50,397 research outputs found
Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics
Full text linkTamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an overview of the research to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Based on the evidence to date, the impact of drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline approved endocrine therapy.</p
The risk of questioning the safety of drugs considered safe in pregnancy at the era of big data - the everlasting case of doxylamine [letter].
Full text linkOndansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC)
No full textOndansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision
Pharmacogenetics in Psychiatry
No full textMental illness represents a major health issue both at the individual and at the socioeconomical level. This is partly due to the current suboptimal treatment options: existing psychotropic medications, including antidepressants, antipsychotics, and mood stabilizers, are effective only in a subset of patients or produce partial response and they are often associated with debilitating side effects that discourage adherence. Pharmacogenetics is the study of how genetic information impacts on drug response/side effects with the goal to provide tailored treatments, thereby maximizing efficacy and tolerability. The first pharmacogenetic studies focused on candidate genes, previously known to be relevant to the pharmacokinetics and pharmacodynamics of psychotropic drugs. Results were mainly inconclusive, but some replicated candidates were identified and included as pharmacogenetic biomarkers in drug labeling and in some commercial kits. With the advent of the genomic revolution, it became possible to study the genetic variation on an unprecedented scale, throughout the whole genome with no need of a priori hypothesis. This may lead to the personalized prescription of existing medications and potentially to the development of innovative ones, thanks to new insights into the genetics of mental illness. Promising findings were obtained, but methods for the generation and analysis of genome-wide and sequencing data are still in evolution. Future pharmacogenetic tests may consist of hundreds/thousands of polymorphisms throughout the genome or selected pathways in order to take into account the complex interactions across variants in a number of genes
SSRIs in Pregnancy-What Offspring Brain Volumes Can and Cannot Tell Us [letter to the editor].
No full textObviously nine believers: Actionable germline genetic variants for pre‐emptive pharmacogenetic testing
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