The population pharmacokinetics of citalopram after deliberate self-poisoning: A Bayesian approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-I trials

Objectives: To investigate the effectiveness of valerian for the management of chronic insomnia in general practice. Design: Valerian versus placebo in a series of n-of-1 trials, in Queensland, Australia. Results: Of 42 enrolled patients, 24 (57%) had sufficient data for inclusion into the n-of-1 analysis. Response to valerian was fair for 23 (96%) participants evaluating their 'energy level in the previous day' but poor or modest for all 24 (100%) participants' response to 'total sleep time' and for 23 (96%) participants' response to 'number of night awakenings' and 'morning refreshment'. As a group, the proportion of treatment successes ranged from 0.35 (95% CI 0.23, 0.47) to 0.55 (95% CI 0.43, 0.67) for the six elicited outcome sleep variables. There was no significant difference in the number (P = 0.06), distribution (P = 1.00) or severity (P = 0.46) of side effects between valerian and placebo treatments. Conclusions: Valerian was not shown to be appreciably better than placebo in promoting sleep or sleep-related factors for any individual patient or for all patients as a group. (C) 2003 Elsevier Ltd. All rights reserved.

Serious lead poisoning in childhood: Still a problem after a century

Objective: To describe a series of patients with clinically significant lead poisoning. Methodology: A case series of nine patients with lead poisoning who required inpatient management, identified through a Clinical Toxicology Service. Results: Nine children presented with clinically significant lead poisoning. The median serum lead was 2.5 mumol/L (range 1.38-4.83). Eight of the children were exposed to lead-based paint, with seven due to dust from sanded lead paint during house renovations. Serial blood determinations suggested re-exposure in four of the patients, and in one of these patients the re-exposure was from a different source of lead. Eight of the patients required chelation therapy. Conclusions: Serious lead poisoning continues to occur and there appears to be complacency regarding the hazard posed by lead paint in old houses.

OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited.

Background: The OARSI Standing Committee for Clinical Trials Response Criteria Initiative had developed two sets of responder criteria to present the results of changes after treatment in three symptomatic domains (pain, function, and patient's global assessment) as a single variable for clinical trials (1). For each domain, a response was defined by both a relative and an absolute change, with different cut-offs with regard to the drug, the route of administration and the OA localization. Objective: To propose a simplified set of responder criteria with a similar cut-off, whatever the drug, the route or the OA localization. Methods: Data driven approach: (1) Two databases were considered The 'elaboration' database with which the formal OARSI sets of responder criteria were elaborated and The 'revisit' database. (2) Six different scenarios were evaluated: The two formal OARSI sets of criteria Four proposed scenarios of simplified sets of criteria Data from clinical randomized blinded placebo controlled trials were used to evaluate the performances of the two formal scenarios with two different databases ('elaboration' versus 'revisit') and those of the four proposed simplified scenarios within the 'revisit' database. The placebo effect, active effect, treatment effect, and the required sample arm size to obtain the placebo effect and the active treatment effect observed were the performances evaluated for each of the six scenarios. Experts' opinion approach: Results were discussed among the participants of the OMERACT VI meeting, who voted to select the definite OMERACT-OARSI set of criteria (one of the six evaluated scenarios). Results: Data driven approach: Fourteen trials totaling 1886 CA patients and fifteen studies involving 8164 CA patients were evaluated in the 'elaboration' and the 'revisit' databases respectively. The variability of the performances observed in the 'revisit' database when using the different simplified scenarios was similar to that observed between the two databases ('elaboration' versus 'revisit') when using the formal scenarios. The treatment effect and the required sample arm size were similar for each set of criteria. Experts' opinion approach: According to the experts, these two previous performances were the most important of an optimal set of responder criteria. They chose the set of criteria considering both pain and function as evaluation domain and requiring an absolute change and a relative change from baseline to define a response, with similar cut-offs whatever the drug, the route of administration or the CA localization. Conclusion: This data driven and experts' opinion approach is the basis for proposing an optimal simplified set of responder criteria for CA clinical trials. Other studies, using other sets of CA patients, are required in order to further validate this proposed OMERACT - OARSI set of criteria. (C) 2004 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Multidisciplinary strategies for the management of heart failure patients at high risk for admission - A systematic review of randomized trials

