 100, 84 and 62%, respectively. Among the 15 potential prognostic variables investigated, only three variables, namely a serum albumin level ,,3.5 g/dL, the presence of tumor stain and a serum glutamic oxaloacetic transaminase level>,66 IU/L, were identified as factors independently associated with a shorter survival. A prognostic index based on the regression coefficients of these three factors was proposed to classify patients into three groups, those with a good (5 year survival rate 91%), intermediate (64%) and poor prognosis (22%). Conclusions: The results of the present study may be useful in predicting the survival of HCC patients treated with PEI and in the design and analysis of future clinical trials of PEI for HCC. © 2002 Blackwell Publishing Asia Pty Ltd [source]


Issues facing clinical trials of the future

JOURNAL OF INTERNAL MEDICINE, Issue 5 2003
R. M. Califf
Abstract. Califf RM (Duke University Medical Center, Durham, NC, USA). Issues facing clinical trials of the future (Clinical Trials). J Intern Med 2003; 254: 426,433. Diagnostic and therapeutic technology continues to advance rapidly, as does our knowledge of therapeutics and of clinical research methods. Unfortunately, these advances have been only poorly coupled with our knowledge of therapeutic principles, leading to increasing uncertainty about which technologies are truly effective and, amongst those that are effective, which are most effective for the cost. This article presents general principles derived from several investigators' experiences with clinical trials, and uses them to suggest how future clinical trials may differ from current approaches. A proposed organization for future trials also is elucidated. [source]


Use of the DirecNet Applied Treatment Algorithm (DATA) for diabetes management with a real-time continuous glucose monitor (the FreeStyle Navigator)

PEDIATRIC DIABETES, Issue 2 2008
Diabetes Research In Children Network (DirecNet) Study Group
Background:, There are no published guidelines for use of real-time continuous glucose monitoring data by a patient; we therefore developed the DirecNet Applied Treatment Algorithm (DATA). The DATA provides algorithms for making diabetes management decisions using glucose values: (i) in real time which include the direction and rate of change of glucose levels, and (ii) retrospectively based on downloaded sensor data. Objective:, To evaluate the use and effectiveness of the DATA in children with diabetes using a real-time continuous glucose sensor (the FreeStyle Navigator). Subjects:, Thirty children and adolescents (mean ± standard deviation age = 11.2 ± 4.1 yr) receiving insulin pump therapy. Methods:, Subjects were instructed on use of the DATA and were asked to download their Navigator weekly to review glucose patterns. An Algorithm Satisfaction Questionnaire was completed at 3, 7, and 13 wk. Results:, At 13 wk, all of the subjects and all but one parent thought that the DATA gave good, clear directions for insulin dosing, and thought the guidelines improved their postprandial glucose levels. In responding to alarms, 86% of patients used the DATA at least 50% of the time at 3 wk, and 59% reported doing so at 13 wk. Similar results were seen in using the DATA to adjust premeal bolus doses of insulin. Conclusions:, These results show the feasibility of implementing the DATA when real-time continuous glucose monitoring is initiated and support its use in future clinical trials of real-time continuous glucose monitoring. [source]


Relationship between antimicrobial proteins and airway inflammation and infection in cystic fibrosis

PEDIATRIC PULMONOLOGY, Issue 4 2009
Scott D. Sagel MD
Abstract Antimicrobial proteins are important in lung defense and are potential therapeutic agents in chronic airways infection such as seen in cystic fibrosis (CF). In preparation for future clinical studies, we sought (1) to determine levels of three antimicrobial proteins [lactoferrin, lysozyme, and secretory leukoprotease inhibitor (SLPI)] in the CF airway and (2) to examine the relationships between these antimicrobial proteins and airway inflammation and infection. We examined bronchoalveolar lavage fluid (BALF) from 45 individuals with CF and 23 disease control individuals. Airway inflammation was measured through BALF neutrophil counts and neutrophil elastase activity. Infection was assessed through quantitative counts of CF-related bacterial pathogens. BALF lysozyme activity and lactoferrin levels were elevated in individuals with CF compared to controls whereas SLPI levels were not different between the groups. Among the CF subjects, lysozyme activity and lactoferrin increased with age while SLPI decreased with age. Lysozyme activity and lactoferrin concentrations correlated positively with neutrophil counts but not with bacterial colony counts. SLPI levels were inversely related to both neutrophil counts and bacterial colony counts. This study provides information concerning the levels of antimicrobial proteins present in the CF airway that are relevant to future clinical trials of these compounds and demonstrates clear relationships between antimicrobial protein-specific levels and airway inflammation and infection. Pediatr Pulmonol. 2009; 44:402,409. © 2009 Wiley-Liss, Inc. [source]


