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pharmacogenomics

These pubmed results were generated on 2020/07/27

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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 2020/07/24

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.

12 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 2020/07/24

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.

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 2020/07/23

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.

A genetic model of ivabradine recapitulates results from randomized clinical trials.

PLoS One. 2020;15(7):e0236193

Authors: Legault MA, Sandoval J, Provost S, Barhdadi A, Lemieux Perreault LP, Shah S, Lumbers RT, de Denus S, Tyl B, Tardif JC, Dubé MP

Abstract
BACKGROUND: Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints.
METHODS: We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes.
RESULTS: Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61).
CONCLUSION: Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.

PMID: 32692755 [PubMed - as supplied by publisher]

A New FGF21 Analog for the Treatment of Fatty Liver Disease.

Diabetes. 2020 Aug;69(8):1605-1607

Authors: Kleinert M, Müller TD

PMID: 32690662 [PubMed - in process]

Early Improvements of Individual Symptoms With Antipsychotics Predict Subsequent Treatment Response of Neuropsychiatric Symptoms in Alzheimer's Disease: A Re-Analysis of the CATIE-AD Study.

J Clin Psychiatry. 2020 02 11;81(2):

Authors: Nagata T, Shinagawa S, Yoshida K, Noda Y, Shigeta M, Mimura M, Nakajima S

Abstract
OBJECTIVE: The aim of the present study was to identify individual symptoms whose early improvements contributed to subsequent treatment response to antipsychotics for neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD) using the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD).
METHODS: The CATIE-AD study was conducted between April 2001 and November 2004 at 45 sites in the United States. Data for 421 patients with DSM-IV AD with NPSs treated with antipsychotics were analyzed in the present study. Treatment response was defined as a reduction of ≥ 9 points in the Neuropsychiatric Inventory (NPI) score or a reduction of ≥ 25% from baseline in Brief Psychiatric Rating Scale (BPRS) total score at week 8. Logistic regression analyses were performed to examine associations between response and clinical and demographic characteristics, including each total or individual symptom score reduction at week 2.
RESULTS: Reduction in NPI or BPRS total score at week 2 and several individual symptom score reductions (euphoria/elation, irritability, hallucinations, anxiety, agitation, apathy, disinhibition, and depression among NPI subitems; excitement, suspiciousness, disorientation, hostility, depressive mood, and emotional withdrawal among BPRS subitems) at week 2 were significantly associated with subsequent treatment response at week 8 (all P values < .05); Early non-improvements of irritability and suspiciousness were shown to be especially influential clinical markers in predicting subsequent treatment nonresponse. Furthermore, healthier condition at baseline was significantly associated with treatment response at week 8 (P < .05).
CONCLUSIONS: Although further research to validate these preliminary findings is needed, focusing on early improvements of individual symptoms could help identify subsequent treatment responders to antipsychotics in AD patients with NPSs.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00015548.

PMID: 32074412 [PubMed - indexed for MEDLINE]

The effects of rosiglitazone on the neonatal rat cardiomyocyte transcriptome: a temporal analysis.

Pharmacogenomics. 2019 11;20(16):1125-1141

Authors: da Silveira WA, Vazquez-Hidalgo E, Bartolotta E, Renaud L, Paolini P, Hardiman G

Abstract
Aim: The objective was to determine via high-throughput RNA sequencing the temporal effects of rosiglitazone (Avandia®) on the neonatal rat ventricular myocyte transcriptome. Materials & methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to rosiglitazone in vitro. Meta analyses utilized temporal comparisons of 0.5 h control versus 0.5 h treatment, 0.5 h treatment versus 24 h treatment and 24 h treatment versus 48 h treatment. Results: Time dependent responses were observed. At 0.5 h, the PI3K-AKT signaling pathway was impacted. At 24 h endoplasmic reticulum activity and protein degradation were altered. At 48 h, oxytocin signaling was perturbed. Conclusion: The effects of rosiglitazone occured early and increased in magnitude over time. A protective molecular response was triggered at 24 h and maintained until 48 h. In parallel, a response that can cause cardiac damage was activated. Our findings suggest that rosiglitazone has deleterious effects.