OBJECTIVES The aim of this study was to determine whether multidisciplinary strategies improve outcomes for heart failure (HF) patients. BACKGROUND Because the prognosis of HF remains poor despite pharmacotherapy, there is increasing interest in alternative models of care delivery for these patients. METHODS Randomized trials of multidisciplinary management programs in HF were identified by searching electronic databases and bibliographies and via contact with experts. RESULTS Twenty-nine trials (5,039 patients) were identified but were not pooled, because of considerable heterogeneity. A priori, we divided the interventions into homogeneous groups that were suitable for pooling. Strategies that incorporated follow-up by a specialized multidisciplinary team (either in a clinic or a non-clinic setting) reduced mortality (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.59 to 0.96), HF hospitalizations (RR 0.74, 95% CI 0.63 to 0.87), and all-cause hospitalizations (RR 0.81, 95% CI 0.71 to 0.92). Programs that focused on enhancing patient self-care activities reduced HF hospitalizations (RR 0.66, 95% CI 0.52 to 0.83) and all-cause hospitalizations (RR 0.73, 95% CI 0.57 to 0.93) but had no effect on mortality (RR 1.14, 95% CI 0.67 to 1.94). Strategies that employed telephone contact and advised patients to attend their primary care physician in the event of deterioration reduced HF hospitalizations (RR 0.75, 95% CI 0.57 to 0.99) but not mortality (RR 0.91, 95% CI 0.67 to 1.29) or all-cause hospitalizations (RR 0.98, 95% CI 0.80 to 1.20). In 15 of 18 trials that evaluated cost, multidisciplinary strategies were cost-saving. CONCLUSIONS Multidisciplinary strategies for the management of patients with HF reduce HF hospitalizations. Those programs that involve specialized follow-up by a multidisciplinary team also reduce mortality and all-cause hospitalizations. (C) 2004 by the American College of Cardiology Foundation.

The comprehensive osteoarthritis test: a simple index for measurement of treatment effects in clinical trials

Objective. To assess the measurement properties of a simple index of symptom severity in osteoarthritis (OA) of the hips and knees. Methods. Both the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the proposed new Comprehensive Osteoarthritis Test (COAT) instrument were completed weekly by 125 subjects in the context of a randomized, 12-week, 3 parallel-arm clinical trial. The reliabilities of the various scales were assessed on a weekly basis by use of Cronbach's alpha coefficients. The validity of the COAT total scale was assessed by correlation with the WOMAC total scale on a weekly basis with correlation coefficients, and in terms of the correlations between subject-level intercepts and slopes over time. The relative responsiveness of the WOMAC and COAT total scales was assessed using a multilevel (longitudinal) multivariate (WOMAC, COAT) linear model. Results. The WOMAC and COAT total scales were highly reliable (mean over weeks: WOMAC alpha = 0.98; COAT alpha = 0.97). The correlations between the WOMAC and COAT scales were very high (mean over weeks = 0.92; subject-level intercepts = 0.91, slopes = 0.88). The COAT total scale was significantly more responsive than the WOMAC total scale in the active treatment (34.8% improvement vs 26.8%; p = 0.002). Conclusion. The COAT total scale is simple to administer, reliable, valid, and responsive to treatment effects.

Mixed model formulations for multi-environment trials

When studying genotype X environment interaction in multi-environment trials, plant breeders and geneticists often consider one of the effects, environments or genotypes, to be fixed and the other to be random. However, there are two main formulations for variance component estimation for the mixed model situation, referred to as the unconstrained-parameters (UP) and constrained-parameters (CP) formulations. These formulations give different estimates of genetic correlation and heritability as well as different tests of significance for the random effects factor. The definition of main effects and interactions and the consequences of such definitions should be clearly understood, and the selected formulation should be consistent for both fixed and random effects. A discussion of the practical outcomes of using the two formulations in the analysis of balanced data from multi-environment trials is presented. It is recommended that the CP formulation be used because of the meaning of its parameters and the corresponding variance components. When managed (fixed) environments are considered, users will have more confidence in prediction for them but will not be overconfident in prediction in the target (random) environments. Genetic gain (predicted response to selection in the target environments from the managed environments) is independent of formulation.