PubMed · 17110724
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Adam Bakker, Cindy Fazey. 2006-11-18. Methadone tolerance testing in drug misusers.. https://doi.org/10.1136/bmj.39016.471840.68
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PURPOSE: Our objective was to evaluate the incidence of adverse patient outcomes due to drug-drug interactions (D-DIs), the type of drugs involved and the underlying reason. As a proxy for adverse patient outcomes, emergency department (ED) visits, hospital admissions and re-hospitalisations were assessed. METHODS: A literature search in the Medline and Embase database (1990-2006) was performed and references were tracked. An overall cumulative incidence was estimated by dividing the sum of the cases by the sum of the study populations. RESULTS: Twenty-three studies were found assessing the relationship between D-DIs and ED-visits, hospitalisations or re-hospitalisations. The studies with a large study size showed low incidences and vice versa. D-DIs were held responsible for 0.054% of the ED-visits, 0.57% of the hospital admissions and 0.12% of the re-hospitalisations. In the elderly population, D-DIs were held responsible for 4.8% of the admissions. Drugs most often involved were NSAIDs and cardiovascular drugs. The reasons for admissions or ED-visits, which were most often found were GI-tract bleeding, hyper- or hypotension and cardiac rhythm disturbances. CONCLUSION: This review provides information on the overall incidence of D-DIs as a cause of adverse patient outcomes, although there is still uncertainty about the impact of D-DIs on adverse patient outcomes. Our results suggest that a limited number of drugs are involved in the majority of cases and that the number of reasons for admission as a consequence of D-DIs seems to be modest.
PURPOSE OF REVIEW: A wide array of drugs can cause marked QT prolongation with the associated risk of torsade de pointes. The large number of drugs with this potential, the correspondingly large number of patients exposed to such drugs, and the potentially fatal outcome make drug-induced long QT syndrome an important public health problem. This review focuses on mechanisms underlying QT prolongation and proarrhythmia, risk factors, including the role of genetic variants, and the unifying framework of reduced repolarization reserve. RECENT FINDINGS: While most drugs that prolong the QT block a specific potassium channel, novel mechanisms altering protein trafficking have been discovered. The progression to torsade de pointes may be less related to degree of QT prolongation than to drug effects on transmural dispersion or variability of repolarization. Our understanding of certain predisposing risk factors has been further refined. SUMMARY: Ongoing research continues to elucidate the mechanisms underlying drug-induced long QT syndrome. Importantly, studies are establishing improved predictors of risk for progression to torsade de pointes, in addition to the degree of QT prolongation, which is an imperfect predictor. Nonetheless, drug-induced long QT syndrome and torsade de pointes pose unique challenges for clinicians, researchers, drug-development programs, and regulatory agencies.
Interest in cannabinoid pharmacology increased dramatically upon the identification of the first cannabinoid receptor (CB1) in 1998 and continues to expand as additional endocannabinoids and cannabinoid receptors are discovered. Using CB1 receptor (CB1R) systems, medicinal chemistry programs began screening libraries searching for cannabinoid ligands, ultimately leading to the discovery of the first potent cannabinoid receptor antagonist, SR141716A (Rimonabant). Its demonstrated efficacy in treating obesity and facilitating smoking cessation, among other impressive pharmacological activities, has furthered the interest in cannabinoid receptor antagonists as therapeutics, such that the number of patents and publications covering this class of compounds continues to grow at an impressive rate. At this time, medicinal chemistry approaches including combinatorial chemistry, conformational constraint, and scaffold hopping are continuing to generate a large number of cannabinoid antagonists. These molecules provide an opportunity to gain insight into the 3-dimensional structure-activity relationships that appear crucial for CB1R-ligand interaction. In particular, studies in which conformational constraints have been imposed on the various pyrazole ring substituents of SR141716A provide a direct opportunity to characterize changes in conformation/conformational freedom within a single class of compounds. While relatively few conformationally constrained molecules have been synthesized to date, the structure-activity information is often more readily interpreted than in studies where entire substituents are replaced. Thus, it is the focus of this mini-review to examine the structural properties of SR141716A, and to use conformationally constrained molecules to illustrate the importance of conformation and conformational freedom to CB1R affinity, selectivity, and efficacy.