PMID: 31755367 [PubMed - indexed for MEDLINE]

Targeting DNA methylation for treating triple-negative breast cancer.

Pharmacogenomics. 2019 11;20(16):1151-1157

Authors: Yu J, Zayas J, Qin B, Wang L

Abstract
Triple-negative breast cancer (TNBC) accounts for 15-20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.

PMID: 31755366 [PubMed - indexed for MEDLINE]

DNA repair capacity and response to treatment of colon cancer.

Pharmacogenomics. 2019 11;20(17):1225-1233

Authors: Vodicka P, Vodenkova S, Buchler T, Vodickova L

Abstract
DNA repair, a complex biological process, ensures genomic integrity. Alterations in DNA repair, occurring in many cancers, contribute to the accumulation of mutations in the genome, resulting in genomic instability and cancer progression. DNA repair also plays a substantial role in response to chemotherapeutics: rapidly dividing colon cancer cells, vulnerable to DNA-damaging agents and overcoming DNA repair, undergo cell death. DNA repair capacity represents a complex biomarker, integrating gene variants, gene expressions, the stability of gene products, the effect of inhibitors/stimulators, lifestyle and environmental factors. Here, we discuss DNA repair capacity in sporadic colon cancer, a frequent malignancy worldwide, in relation to tumor heterogeneity, prognosis and prediction, measurements in surrogate and target tissues and suggest important tasks to be addressed.

PMID: 31691643 [PubMed - indexed for MEDLINE]

Severe and prolonged cyclophosphamide-induced hepatotoxicity in a breast cancer patient carrying a CYP2B6*7 variant.

Pharmacogenomics. 2019 11;20(16):1119-1124

Authors: Ming Z, Yongqiang Z, Zijin Z, Yan X, Di C, Xiaoxin T

Abstract
As a widely used alkylating agent, cyclophosphamide often leads to various toxicities. Severe hepatotoxicity has been rarely reported in breast cancer patients receiving chemotherapy containing cyclophosphamide. Differences in cyclophosphamide metabolism may contribute to variability in adverse events of patients. Here, we report on a case of a 68-year-old Chinese female with breast cancer who experienced severe and prolonged hepatotoxicity induced by cyclophosphamide. Pharmacogenetic tests showed that she was a carrier of CYP2B6*7 allele and this is the first case of a CYP2B6*7 variant in the Han Chinese population so far reported. In addition, the patient was also a carrier of an ALDH3A1*2 variant potentially contributing to the occurrence of hepatotoxicity. CYP2B6 and ALDH3A1 genotyping may play a role in guiding cyclophosphamide therapy.

PMID: 31686598 [PubMed - indexed for MEDLINE]

Genes identified through genome-wide association studies of osteonecrosis in childhood acute lymphoblastic leukemia patients.

Pharmacogenomics. 2019 11;20(17):1189-1197

Authors: Gagné V, Aubry-Morin A, Plesa M, Abaji R, Petrykey K, St-Onge P, Beaulieu P, Laverdière C, Alos N, Leclerc JM, Sallan SE, Neuberg D, Kutok JL, Silverman LB, Sinnett D, Krajinovic M

Abstract
Aim: To evaluate top-ranking genes identified through genome-wide association studies for an association with corticosteroid-related osteonecrosis in children with acute lymphoblastic leukemia (ALL) who received Dana-Farber Cancer Institute treatment protocols. Patients & methods: Lead SNPs from these studies, as well as other variants in the same genes, pooled from whole exome sequencing data, were analyzed for an association with osteonecrosis in childhood ALL patients from Quebec cohort. Top-ranking variants were verified in the replication patient group. Results: The analyses of variants in the ACP1-SH3YL1 locus derived from whole exome sequencing data showed an association of several correlated SNPs (rs11553746, rs2290911, rs7595075, rs2306060 and rs79716074). The rs79716074 defines *B haplotype of the APC1 gene, which is well known for its functional role. Conclusion: This study confirms implication of the ACP1 gene in the treatment-related osteonecrosis in childhood ALL and identifies novel, potentially causal variant of this complication.