The Ginkgo biloba extract, EGb 761, fails to reduce brain infarct size in rats after transient, middle cerebral artery occlusion in conditions of unprevented, ischemia-induced fever

PHYTOTHERAPY RESEARCH, Issue 6 2006
Keli Carina Miltus de Lima
Abstract There is much biochemical evidence, but very few studies in animal models of stroke in vivo, to suggest that Ginkgo biloba (EGb 761) may offer neuroprotection against regional, ischemic brain damage; additional investigations are needed to ensure future clinical trials. This study reports the effects of EGb 761 given acutely or chronically before ischemia. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and the brain infarct size was assessed 24 h later. Dipyrone (100 mg/kg, i.p.) was injected 30 min before ischemia, and 2.5 and 5.5 h after ischemia, to reduce ischemia-induced fever. EGb 761 (Tebonin®) was given acutely (200 mg/kg, p.o., 60 min before ischemia) or chronically (100 mg/kg, p.o., once daily, for 14 days before ischemia). Acute or chronic treatment with EGb 761, either alone or in combination with dipyrone, did not reduce the infarct size compared with saline alone (p > 0.05). Dipyrone failed to prevent ischemia-induced fever during the intra-ischemic period (p > 0.05 vs saline; p < 0.001 vs sham). In the reperfusion phase, dipyrone reduced fever to normothermic levels in the group treated acutely with EGb 761 (p < 0.01 vs saline, p > 0.05 vs sham) but not after chronic EGb 761 (p < 0.01 vs sham), indicating possible pharmacokinetic interaction. In conclusion, within the context of unprevented, ischemia-induced fever, the present results demonstrate that EGb 761 has no significant effect on brain infarct size. Copyright © 2006 John Wiley & Sons, Ltd. [source]


Healthy aging demonstration project: Nurse coaching for behavior change in older adults,

RESEARCH IN NURSING & HEALTH, Issue 3 2005
Jill A. Bennett
Abstract The Healthy Aging Project (HAP) tested nurse coaching as a method to support healthy behavior change in older adults. The sample included 111 individuals randomized to a nurse coaching group or usual-care control group. Participants in the intervention group chose the health behaviors they wanted to change and received coaching by nurses in a single in-person session followed by telephone calls or email contact for 6 months. Nurses were trained in motivational interviewing (MI). The intervention group had significantly less illness intrusiveness and health distress than the control group at 6 months, although it is not known whether these health outcomes resulted from behavior changes. This clinical demonstration project showed that nurse-delivered MI, primarily using the telephone and email, is a feasible method to discuss behavioral change with older adults. However, future clinical trials will be needed to evaluate the efficacy of nurse-delivered MI on actual behavioral changes in older adults. © 2005 Wiley Periodicals, Inc. Res Nurs Health 28: 187,197, 2005 [source]


Free radical damage to cerebral cortex in Alzheimer's disease, microvascular brain injury, and smoking,

ANNALS OF NEUROLOGY, Issue 2 2009
Joshua A. Sonnen MD
Evidence supports a pathogenic role for free radical injury to brain in Alzheimer's disease; however, clinical trial results are only mildly encouraging. Examining brains from The Adult Changes in Thought study offers a unique perspective. Selectively increased free radical damage to cerebral cortex was associated with Alzheimer's disease, microvascular brain injury, and current smoking, but not with antioxidant supplement usage. Our results support suppression of free radical injury to brain as a therapeutic target for Alzheimer's disease and microvascular brain injury; however, future clinical trials should consider other antioxidants or doses than those identified in our study. Ann Neurol 2009;65:226,229 [source]


Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy

ANNALS OF NEUROLOGY, Issue 1 2007
Gerd Meyer zu Horste MD
Objective Charcot,Marie,Tooth disease (CMT) is the most common inherited neuropathy, and a duplication of the Pmp22 gene causes the most frequent subform CMT1A. Using a transgenic rat model of CMT1A, we tested the hypothesis that long-term treatment with anti-progesterone (Onapristone) reduces Pmp22 overexpression and improves CMT disease phenotype of older animals, thereby extending a previous proof-of-concept observation in a more clinically relevant setting. Methods We applied placebo-controlled progesterone-antagonist therapy to CMT rats for 5 months and performed grip-strength analysis to assess the motor phenotype. Quantitative Pmp22 RT-PCR and complete histological analysis of peripheral nerves and skin biopsies were performed. Results Anti-progesterone therapy significantly increased muscle strength and muscle mass of CMT rats and reduced the performance difference to wildtype rats by about 50%. Physical improvements can be explained by the prevention of axon loss. Surprisingly, the effects of anti-progesterone were not reflected by improved myelin sheath thickness. Electrophysiology confirmed unaltered NCV, but less reduced CMAP recordings in the treatment group. Moreover, the reduction of Pmp22 mRNA, as quantified in cutaneous nerves, correlated with the clinical phenotype at later stages. Interpretation Progesterone-antagonist treatment. Pmp22 overexpression to a degree at which the axonal support function of Schwann cells is better maintained than myelination. This suggests that axonal loss in CMT1A is not caused by demyelination, but rather by a Schwann cell defect that has been partially uncoupled by anti-progesterone treatment. Pmp22 expression analysis in skin may provide a prognostic marker for disease severity and for monitoring future clinical trials. Ann Neurol 2007;61:61,72 [source]


The impact of targeted training, a dedicated protocol and on-site training material in reducing observer variability of prostate and transition zone dimensions measured by transrectal ultrasonography, in multicentre multinational clinical trials of men with symptomatic benign prostatic enlargement

BJU INTERNATIONAL, Issue 1 2007
Philip S. Murphy
OBJECTIVE To assess the variability of a standardized protocol of transrectal ultrasonography (TRUS), with targeted training, and compare it to the variability in other multicentre clinical trials, as TRUS-estimated total prostate volume (TPV) and transition zone volume (TZV) are considered important efficacy endpoints in assessing new drug therapies for benign prostatic enlargement (BPE), but standardizing TRUS remains a challenge in such studies. PATIENTS AND METHODS In all, 174 patients with BPE in the placebo arm of a 30-centre clinical trial were analysed at baseline, 13 and 26 weeks with TRUS, to extract TPV and TZV values. All TRUS operators received training in the standardized methods, which was supplemented at the outset by a compact disc-based video. RESULTS The mean (sd) changes from baseline in TPV at 13 and 26 weeks were ,,2.9 (8.9) and ,1.9 (8.5) mL, respectively; the respective mean changes from baseline in TZV were ,1.2 (6.4) and +,0.7 (7.8) mL. For TPV, 80% of the measurements had differences of +,5.2 to ,13.4 mL at 13 weeks, and +,8.0 to ,,10.9 mL at 26 weeks. For TZV, 80% of the differences were +,5.8 to ,,7.4 at 13 weeks, and +,9.3 to ,6.5 mL at 26 weeks. CONCLUSION The performance of TRUS compared favourably with similar published multicentre studies, which we suggest relates in part to the careful implementation of the protocol. We showed that diligent implementation of a detailed protocol, supplemented by targeted training of investigators and provision of on-site training material, promoted consistent acquisition and successful derivation of key clinical trial endpoints. Quantifying the variability of such endpoints will enable us to track deployment quality for future clinical trials, and will ensure that trials are sufficiently powered to define small changes in prostate size. [source]


Development of a drug,disease simulation model for rituximab in follicular non-Hodgkin's lymphoma

