Could conditional release of new drugs provide the information required to study drug effectiveness? - A discussion paper.

Conditional release is the approval of a new drug onto the market, subject to specific conditions relating to effectiveness and safety that, if achieved, will lead to full approval. Conditional approval of a new drug, during which time it is used in normal clinical practice, should allow the collection of data on effectiveness and safety to provide a genuine cost effectiveness evaluation. Proposals put forward in 1977 in the United Kingdom for approving a drug on a conditional basis while monitoring for adverse drug reactions are examined, and issues that would affect a present day conditional release scheme are identified. These issues are: who would do the evaluation and who would pay for it; how would patients be identified and registered; would all new drugs be monitored and for how long; what data would be reported and evaluated; and who would do the reporting? How a conditional release scheme would work in Canada in light of these questions is considered and a method based on pharmacists registering patients and on physicians and/or patients reporting data to an independent organization funded by governments and the pharmaceutical industry is outlined. Under certain conditions, conditional release would provide the information to allow true cost effectiveness and safety assessments instead of the current inadequate predictions based on efficacy and safety data from clinical trials. It is important that academics and drug approval and monitoring agencies work together to develop active systems to improve the postapproval evaluation of effectiveness, safety and cost effectiveness of new drugs in Canada.

The effect of alcohol abuse on the risk of NSAID-related gastrointestinal events.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of gastrointestinal (GI) complications. Excessive alcohol consumption may further increase this risk and the FDA is requiring warnings on over-the-counter (OTC) NSAIDs. Our objective is to evaluate the risk of NSAID-related GI events for persons with a history of alcohol abuse. METHODS: This case control study used data from Saskatchewan Health. Cases consisted of 1083 patients hospitalized for severe GI events, whereas the control group consisted of 14,754 persons without such hospitalizations. RESULTS: Five percent of cases and 1.9% of controls had a history of treatment for alcohol abuse. The presence of either NSAID use or a history of alcohol abuse led to an odds ratio (OR) of 2.9* for severe GI events, whereas the presence of both risk factors simultaneously led to an OR of 10.2* (additive would be 5.8). Similarly, the presence of ibuprofen and naproxen use, which are OTC in the USA, without alcohol abuse led to an OR of 1.9*, whereas alcohol abuse by itself led to an OR of 2.4*. The presence of both OTC NSAIDs and alcohol abuse simultaneously, led to an OR of 6.5 (additive would be 4.3). Thus with both risk factors present, the resulting risk ratio is greater than the additive risk of the separate risk factors. CONCLUSIONS: The Food and Drug Administration (FDA) warning concerns concurrent use of alcohol with NSAIDs, whereas the present study presents the effect of long term alcohol abuse. Further research is needed to separate these two issues to allow physicians to provide the best advice to their patients. *Statistically significant at p<0.05.

Differences between males and females in risk of NSAID-related severe gastrointestinal events.

PURPOSE: NSAID use has long been established as a risk factor for severe gastrointestinal (GI) events. It is also known that age and gender affect the risk of such events independently of nonsteroidal antiinflammatory drug (NSAID) use. The objective of the present study is to distinguish between gender as an independent risk factor for severe GI events, and the differences between males and females in risk of NSAID-related severe GI events. METHODS: The study design was a nested case-control study. During the study period, 1029 cases were hospitalized with GI bleeds and/or perforations and 14 481 controls without such GI events were selected. Exposure consisted of the number of NSAID prescriptions dispensed by a pharmacy, prior to the data of hospitalization for cases and a corresponding date for controls. RESULTS: Males have a risk of serious GI events 1.4 times greater than females, independent of NSAID use. However, females have the greater increase in risk of NSAID-related GI events, e.g. at four prescriptions women have an odds ratio (OR) of 7.4 (p<0.05), while men have a corresponding OR of 3.2 (p<0.05). The increasing risk of severe GI events with number of NSAID prescriptions was considerably greater for females than for males, indicating effect-modification. In a stratified analysis by age and gender, it was clear that gender was the greater influence. Various metabolic and epidemiological potential explanations are discussed. CONCLUSIONS: Age and gender are separate risk factors for GI complications as related to NSAID use. Although implied in other studies, the effect of gender on the risk of NSAID-related GI events is clearly stated in this study.

Effects of hemicholinium and bretylium on the release of autonomic transmitters in the isolated sino-atrial node.

1. In the isolated, spontaneously beating, sino-atrial node of the rabbit selective electrical excitation of intranodal autonomic nerve fibres results in a biphasic chronotropic response. This chronotropic response (negative followed by positive chronotropism) is due to the release of the autonomic transmitters (acetylcholine and noradrenaline, respectively) from intranodal nerve fibres.2. In the presence of 2 x 10(-4) g/ml hemicholinium, the negative chronotropic (cholinergic) response is abolished while the positive chronotropic (adrenergic) response is unaltered.3. In the presence of 5 x 10(-6) g/ml bretylium, the positive chronotropic response is abolished while the negative chronotropic response is little affected.4. After blockade of the negative chronotropic response by hemicholinium, bretylium abolishes the remaining positive chronotropic response. The effect of bretylium is not altered in the presence of hemicholinium.5. Considering currently accepted mechanisms of action for hemicholinium and bretylium, the results of these experiments do not lend support to the cholinergic link hypothesis of adrenergic neuro-effector transmission.