PMID: 31686588 [PubMed - indexed for MEDLINE]

Developmental population pharmacokinetics of caffeine in Chinese premature infants with apnea of prematurity: a post-marketing study to support pediatric labeling in China.

Br J Clin Pharmacol. 2020 Jul 20;:

Authors: Gao XB, Zheng Y, Yang F, Wang CH, Jiang ZH, Wu YE, Jacqz-Aigrain E, Ni SQ, Zhao W

Abstract
OBJECTIVE: The aim of the study was to evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modeling and simulation approach.
METHODS: Pharmacokinetic samples were collected from 99 Chinese newborns with premature apnea. The median (range) of gestational age and postmenstrual age were 28.3 (25.0-33.4) weeks and 31.1 (26.4-38.0) weeks, respectively. Newborns were receiving caffeine citrate at a loading dose of 20 mg/kg/d and a maintenance dose of 5-10 mg/kg/d. Caffeine concentrations and CYP1A2 polymorphisms were investigated. Population pharmacokinetic modeling of caffeine in Chinese preterm newborn on a population wide scale was conducted using NONMEM.
RESULTS: A one-compartment model with first-order elimination was used to describe population pharmacokinetic. With current weight implemented using 0.75 allometric scaling, clearance (CL) was positively related to current weight and postmenstrual age, but, a negative relationship was observed with serum creatinine concentration. Eight genotypes of CYP1A2 were tested and none of them had a significant impact on caffeine pharmacokinetic parameters. Interindividual variability of CL and volume of distribution was 7.70% and 65.9%. The median (range) of 95% confidence intervals of CL were 0.0128 (0.0128-0.0131) L/h/kg. Monte Carlo simulation demonstrated that 80% (loading dose) and 98% (maintenance dose) of premature infants treated with a labelled dosing regimen attained the concentration target range of 5-20 mg/L.
CONCLUSION: A PPK model of caffeine was developed in Chinese newborns. Body weight implemented allometric scaling, postmenstrual age, and serum creatinine concentration markedly affected caffeine clearance. The labelled dosing regimen is suitable for Chinese premature infants.

PMID: 32687613 [PubMed - as supplied by publisher]

Patterns of lapses and recoveries during a quit attempt using varenicline and behavioral counseling among smokers with and without HIV.

Psychol Addict Behav. 2020 Jul 20;:

Authors: Ashare RL, Wileyto EP, Logue-Chamberlain E, Gross R, Tyndale RF, Lerman C, Hawk LW, Cinciripini P, George TP, Lubitz SF, Schnoll R

Abstract
Addressing tobacco use among HIV+ smokers is a priority. Lack of knowledge about how HIV+ smokers respond to tobacco use treatments limits our ability to effectively treat this population of smokers. Using data from 2 clinical trials that provided 12 weeks of varenicline and behavioral counseling, 1 with smokers with HIV (n = 89) and 1 with smokers without HIV (n = 179), we used mixed logistic regression modeling to compare point-prevalence abstinence rates and adherence to the initial target quit date (TQD) and Cox regression for repeated outcomes to evaluate lapse and recovery dynamics between the groups. Sixty percent of HIV- smokers refrained from smoking at the TQD while only 33% of HIV+ smokers did (odds ratio [OR] = 0.32, 95% CI [0.18, 0.56], p < .001). The point-prevalence abstinence rates at Week 12 were 31% (HIV-) and 28% (HIV+; OR = 0.7, 95% CI [0.42, 1.16], p = .16) and the point prevalence abstinence rates at Week 24 were 22% (HIV-) and 15% (HIV+; OR = 0.87, 95% CI [0.49, 1.57], p = .65). Although there was no interaction between HIV status and lapse risk, χ2(3) < 1, there was a significant interaction for the recovery model, (χ2(3) = 20.4, p < 0.001): as the number of events increased, the time to the next recovery became longer among smokers with HIV, compared to smokers without HIV. Although HIV+ smokers were treated effectively with varenicline, compared to HIV- smokers, they showed significantly lower initial cessation at the TQD and took increasingly longer to recover following lapses. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