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2009
David Ternant
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Serum concentrations of rituximab influence its clinical efficacy in follicular lymphoma (FL), but its concentration,effect relationship has not been described by pharmacokinetic,pharmacodynamic (PK,PD) modelling. , The genetic polymorphism of FCGR3A influences rituximab efficacy and its in vitro concentration,effect relationship. , Increasing rituximab dose and/or number of infusions may lead to a better clinical response in FL. WHAT THIS PAPER ADDS , This study is the first to describe the concentration,effect relationship of rituximab in populations of FL patients. , This PK,PD model relates progression-free survival with rituximab concentrations and takes into account the influence of FCGR3A polymorphism. , Clinical trials testing new dosing regimens of rituximab can be designed using this PK,PD model. AIM Rituximab has dramatically improved the survival of patients with non-Hodgkin's lymphomas (NHL), but the dosing regimen currently used should be optimized. However, the concentration,effect relationship of rituximab has never been described by pharmacokinetic,pharmacodynamic (PK,PD) modelling, precluding the simulation of new dosing regimens. The aim of this study was to develop a PK,PD model of rituximab in relapsed/resistant follicular NHL (FL). METHODS A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism on the efficacy of rituximab was quantified using data from 87 relapsed/resistant FL patients. The predictive performance of the model was analysed using two independent datasets: a study that evaluated rituximab combined with chemotherapy [rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP)] in 334 relapsed/resistant FL patients and a study that evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype. RESULTS For R-CHOP, observed and model-predicted PFS (90% confidence interval) at 24 months were 0.50 and 0.48 (0.40, 0.56), respectively, for the observation arm, and 0.62 and 0.59 (0.50, 0.65), respectively, for the rituximab maintenance arm. For rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively, for FCGR3A -V/V patients, and 0.41 and 0.36 (0.25, 0.49), respectively, for FCGR3A -F carriers. CONCLUSIONS Our model provides a satisfactory prediction of PFS at 24 months. It can be used to simulate new dosing regimens of rituximab in populations of FL patients and should improve the design of future clinical trials. [source]


Use of tamoxifen in advanced-stage hepatocellular carcinoma,

CANCER, Issue 7 2005
A systematic review
Abstract BACKGROUND Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. Survival is poor for patients with advanced-stage HCC, and small trials of tamoxifen for patients with this disease have shown conflicting results. The authors conducted a systematic review of randomized clinical trials to compare the effect of a tamoxifen-containing arm with a nontamoxifen-containing arm in advanced HCC. METHODS Eligible trials were identified from the Cochrane Hepato-Biliary Group register and other databases. Studies were selected for inclusion and their methodologic quality assessed by three independent reviewers. Hazard ratios (HR) were derived for overall survival where possible. Metaanalysis was performed using a fixed-effect model. RESULTS The authors identified 10 randomized trials with a total of 1709 patients. Use of tamoxifen had no effect on median survival (HR, 1.05; 95% confidence interval, 0.94,1.16; P = 0.4) or tumor response rate. The findings were stable in sensitivity analyses and were not affected by publication bias or inclusion of low-quality studies or studies reported in abstract form only. Few adverse events or withdrawals were noted. CONCLUSIONS There was no support for the therapeutic use of tamoxifen in advanced HCC, nor for its use as a control arm in future clinical trials. Cancer 2005. © 2005 American Cancer Society. [source]


Resuscitating the Microcirculation in Sepsis: The Central Role of Nitric Oxide, Emerging Concepts for Novel Therapies, and Challenges for Clinical Trials

ACADEMIC EMERGENCY MEDICINE, Issue 5 2008
Stephen Trzeciak MD
Abstract Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: 1) the central role of the microcirculation in the pathophysiology of sepsis; 2) new translational research techniques of in vivo video microscopy for assessment of microcirculatory flow in human subjects; 3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; 4) the potential role of novel agents to "rescue" the microcirculation in sepsis; 5) current challenges facing this emerging field of clinical investigation; and 6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide (NO) molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis). We also present the scientific rationale for clinical trials of exogenous NO administration to treat microcirculatory dysfunction and augment microcirculatory blood flow in early sepsis therapy. [source]


Will the potential of peroxisome proliferator-activated receptor agonists be realized in the clinical setting?

CLINICAL CARDIOLOGY, Issue S4 2004
Florian Blaschke M.D.
Abstract Drugs targeting both peroxisome proliferator-activated receptor-gamma (PPAR-,) agonists (the thiazolidinediones) and PPAR-, (the fibrates) have already been developed for clinical use. However, the thiazolidinediones, currently prescribed to treat hyperglycemia and improve peripheral insulin resistance, may also have cardiovascular benefits that have yet to be fully realized. Animal models of atherosclerosis have shown that the thiazolidinediones reduce the extent of atherosclerotic lesions and inhibit macrophage accumulation. Clinical studies have also shown that these drugs improve the lipid profile of patients at risk of developing atherosclerosis and reduce circulating levels of inflammatory markers. This combination of lower lipid concentrations and reduced inflammation may explain the cardiovascular benefits of this class of drugs. Early trials in patients with coronary stents have reported promising findings, with restenosis rates being greatly reduced with thiazolidinedione therapy. It is hoped that the results of future clinical trials will continue to be encouraging, so that the thiazolidinediones' cardiovascular benefits can be fully realized in the clinic. [source]