Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence

A cocaine vaccine'' is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

Physical enhancement of transdermal drug application: is delivery technology keeping up with pharmaceutical development?

Advances in molecular biology have given us a wide range of protein and peptide-based drugs that are unsuitable for oral delivery because of their high degree of first-pass metabolism. Though parenteral delivery is the obvious answer, for the successful development of commercial chronic and self-administration usage formulations it is not the ideal choice. Transdermal delivery is emerging as the biggest application target for these agents, however, the skin is extremely efficient at keeping out such large molecular weight compounds and therapeutic levels are never going to be realistically achieved by passive absorption. Physical enhancement mechanisms including: iontophoresis, electroporation, ultrasound, photomechanical waves, microneedles and jet-propelled particles are emerging as solutions to this topical delivery dilemma. Adding proteins and peptides to the list of other large molecular weight drugs with insufficient passive transdermal fluxes to be therapeutically useful, we have a collection of pharmacological agents waiting for efficient delivery methods to be introduced. This article reviews the current state of physical transdermal delivery technology, assesses the pros and cons of each technique and summarises the evidence-base of their drug delivery capabilities.

Differences in mail and telephone responses to self-rated health: use of multiple imputation in correcting for response bias

Objectives: To estimate differences in self-rated health by mode of administration and to assess the value of multiple imputation to make self-rated health comparable for telephone and mail. Methods: In 1996, Survey 1 of the Australian Longitudinal Study on Women's Health was answered by mail. In 1998, 706 and 11,595 mid-age women answered Survey 2 by telephone and mail respectively. Self-rated health was measured by the physical and mental health scores of the SF-36. Mean change in SF-36 scores between Surveys 1 and 2 were compared for telephone and mail respondents to Survey 2, before and after adjustment for socio-demographic and health characteristics. Missing values and SF-36 scores for telephone respondents at Survey 2 were imputed from SF-36 mail responses and telephone and mail responses to socio-demographic and health questions. Results: At Survey 2, self-rated health improved for telephone respondents but not mail respondents. After adjustment, mean changes in physical health and mental health scores remained higher (0.4 and 1.6 respectively) for telephone respondents compared with mail respondents (-1.2 and 0.1 respectively). Multiple imputation yielded adjusted changes in SF-36 scores that were similar for telephone and mail respondents. Conclusions and Implications: The effect of mode of administration on the change in mental health is important given that a difference of two points in SF-36 scores is accepted as clinically meaningful. Health evaluators should be aware of and adjust for the effects of mode of administration on self-rated health. Multiple imputation is one method that may be used to adjust SF-36 scores for mode of administration bias.

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.