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pharmacogenomics

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Antidepressant-Associated Mania in Bipolar Disorder: A Review and Meta-analysis of Potential Clinical and Genetic Risk Factors.

J Clin Psychopharmacol. 2020 Mar/Apr;40(2):180-185

Authors: Melhuish Beaupre LM, Tiwari AK, Gonçalves VF, Lisoway AJ, Harripaul RS, Müller DJ, Zai CC, Kennedy JL

Abstract
PURPOSES/BACKGROUND: Antidepressants (ADs) play a valuable role in treating the depressive episodes of bipolar disorder. However, 14% of these individuals taking ADs experience AD-associated mania (AAM) within a few weeks of starting treatment. Numerous studies have suggested potential clinical and genetic risk factors. We aimed to conduct a comprehensive systematic review and meta-analysis that integrates the past literature with the recent studies and identifies important predictors for AAM.
METHODS/PROCEDURES: The review was limited to experimentally designed studies that contain the relevant search terms in PubMed and PsychInfo. After removing studies that were in discordance with our criteria, the review included 24 reports examining clinical risk factors and 10 investigating genetic risk factors. Our meta-analysis was conducted on 5 clinical risk factors, each of which had at least 4 articles with extractable data.
FINDINGS/RESULTS: The only clinical factors in the literature that have been shown to be more indicative of AAM risk are AD monotherapy and tricyclic ADs. Among genetic factors, the serotonin transporter gene polymorphism may play a minor role in AAM. Our meta-analysis provided support for the number of prior depressive episodes.
IMPLICATIONS/CONCLUSION: Prevention of AAM may be served by early detection of recurrent depression episodes. Further large-scale longitudinal studies are required to determine the underpinnings of AAM.

PMID: 32134853 [PubMed - as supplied by publisher]

Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease.

Drug Metab Pers Ther. 2020 Mar 05;:

Authors: Sychev D, Skripka A, Ryzhikova K, Bochkov P, Shevchenko R, Krupenin P, Ivashchenko D, Kogay V, Listratov A, Krainyaya A, Gurinovich O, Sokolova A, Napalkov D, Fomin V

Abstract
Background Despite the well-studied safety profile of dabigatran, its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). The study assessed whether genetic factors can contribute to CKD and alter dabigatran concentration. Methods Patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110 or 150 mg have been included in the study. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Results A total of 96 patients aged 51-89 years (median age: 75 years) were evaluated. Patients on a reduced regimen of 110 mg twice a day were older (79.8 vs. 67.9, p < 0.0001) and had lower creatinine clearance (49.7 vs. 62.3 mL/min/1.73 m2, p = 0.015). Patients with the rs2244613 CC genotype had lower C/D values (70% reduction in the mean C/D vs. AA genotype, p = 0.001). Linear stepwise regression has shown the CKD epidemiology collaboration to be the only significant predictor of C/D among genetic factors and kidney function characteristics. During the median follow-up of 15 months, there were 15 bleedings in 13 patients. Conclusions Polymorphism of CES1 rs2244613 can contribute to the safety of dabigatran in patients with AF and CKD. There was no influence of the aforementioned polymorphisms of ABCB1 on dabigatran trough plasma concentrations and C/D. Kidney function is a mainstay of clinical decision-making on direct oral anticoagulant (DOAC) dose, and further knowledge should be accumulated on the role of genetic factors.

PMID: 32134727 [PubMed - as supplied by publisher]

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

Drug Metab Pers Ther. 2020 Mar 05;:

Authors: Skryabin VY, Zastrozhin MS, Torrado MV, Grishina EA, Ryzhikova KA, Shipitsyn VV, Galaktionova TE, Sorokin AS, Bryun EA, Sychev DA

Abstract
Background Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS. Methods The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Results Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) -8.5 [-15.0; -5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) -12.0 [-13.0; -9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 -806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates. Conclusions Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.

PMID: 32134726 [PubMed - as supplied by publisher]

Genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions in Thai population.

