Impact of SLCO1B1 genetic variation on rosuvastatin systemic exposure in pediatric hypercholesterolemia.

Clin Transl Sci. 2020 Jan 25;:

Authors: Wagner JB, Abdel-Rahman S, Gaedigk A, Gaedigk R, Raghuveer G, Staggs VS, Van Haandel L, Steven Leeder J

Abstract
This study investigated the impact of SLCO1B1 genotype on rosuvastatin systemic exposure in hypercholesterolemic children and adolescents. Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n=13; 521CC, n=2) and wild type controls (521TT, n=13) completed a single oral dose pharmacokinetic study. The variability contributed by SLCO1B1 c.521 sequence variation to rosuvastatin (RVA) systemic exposure amongst our pediatric cohort was comparable to previous studies in adults. Rosuvastatin concentration-time curve from 0 to 24h (AUC0-24 ) was 1.4- and 2.2-fold higher in participants with c.521TC and c.521CC genotype compared 521TT participants, respectively. Inter-individual variability of RVA exposure within SLCO1B1 genotype groups exceeded the ~1.5- to 2-fold difference in mean RVA exposure observed between SLCO1B1 genotype groups, suggesting that other factors also contribute to inter-individual variability in the rosuvastatin dose-exposure relationship. A multivariate model performed confirmed SLCO1B1 c.521T>C genotype as the primary factor contributing to RVA systemic exposure in this pediatric cohort, accounting for ~30% of the variability RVA AUC0-24 . However, of the statin investigated to date in the pediatric population, rosuvastatin has the lowest magnitude of variability in systemic exposure.

PMID: 31981411 [PubMed - as supplied by publisher]

Alternative Splicing in the Nuclear Receptor Superfamily Redirects Human Metabolic Homeostasis.

Drug Metab Dispos. 2020 Jan 24;:

Authors: Annalora AJ, Marcus CB, Iversen PL

Abstract
TThe human genome encodes 48 nuclear receptor (NR) genes, whose translated products transform chemical signals from endo-xenobiotics into pleotropic RNA transcriptional profiles that refine drug metabolism. This review describes the remarkable diversification of the 48 human NR genes, which are potentially processed into over 1000 distinct mRNA transcripts by alternative splicing (AS). The average human NR expresses ~21 transcripts per gene and is associated with ~7000 single nucleotide polymorphisms (SNP). However, the rate of SNP accumulation does not appear to drive the AS process, highlighting the resilience of NR genes to mutation. Here we summarize the altered tissue distribution/function of well-characterized NR splice variants associated with human disease. We also describe a cassette exon visualization pictograph (CEViP) methodology for illustrating the location of modular, cassette exons in genes, which can be skipped in-frame, to facilitate the study of their functional relevance to both drug metabolism and NR evolution. We find cassette exons associated with all of the functional domains of NR genes including the DNA- and ligand-binding domains. The matrix of inclusion or exclusion for functional domain-encoding cassette exons is extensive and capable of significant alterations in cellular phenotypes that modulate endo-xenobiotic metabolism. Exon inclusion options are differentially distributed across NR subfamilies, suggesting group-specific conservation of resilient functionalities. A deeper understanding of this transcriptional plasticity expands our understanding of how chemical signals are refined and mediated by NR genes. This expanded view of the NR transcriptome informs new models of chemical toxicity, disease diagnostics and precision-based approaches to personalized medicine. SIGNIFICANCE STATEMENT: This review explores the impact of AS on the human NR superfamily and highlights the dramatic expansion of >1,000 potential transcript variants from 48 individual genes. Xenobiotics are increasingly recognized for their ability to perturb gene splicing events, but the physiological impact of AS remains poorly understood. Here we explore the differential sensitivity of NR genes to AS and discuss how their differential expression profiles may augment cellular resilience to stress and fine-tune adaptive, metabolic responses to endo-xenobiotic exposure.

PMID: 31980501 [PubMed - as supplied by publisher]

Nanomedicine and Immunotherapy: A Step Further towards Precision Medicine for Glioblastoma.