PMID: 32686950 [PubMed - as supplied by publisher]

Using pharmacogenomics and therapeutic drug monitoring to guide drug selection and dosing in outpatient mental health comprehensive medication management.

Ment Health Clin. 2020 Jul;10(4):254-258

Authors: Brown JT, Bishop JR, Schneiderhan ME

Abstract
Pharmacogenomic (PGx) testing aided by therapeutic drug monitoring (TDM) has the potential to improve medication-related outcomes in some individuals prescribed psychiatric medications. Many commonly prescribed psychiatric medications are metabolized through polymorphic drug metabolizing enzymes such as cytochrome p450 (CYP) 2D6 (CYP2D6) and CYP2C19. Through PGx testing, clinicians can make biologically informed choices when selecting a new medication, and TDM may help inform dose adjustments or assess exposures to current treatments. Herein, we describe 2 complex case reports of individuals with multiple psychiatric diagnoses and extensive histories of medication failures who underwent PGx testing in addition to TDM as part of a pharmacist-led comprehensive medication therapy management evaluation in a community mental health clinic setting.

PMID: 32685338 [PubMed]

Regulation of melanocortin-4-receptor (MC4R) expression by SNP rs17066842 is dependent on glucose concentration.

Eur Neuropsychopharmacol. 2020 Jul 16;:

Authors: Qin L, Tiwari AK, Zai CC, Freeman N, Zhai D, Liu F, Stachelscheid H, Mergenthaler P, Kennedy JL, Müller DJ

Abstract
Melanocortin-4-receptor (MC4R) gene codes for a G-protein-coupled receptor that is highly expressed in the hypothalamus and involved in the regulation of appetite. Single-nucleotide polymorphisms (SNPs) in the MC4R gene region have been associated with obesity, type 2-diabetes (T2D) and with antipsychotic-induced weight gain. Of these, rs17066842 (G>A) in the MC4R promoter region is the top variant associated with obesity and diabetes. In this study, we investigated the effect of rs17066842 on MC4R expression at various glucose concentrations using reporter gene expression in the SH-SY5Y cell line and regulation of MC4R expression in human cerebral organoids. We observed that higher glucose concentrations significantly reduced MC4R mRNA expression in SH-SY5Y cells. In addition, at high glucose concentrations, the luciferase reporter plasmid containing the MC4R promoter insert with the G-allele of rs170066842 showed significantly reduced activity compared to the A-allele carrying plasmid. The immediate early gene product, early growth-response 1 (EGR-1), was identified to bind to the sequence containing the G-allele at rs17066842 but not to the A-allele-containing sequence. Interestingly, in human induced pluripotent stem cell (hiPSC)-derived cerebral organoids, we observed increased MC4R expression in response to high glucose exposure. These opposite observations might suggest that glucose regulation is complex and may be cell-specific. This study provides evidence that rs17066842 regulates MC4R gene expression through binding of EGR-1 and that this process is influenced by glucose concentration.

PMID: 32684494 [PubMed - as supplied by publisher]

Can Gi1 biased 5-HT2A inverse agonists improve the treatment of psychosis?

Eur Neuropsychopharmacol. 2020 Jul 16;:

Authors: Jukić MM

PMID: 32684493 [PubMed - as supplied by publisher]

Group-based pharmacogenetic prediction: is it feasible and do current NHS England ethnic classifications provide appropriate data?

