warfarin and Malaria

The cytochome P450 enzyme system is responsible for the metabolism of xenobiotics, including > 75% of commonly prescribed medications. Many of the cytochrome enzymes exhibit polymorphic genotypes, partly accounting for the variations observed in individual drug responses. Recent advances in the understanding of functional alleles of cytochrome P450 enzymes have changed the use of medications. Improvements in drug efficacy and the prevention of toxicity, as well as improvements in clinical drug dosing, have enhanced pharmacotherapy decisions in medical practice. In addition to personalizing medicine, the identification and quantification of genotypic differences in cytochrome P450 metabolism has the potential to facilitate population-based personalized medicine in countries without the resources to perform genotypic tests at the point of care. This review provides an update on the utility of genotype-guided therapy when treating breast cancer, malaria and coagulation disorders. Also discussed are advancements made in diagnostic tests for cytochrome genotypes and the need for future research in the area of diagnostic tests.

Topics: Amodiaquine; Anticoagulants; Antimalarials; Breast Neoplasms; Cytochrome P-450 Enzyme System; Estrogen Antagonists; Female; Genotype; Humans; Isoenzymes; Malaria; Molecular Structure; Pharmaceutical Preparations; Precision Medicine; Tamoxifen; Warfarin; Xenobiotics

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Topics: Animals; Antimalarials; Benzimidazoles; Life Cycle Stages; Malaria; Male; Mice; Plasmodium berghei; Structure-Activity Relationship

Topics: Administration, Oral; Aminopyridines; Aminoquinolines; Animals; Antimalarials; Cell Membrane Permeability; Chloroquine; CHO Cells; Cricetulus; Drug Evaluation, Preclinical; Drug Resistance, Microbial; ERG1 Potassium Channel; Hemeproteins; Humans; Malaria; Male; Mice, Inbred BALB C; Plasmodium berghei; Plasmodium falciparum; Solubility; Structure-Activity Relationship

The cluster-randomized trial is the methodology of choice for evaluating interventions administered at the group level such as public health and healthcare quality improvement interventions. Because of unique features of this design, it can be difficult to apply standard research ethics guidelines to cluster-randomized trials. The Ottawa Statement on the Ethical Design and Conduct of Cluster-Randomized Trials provides researchers and research ethics committees with comprehensive guidance on the ethical design, conduct and review of cluster-randomized trials. The Ottawa Statement supplements current national and international research ethics guidelines with guidance that is specific to cluster-randomized trials. In a recently published commentary, three examples drawn from the ClinicalTrials.gov registry were used to illustrate challenges associated with the cluster-randomized trial design. The commentary argued that the Ottawa Statement fails to provide comprehensive ethical guidance. In this article, we illustrate the application of the Ottawa Statement to the three trials. We challenge the conclusions reached in the commentary by demonstrating that an ethical analysis requires complete information. We correct some misperceptions about the cluster-randomized trial design.. We collected essential additional information by contacting the authors of trials and by referring to published trial articles. We used the Ottawa Statement to conduct an ethical analysis of each trial and to address a number of substantive concerns raised regarding the identification of study participants, informed consent and harm benefit analysis.. In the two cases in which we were able to obtain detailed study information, we were able to complete the ethical analysis prescribed by the Ottawa Statement.. The Ottawa Statement does provide a useful framework for the ethical design, review and conduct of cluster-randomized trials.

Topics: Anticoagulants; Disease Management; Ethics Committees, Research; Ethics, Research; Family Planning Services; Guidelines as Topic; Health Services; HIV Infections; Humans; Informed Consent; Malaria; Randomized Controlled Trials as Topic; Registries; Research Design; Risk Assessment; Warfarin