Molecules. 2020 Jan 23;25(3):

Authors: Šamec N, Zottel A, Videtič Paska A, Jovčevska I

Abstract
Owing to the advancement of technology combined with our deeper knowledge of human nature and diseases, we are able to move towards precision medicine, where patients are treated at the individual level in concordance with their genetic profiles. Lately, the integration of nanoparticles in biotechnology and their applications in medicine has allowed us to diagnose and treat disease better and more precisely. As a model disease, we used a grade IV malignant brain tumor (glioblastoma). Significant improvements in diagnosis were achieved with the application of fluorescent nanoparticles for intraoperative magnetic resonance imaging (MRI), allowing for improved tumor cell visibility and increasing the extent of the surgical resection, leading to better patient response. Fluorescent probes can be engineered to be activated through different molecular pathways, which will open the path to individualized glioblastoma diagnosis, monitoring, and treatment. Nanoparticles are also extensively studied as nanovehicles for targeted delivery and more controlled medication release, and some nanomedicines are already in early phases of clinical trials. Moreover, sampling biological fluids will give new insights into glioblastoma pathogenesis due to the presence of extracellular vesicles, circulating tumor cells, and circulating tumor DNA. As current glioblastoma therapy does not provide good quality of life for patients, other approaches such as immunotherapy are explored. To conclude, we reason that development of personalized therapies based on a patient's genetic signature combined with pharmacogenomics and immunogenomic information will significantly change the outcome of glioblastoma patients.

PMID: 31979318 [PubMed - in process]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/01/25

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change.

NPJ Genom Med. 2020;5:1

Authors: Oni-Orisan A, Haldar T, Ranatunga DK, Medina MW, Schaefer C, Krauss RM, Iribarren C, Risch N, Hoffmann TJ

Abstract
In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.

PMID: 31969989 [PubMed]

Human leukocyte antigen DRB1*04:05 and clozapine-induced agranulocytosis/granulocytopenia.

Aust N Z J Psychiatry. 2020 Jan 22;:4867419900296

Authors: Saito T, Ikeda M, Mushiroda T, Iwata N, Clozapine Pharmacogenomics Consortium of Japan (CPC-J)

PMID: 31968985 [PubMed - as supplied by publisher]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/01/23

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Genetics of Treatment Outcomes in Major Depressive Disorder: Present and Future.

Clin Psychopharmacol Neurosci. 2020 Feb 29;18(1):1-9

Authors: Fabbri C, Serretti A

Abstract
Pharmacogenetic testing is a useful and increasingly widespread tool to assist in antidepressant prescription. More than ten antidepressants (including tricyclics, selective serotonin reuptake inhibitors and venlafaxine) have already genetic biomarkers of response/side effects in clinical guidelines and drug labels. These are represented by functional genetic variants in genes coding for cytochrome enzymes (CYP2D6 and CYP2C19). Depending on the predicted metabolic activity, guidelines provide recommendations on drug choice and dosing. Despite not conclusive, the current evidence suggests that testing can be useful in patients who did not respond or tolerate at least one previous pharmacotherapy. However, the current recommendations are based on pharmacokinetic genes only (CYP450 enzymes), while pharmacodynamic genes (modulating antidepressant mechanisms of action in the brain) are still being studied because of their greater complexity. This may be captured by polygenic risk scores, which reflect the cumulative contribution of many genetic variants to a trait, and they may provide future clinical applications of pharmacogenetics. A more extensive use of genotyping in clinical practice may lead to improvement in treatment outcomes thanks to personalized treatments, but possible ethical issues and disparities should be taken into account and prevented.

PMID: 31958900 [PubMed]

Systematic Review and Meta-Analysis of the Moderating Effect of rs1799971 in OPRM1, the Mu-opioid Receptor Gene, on Response to Naltrexone Treatment of Alcohol Use Disorder.

Addiction. 2020 Jan 21;:

Authors: Hartwell EE, Feinn R, Morris PE, Gelernter J, Krystal J, Arias AJ, Hoffman M, Petrakis I, Gueorguieva R, Schacht JP, Oslin D, Anton RF, Kranzler HR

Abstract
BACKGROUND AND AIMS: There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment.
METHODS: We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percent heavy drinking days, percent days abstinent, and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model.
RESULTS: Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d = -0.18, p = 0.02). However, the effect was not significant when multiple comparisons were taken into account.
CONCLUSIONS: From the evidence to date, it remains unclear whether Rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.

PMID: 31961981 [PubMed - as supplied by publisher]

Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings.

