Comparative evaluation of US Food and Drug Administration and pharmacologically guided approaches to determine the maximum recommended starting dose for first-in-human clinical trials in adult healthy men.

The authors compared US Food and Drug Administration (FDA) and 9 pharmacologically guided approaches (PGAs; simple allometry, maximum life span potential [MLP], brain weight, rule of exponent [ROE], two 2-sp methods and 3 one-sp methods) to determine the maximum recommended starting dose (MRSD) for first-in-human clinical trials in adult healthy men using 10 drugs. The ROE method as suggested by Mahmood and Balian1 gave the best prediction accuracy for a pharmacokinetic (PK) parameter. Values derived from clearance were consistently better than volume of distribution (Vd)-based methods and had lower root mean square error (RMSE) values. A pictorial method evaluation chart was developed based on fold errors for simultaneous evaluation of various methods. The one-sp method (rat) and the US FDA methods gave the highest prediction accuracy and low RMSE values, and the 2-sp methods gave the least prediction accuracy with high RMSE values. The ROE method gave more consistent predictions for PK parameters than other allometric methods. Despite this, the MRSD predictions were not better than US FDA methods, probably indicating that across-species variation in clearance may be higher than variation in no observed adverse effect level (NOAEL) and that PGA methods may not be consistently better than the NOAEL based methods.

Evaluation of the ability of clinical research participants to comprehend informed consent form.

BACKGROUND: The comprehension of informed consent is an integral part of clinical trials. Though India is rapidly becoming a hub of clinical trials very few studies have dealt with the issue of comprehension of informed consent by the patients participating in these trials. METHODS: Patients who were invited to participate in a phase 3 multicentric trial of a novel lipid lowering agent were evaluated for comprehension score. The participants were explained about the structured consent form which included the question on background details for the study, design of the study, rights of the patients and miscellaneous aspects pertinent to the clinical trial. The questionnaire comprised of 24 items and each correct answer was assigned a score of 1. Total comprehension score (CS) was obtained by summing all the scores. RESULTS: Participants were from diverse socio economic and educational backgrounds. The mean +/- SD CS achieved by the participants was 13.4 +/- 2.9; median 14(6 to 20). The highest correct responses were obtained for questions on background details (38%). For most of the categories the mean CS was more than 50%. Aspects related to design were mostly difficult to comprehend. No significant difference in the CS was noted between participants from different educational and socioeconomic groups. 8 patients refused to give consent, fear of adverse drug reactions (n = 3) and inability to follow up (n = 5) were the reasons cited by the patients. CONCLUSION: In conclusion, CS of patients in trials conducted in developing countries can be reasonably good if the investigators explain the consent form in simple language to the participants and CS is not related to the educational status of the participants. Moreover, though a larger majority of patients agree to participate after knowing study details, some patients exercise their right to refuse.

Efficacy of biologicals in the treatment of rheumatoid arthritis. a meta-analysis.

Rheumatoid arthritis (RA) is a chronic multisystem disease. A characteristic feature of RA is persistent inflammatory synovitis, usually involving the peripheral joints in a symmetric distribution. The prevalence of RA is approximately 0.8% of the population (range: 0.3-2.1%); women are affected approximately 3 times more often than men. The current therapeutic approach is to start a disease-modifying agent early in the illness to prevent eventual joint damage. Older disease-modifying anti-rheumatic drugs include methotrexate, sulphasalazine and hydroxychloroquine. Newer ones such as leflunomide and cyclosporin are also used. A recent advance in the management of rheumatoid arthritis is the use of biological agents, which block certain key molecules involved in the pathogenesis of the illness. They include tumour-necrosis-factor-alpha-blocking agents such as infliximab, etanercept and adalimumab, the anti-CD-20 agent, rituximab, and CTLA-4 Ig abatacept. The present study was planned with the aim of evaluating the efficacy of such newer biological therapies in refractory RA at various time points. Databases including Medline, Embase and the Cochrane Library were searched for all relevant studies up to January 2007. A total of 26 studies were included in present meta-analysis. The method of DerSimonian and Laird [Control Clin Trials 1986;7:177-188] was used to calculated a pooled odds ratio (OR) for the American College of Rheumatology (ACR) criteria 20, 50 and 70, at 24, 54 and 96 weeks. The overall pooled OR were found to be significantly more than the placebo at all 3 time points for all 3 criteria (ACR 20, 50 70). In conclusion, biologicals as a group are highly effective in the treatment of RA. Biologicals were efficacious both in treatment naïve and methotrexate-refractory patients.

Association of anticardiolipin antibodies levels with instent restenosis in patients with coronary artery disease.

Present study was conducted to evaluate the association of IgG anticardiolipin antibodies with instent restenosis in patients having undergone percutaneous intervention with bare metal or drug eluting stents. Coronary artery disease patients with stent placement at least 6 months prior were screened for eligibility. 26 satisfied the inclusion/exclusion criteria. 10 patients with symptoms of restenosis, confirmed on check angiography served as cases and 16 without symptoms of restenosis served as control. Unpaired t- test was applied to ascertain the significance of any difference between control and study groups. Antibody levels were estimated on ELISA reader. The mean (+/- SD) anticardiolipin antibodies levels in cases and controls were 11.8 +/- 5.1 GPL/U/ml and 14.3 +/- 10.2 GPL/U/ml, respectively. The difference was not statistically significant (P > 0.05). In conclusion, we did not observe any significant correlation between the level of IgG aCL and instent restenosis.

A meta-analysis to evaluate the efficacy of statins in children with familial hypercholesterolemia.

This meta-analysis was conducted to evaluate the effect of statins on the lipid profile in pediatric and adolescent patients with familial hypercholesterolemia (FH). Randomized, double-blind, controlled trials comparing statins with placebo were identified through electronic and manual search; percent reductions from baseline were calculated for various lipid parameters. Standardized mean differences (effect size) with 95% confidence interval (CI) were calculated for each study and pooled effect size was calculated. A total of 6 studies were included in the meta-analysis. As compared to placebo, statins caused a significant decrease in total cholesterol (TC) [-3.11% (95% CI -3.46 to -2.99)], low-density lipoprotein (LDL) [-4.01% (95% CI -4.27 to -3.81)], triglyceride (TG) [-1.41 (95% CI -1.66 to -1.26)] and a significant increase in high-density lipoprotein (HDL) [1.12 (95% CI 0.73 1.13)]. In conclusion, statins were shown to have good efficacy for the treatment of FH in children.

Technique for measuring the beam shape of pulsed lasers.

A simple technique for the measurement of the beam shape parameters of pulsed lasers, with just a single pulse of the laser is described. It involves the use of several beam dividers inclined at very small angles to the beam axis, reflecting the beam back to a screen or a phosphor placed near the exit of the laser. The reflected images are then photographed by a camera to yield the beam parameters.

Device for reusing damaged laser mirrors.

A simple mirror holder which permits the use of locally damaged laser morrors by allowing the undamaged areas of the reflector to be aligned along the laser optic axis is described. The mirror holder has an eccentric step for housing the mirror and a concentric aperture through which the undamaged surface of the reflector is utilised. By varying the eccentricity and by rotating the mirror inside the step the entire surface area of the reflector can be used successively.