Exposure of DNA to chemicals can result in the formation of DNA adducts, a molecular initiating event in genotoxin-induced carcinogenesis. O(6)-Methylguanine (O(6)-MeG) is a highly mutagenic DNA adduct that forms in human genomic DNA upon reaction with methylating agents of dietary, environmental, or endogenous origin. In this work, we report the design and synthesis of novel non-natural nucleoside analogues 1'-β-[1-naphtho[2,3-d]imidazol-2(3H)-one)]-2'-deoxy-d-ribofuranose and 1'-β-[1-naphtho[2,3-d]imidazole]-2'-deoxy-d-ribofuranose and their use for quantifying O(6)-MeG within mutational hotspots of the human KRAS gene. The novel nucleoside analogues were incorporated into oligonucleotides conjugated to gold nanoparticles to comprise a DNA hybridization probe system for detecting O(6)-MeG in a sequence-specific manner on the basis of colorimetric readout of the nanoparticles. The concept described herein is unique in utilizing new nucleoside analogues with elongated hydrophobic surfaces to successfully measure in-gene abundance of O(6)-MeG in mixtures with competing unmodified DNA.
We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.
Genetic predisposition is one factor influencing interindividual drug response. Pharmacogenetic information can be used to guide the selection and dosing of certain drugs. However, the implementation of pharmacogenetics (PGx) in clinical practice remains challenging. Defining a formal structure, as well as concrete procedures and clearly defined responsibilities, may facilitate and increase the use of PGx in clinical practice. Over 140 patient cases from an observational study in Switzerland formed the basis for the design and refinement of a pharmacist-led pharmacogenetics testing and counselling service (PGx service) in an interprofessional setting. Herein, we defined a six-step approach, including: (1) patient referral; (2) pre-test-counselling; (3) PGx testing; (4) medication review; (5) counselling; (6) follow-up. The six-step approach supports the importance of an interprofessional collaboration and the role of pharmacists in PGx testing and counselling across healthcare settings.
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