Clin Transl Sci. 2020 Jan 21;:

Authors: Smith DM, Peshkin BN, Springfield TB, Brown RP, Hwang E, Kmiecik S, Shapiro R, Eldadah Z, Lundergan C, McAlduff J, Levin B, Swain SM

Abstract
Most literature describing pharmacogenetic implementations are within academic medical centers and use single-gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel-based testing in academic and non-academic settings. This was a retrospective analysis of 667 patients from a pilot in four perioperative and five outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and U.S. Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared to 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected.

PMID: 31961467 [PubMed - as supplied by publisher]

Genetic variants in CYP2A6 and UGT1A9 genes associated with urinary nicotine metabolites in young Mexican smokers.

Pharmacogenomics J. 2020 Jan 21;:

Authors: Borrego-Soto G, Perez-Paramo YX, Chen G, Santuario-Facio SK, Santos-Guzman J, Posadas-Valay R, Alvarado-Monroy FM, Balderas-Renteria I, Medina-Gonzalez R, Ortiz-Lopez R, Lazarus P, Rojas-Martinez A

Abstract
Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3'-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p = 0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p = 0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p = 0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.

PMID: 31959879 [PubMed - as supplied by publisher]

Pharmacometabonomics: The Prediction of Drug Effects Using Metabolic Profiling.

Handb Exp Pharmacol. 2019;260:263-299

Authors: Everett JR

Abstract
Metabonomics, also known as metabolomics, is concerned with the study of metabolite profiles in humans, animals, plants and other systems in order to assess their health or other status and their responses to experimental interventions. Metabonomics is thus widely used in disease diagnosis and in understanding responses to therapies such as drug administration. Pharmacometabonomics, also known as pharmacometabolomics, is a related methodology but with a prognostic as opposed to diagnostic thrust. Pharmacometabonomics aims to predict drug effects including efficacy, safety, metabolism and pharmacokinetics, prior to drug administration, via an analysis of pre-dose metabolite profiles. This article will review the development of pharmacometabonomics as a new field of science that has much promise in helping to deliver more effective personalised medicine, a major goal of twenty-first century healthcare.

PMID: 31823071 [PubMed - indexed for MEDLINE]

Co-delivery of 2-Deoxyglucose and a Glutamine Metabolism Inhibitor V9302 via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer.

Acta Biomater. 2020 Jan 17;:

Authors: Luo Z, Xu J, Sun J, Huang H, Zhang Z, Ma W, Wan Z, Liu Y, Pardeshi A, Li S

Abstract
The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells' compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2-DG prodrug-based micellar carrier poly-(oligo ethylene glycol)-co-poly(4-((4-oxo-4-((4-vinylbenzyl)oxy)butyl)disulfaneyl)butanoic acid)-(2-deoxyglucose) (POEG-p-2DG) was developed. POEG-p-2DG well retained the pharmacological activity of 2-DG in vitro and in vivo, More importantly, POEG-p-2DG could self-assemble to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (∼10nm), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo. Interestingly, 2-DG treatment further decreased the glutamine uptake when combined with V9302, likely due to inhibition of ASCT2 glycosylation. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers.

PMID: 31958597 [PubMed - as supplied by publisher]

Metabolomics in pharmacology - a delve into the novel field of pharmacometabolomics.

Expert Rev Clin Pharmacol. 2020 Jan 20;:1-20

Authors: Mussap M, Loddo C, Fanni C, Fanos V

Abstract
Introduction: Pharmacometabolomics is an emerging science pursuing the application of precision medicine. Combining both genetic and environmental factors, the so-called pharmacometabolomic approach guides patient selection and stratification in clinical trials and optimizes personalized drug dosage, improving efficacy and safety.Areas covered: This review illustrates the progressive introduction of pharmacometabolomics as an innovative solution for enhancing the discovery of novel drugs and improving research and development (R&D) productivity of the pharmaceutical industry. An extended analysis on published pharmacometabolomics studies both in animal models and humans includes results obtained in several areas such as hepatology, gastroenterology, nephrology, neuropsychiatry, oncology, drug addiction, embryonic cells, neonatology, and microbiomics.Expert opinion: a tailored, individualized therapy based on the optimization of pharmacokinetics and pharmacodynamics, the improvement of drug efficacy, and the abolition of drug toxicity and adverse drug reactions is a key issue in precision medicine. Genetics alone has become insufficient for deciphring intra- and inter-individual variations in drug-response, since they originate both from genetic and environmental factors, including human microbiota composition. The association between pharmacogenomics and pharmacometabolomics may be considered the new strategy for an in-deep knowledge on changes and alterations in human and microbial metabolic pathways due to the action of a drug.