Pharmacogenomics J. 2020 Jul 18;:

Authors: Ingram CJE, Ekong R, Ansari-Pour N, Bradman N, Swallow DM

Abstract
Inter-individual variation of drug metabolising enzymes (DMEs) leads to variable efficacy of many drugs and even adverse drug responses. Consequently, it would be desirable to test variants of many DMEs before drug treatment. Inter-ethnic differences in frequency mean that the choice of SNPs to test may vary across population groups. Here we examine the utility of testing representative groups as a way of assessing what variants might be tested. We show that publicly available population information is potentially useful for determining loci for pre-treatment genetic testing, and for determining the most prevalent risk haplotypes in defined groups. However, we also show that the NHS England classifications have limitations for grouping for these purposes, in particular for people of African descent. We conclude: (1) genotyping of hospital patients and people from the hospital catchment area confers no advantage over using samples from appropriate existing ethnic group collections or publicly available data, (2) given the current NHS England Black African grouping, a decision as to whether to test, would have to apply to all patients of recent Black African ancestry to cover reported risk alleles and (3) the current scarcity of available genome and drug effect data from Africans is a problem for both testing and treatment decisions.

PMID: 32683419 [PubMed - as supplied by publisher]

Gene variants and treatment outcomes in antineutrophil cytoplasmic antibody-associated vasculitis.

Pharmacogenomics J. 2020 Jul 18;:

Authors: Hessels AC, Sanders JSF, Rutgers A, Stegeman CA

Abstract
The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.

PMID: 32683418 [PubMed - as supplied by publisher]

ABCB1, ABCG2 and CYP2D6 polymorphism effects on disposition and response to long-acting risperidone.

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jul 16;:110042

Authors: Ganoci L, Trkulja V, Živković M, Božina T, Šagud M, Lovrić M, Božina N

Abstract
The relevance of the multidrug resistance (ABCB1) and breast cancer resistance (ABCG2) protein transporter polymorphisms for treatment with long-acting intramuscular (LAI) risperidone is largely unknown. We explored the relationship between these polymorphisms and cytochrome P450 (CYP) 2D6 genotype-predicted phenotype in their effects on drug disposition and clinical outcomes in adults with schizophrenia. In a 24-week observational study, patients initiated on LAI-risperidone (N = 101) were genotyped [enzymes (CYP2D6 dupl,*3,*4,*5,*6,*41; CYP3A4*22, CYP3A5*3), transporters (ABCG2 421C > A; ABCB1 1236C > T, 2677G > T/A, 3435C > T)] and evaluated for steady-state (weeks 6-8) serum levels of dose-corrected risperidone, 9-OH-risperidone, risperidone+9-OH-risperidone (active moiety), and for response to treatment (PANSS, reduction vs. baseline ≥30% at week 12 and ≥ 45% at week 24). CYP2D6 normal/ultrarapid metabolizers (NM/UM) (vs. other) had lower risperidone (29%) and active moiety levels (24%) (9-OH-risperidone not affected). The effect on the three analytes was mild (0 to 23% reduction) in ABCG2 wild-type homozygotes and pronounced (44-55% reduction) in ABCG2 variant allele carriers. ABCG2 variant had no effect on disposition in CYP2D6 "other" phenotypes, while the effect was pronounced in CYP2D6 NM/UM subjects (31-37% reduction). ABCB1 polymorphisms had no effect on exposure to risperidone. CYP2D6 NM/UM phenotype tended to lower odds of PANSS response, ABCG2 variant was associated with 4-fold higher odds and ABCB1 (1236C > T, 2677G > T/A, 3435C > T) overall mainly wild-type genotype was associated with around 4-fold lower odds of response. In patients treated with LAI-risperidone, CYP2D6 phenotype effect on systemic exposure is conditional on the ABCG2 421C > A polymorphism. ABCG2 and ABCB1 polymorphisms affect clinical response independently of systemic risperidone disposition.

PMID: 32682874 [PubMed - as supplied by publisher]