PMID: 31958027 [PubMed - as supplied by publisher]

Relationship between cardiorespiratory phase coherence during hypoxia and genetic polymorphism in humans.

J Physiol. 2020 Jan 20;:

Authors: Lancaster G, Debevec T, Millet GP, Poussel M, Willis SJ, Mramor M, Goričar K, Osredkar D, Dolžan V, Stefanovska A

Abstract
KEY POINTS: High altitude-induced hypoxia in humans evokes a pattern of breathing known as periodic breathing (PB), where the regular oscillations corresponding to rhythmic expiration and inspiration are modulated by slow-periodic oscillations. The phase coherence between instantaneous heart rate (IHR) and respiration is shown to increase significantly at the frequency of periodic breathing during acute and sustained normobaric and hypobaric hypoxia. It is also shown that polymorphism in specific genes, NOTCH4 and CAT, is significantly correlated with this coherence, and thus with the incidence of PB. Differences in phase shifts between blood flow signals and respiratory and PB oscillations clearly demonstrate contrasting origins of the mechanisms underlying normal respiration and PB. These novel findings provide better understanding of both the genetic and physiological mechanisms responsible for respiratory control during hypoxia at altitude, by linking genetic factors with cardiovascular dynamics, as evaluated by phase coherence.
ABSTRACT: Periodic breathing (PB) occurs in most humans at high altitudes and is characterised by low-frequency periodic alternation between hyperventilation and apnoea. In hypoxia-induced PB the dynamics and coherence between heart rate and respiration and their relationship to underlying genetic factors is still poorly understood. The aim of this study was to investigate, through novel usage of time-frequency analysis methods, the dynamics of hypoxia-induced PB in healthy individuals genotyped for a selection of antioxidative and neurodevelopmental genes. Breathing, ECG and microvascular blood flow were simultaneously monitored for 30 minutes in 22 healthy males. The same measurements were repeated under normoxic and hypoxic (normobaric (NH) and hypobaric (HH)) conditions, at real and simulated altitudes of up to 3800 m. Wavelet phase coherence and phase difference around the frequency of breathing (approximately 0.3 Hz) and around the frequency of PB (approximately 0.06 Hz) were evaluated. Subjects were genotyped for common functional polymorphisms in antioxidative and neurodevelopmental genes. During hypoxia, PB resulted in increased cardiorespiratory coherence at the PB frequency. This coherence was significantly higher in subjects with NOTCH4 polymorphism, and significantly lower in those with CAT polymorphism (HH only). Study of the phase shifts clearly indicates that the physiological mechanism of PB is different from that of the normal respiratory cycle. The results illustrate the power of time-evolving oscillatory analysis content in obtaining important insight into high altitude physiology. In particular, it provides further evidence for a genetic predisposition to PB and may partly explain the heterogeneity in the hypoxic response. This article is protected by copyright. All rights reserved.

PMID: 31957891 [PubMed - as supplied by publisher]

Assessment of pharmacogenomic SLCO1B1 assay for prediction of neuromuscular pain in type 2 diabetes mellitus and cardiovascular patients: preliminary results.

Eur Rev Med Pharmacol Sci. 2020 Jan;24(1):469-477

Authors: Licito A, Marotta G, Battaglia M, Benincasa G, Mentone L, Grillo MR, De Lucia V, Leonardi G, Bignucolo A, Comello F, Di Francia R, De Lucia D

Abstract
OBJECTIVE: At present, several strategies for preventing neuromuscular pain in Type 2 Diabetes Mellitus (T2DM) have been investigated. Recently, findings on genetic variants associated with adverse events to statin-based therapy have been reported. The study aimed at measuring whether Pharmacogenomics (PGx) profile can affect neuromuscular pain in patients carrying T2DM and cardiovascular diseases. An extensive panel of 5 polymorphisms on 4 candidate genes, previously validated as significant markers related to Sulphonylureas and Glitinides (SU-G) plus Simvastatin neuromuscular toxicity, is herein analyzed and discussed.
PATIENTS AND METHODS: We genotyped 76 T2DM patients carrying cardiovascular dyscrasia undergone anti-diabetic and anti-cholesterolemic polypharmacy. 35 subjects out of the total received concurrent SU-G and Statin-based therapy. Candidate variants consisted of drug transporters, such as Solute Carrier Organic 1B1 (SLCO1B1) Val174Ala ATP-binding cassette subfamily B member (ABCB1), subfamily C member 8 (ABCC8), and drug biotransformers of Cytochrome P450 Family (CYP) including CYP2C9*2 CYP2C9*3 CYP2C8*3, and CYP3A4*22. Moreover, we also focused on an early outline evaluation of the genotyping costs and benefits.
RESULTS: 6 out of 35 patients treated with SU-G plus statins (17.1% experienced adverse neuropathy events). Pharmacogenomics analysis showed a lack of any correlation between candidate gene polymorphisms and toxicity, except for the SLCO1B1 T521C allele; 14.3% of patients had a high risk for grade >2 neuromuscular pain (Odds Ratio [OR] 2.61.95% CI 0.90-7.61, p=0.03).
CONCLUSIONS: The clinical polymorphism effectiveness outlined therein will be assured by diagnostic improvements suitable for driving treatment decisions. In light of our experimental results and literature data, the analysis of the SLCO1B1 T521C variant will allow clinicians to take advantage from a better treatment planned for their patients in order to minimize neuromuscular pain and maximize benefits.

PMID: 31957862 [PubMed - in process]

Effects of CYP2C19*2 polymorphisms on the efficacy and safety of phenazepam in patients with anxiety disorder and comorbid alcohol use disorder.

Pharmacogenomics. 2020 Jan;21(2):111-123

Authors: Zastrozhin MS, Skryabin VY, Torrado M, Petrovna A, Sorokin AS, Grishina EA, Ryzhikova KA, Bedina IA, Buzik OZ, Chumakov EM, Savchenko LM, Brun EA, Sychev DA

Abstract
Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.

PMID: 31957548 [PubMed - in process]

Genotype-guided treatment of oral P2Y12 inhibitors: where do we stand?

Pharmacogenomics. 2020 Jan;21(2):83-86

Authors: Claassens DM, Ten Berg JM

PMID: 31957547 [PubMed - in process]

The emergent phenomenon of aspirin resistance: insights from genetic association studies.

Pharmacogenomics. 2020 Jan;21(2):125-140

Authors: Ferreira M, Freitas-Silva M, Assis J, Pinto R, Nunes JP, Medeiros R

Abstract
Despite the clinical benefits of aspirin, the interindividual variation in response to this antiplatelet drug is considerable. The manifestation of aspirin resistance (AR) is frequently observed, although this complex process remains poorly understood. While AR etiology is likely to be multifactorial, genetic factors appear to be preponderant. According to several genetic association studies, both genome-wide and candidate gene studies, numerous SNPs in cyclooxygenase, thromboxane and platelet receptors-related genes have been identified as capable of negatively affecting aspirin action. Thus, it is essential to understand the clinical relevance of AR-related SNPs as potential predictive and prognostic biomarkers as they may be essential to defining the AR phenotype.

PMID: 31957546 [PubMed - in process]

Footprints of clinical pharmacology in Turkey: Past, present, and future.

Clin Ther. 2020 Jan 16;:

Authors: Gulmez SE, Aydin V, Akici A

Abstract
Clinical pharmacology is an interdisciplinary field that encompasses all components of the relationship between drugs and humans. All clinical pharmacology professionals aim to support an improved quality of drug-oriented health services by providing teaching, research, and routine health care services that ensure more tolerable and more effective, suitable, and cost-effective use of drugs. Subsections of clinical pharmacology include clinical trials, pharmacoepidemiology and drug use, pharmacovigilance, pharmacoeconomics, the rational use of medicines, pharmacotherapy consultation, drug monitoring, counseling to authorities and industry, pharmacogenetics, and other practices. By approaching these subsections as part of 3 main aspects of clinical pharmacology-education, research, and health care-this review aims to provide local and international practitioners with detailed information about clinical pharmacology practices in Turkey and to contribute to building the network of communication and collaboration. This review also aims to play an encouraging and pioneering role for Turkey's national community and other countries that have not yet made clinical pharmacology functional in improving the quality of health services, promoting the dissemination of rational use of medicines, helping the set-up of clinical pharmacology organizations, enhancing quantity and quality of the clinical pharmacology workforce, and increasing the infrastructural facilities.

PMID: 31955969 [PubMed - as supplied by publisher]