Pharmacoepidemiol Drug Saf. 2020 Mar 05;:

Authors: Sukasem C, Sririttha S, Tempark T, Klaewsongkram J, Rerkpattanapipat T, Puangpetch A, Boongird A, Chulavatnatol S

Abstract
OBJECTIVE: This study aimed to describe the genetic and clinical risk factors associated with phenytoin-induced cutaneous adverse drug reactions (PHT-induced cADRs) in Thai patients.
METHOD: A retrospective case-control study was conducted among 88 PHT- cADRs (25 SJS/TEN, 37 DRESS/DIHS and 26 MPE) compared to 70 PHT-tolerant controls during 2008-2017. Genotyping was performed by Taqman RT-PCR (EPHX1 337 T > C, EPHX1 416A > G and CYP2C9*3), pyrosequencing (UGT1A1*28, UGT1A1*6) and polymerase chain reaction-sequence-specific oligonucleotide probe (HLA-B). Chi-squared test and binary logistic regression were used to identify factors associated with PHT-cADRs.
RESULTS: Multivariate analysis showed that HLA-B*46:01 was significantly associated with all PHT-induced cADRs (OR 2.341; 95% CI, 1.078-5.084; P = .032). Age of ≥60 years showed a significant association with PHT-induced SJS/TEN (OR 3.600; 95% CI, 1.214-10.672; P = .021). CYP2C9*3 was almost reaching statistically associated with an increased risk of PHT-induced SJS/TEN (OR 4.800; 95% CI, 0.960-23.990; P = .056). While HLA-B*56:02/04 was found to have a significant association with PHT-induced DRESS/DIHS (OR 29.312; 95% CI, 1.213-707.994; P = .038). Moreover, female gender and HLA-B*40:01 were associated with an increased risk of PHT-induced MPE at OR 5.734; 95% CI, 0.910-58.351; P = .042 and OR 3.647; 95% CI, 1.193-11.147; P = .023, respectively.
CONCLUSION: Both clinical (advanced age, female gender) and genetic factors (HLA-B*46:01, CYP2C9*3, HLA-B*56:02/04 and HLA-B*40:01) contributed to the risk of PHT-induced cADRs. Further studies with larger sample size may be warranted to confirm these findings and also the influence of EPHX1 gene.

PMID: 32134161 [PubMed - as supplied by publisher]

Genetic Influence on Efficacy of Pharmacotherapy for Pediatric Attention-Deficit/Hyperactivity Disorder: Overview and Current Status of Research.

CNS Drugs. 2020 Mar 04;:

Authors: Elsayed NA, Yamamoto KM, Froehlich TE

Abstract
Multiple stimulant and non-stimulant medications are approved for the treatment of attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent childhood neurodevelopmental disorders. Choosing among the available agents and determining the most effective ADHD medication for a given child can be a time-consuming process due to the high inter-individual variability in treatment efficacy. As a result, there is growing interest in identifying predictors of ADHD medication response in children through the burgeoning field of pharmacogenomics. This article reviews childhood ADHD pharmacogenomics efficacy studies published during the last decade (2009-2019), which have largely focused on pharmacodynamic candidate gene investigations of methylphenidate and atomoxetine response, with a smaller number investigating pharmacokinetic candidate genes and genome-wide approaches. Findings from studies which have advanced the field of ADHD pharmacogenomics through investigation of meta-analytic approaches and gene-gene interactions are also overviewed. Despite recent progress, no one genetic variant or currently available pharmacogenomics test has demonstrated clinical utility in pinpointing the optimal ADHD medication for a given individual patient, highlighting the need for further investigation.

PMID: 32133580 [PubMed - as supplied by publisher]

Cannabinoids as an Alternative Option for Conventional Analgesics in Cancer Pain Management: A Pharmacogenomics Perspective.

Indian J Palliat Care. 2020 Jan-Mar;26(1):129-133

Authors: Jose A, Thomas L, Baburaj G, Munisamy M, Rao M

Abstract
The global cancer burden is significantly increasing at an alarming rate affecting patients, relatives, communities, and health-care system. Cancer patients require adequate pain relief and palliative care throughout the life course, especially in terminal illness. Although opioid treatment is successful in majority of patients, around 40% do not achieve enough analgesia or are prone to serious side effects and toxicity. The treatment of medical conditions with cannabis and cannabinoid compounds is constantly expanding. This review organizes the current knowledge in the context of SNPs associated with opioids and nonopioids and its clinical consequences in pain management and pharmacogenetic targets of cannabinoids, for use in clinical practice.

PMID: 32132797 [PubMed]

Interest of adjusting urine cannabinoids to creatinine level to monitor cannabis cessation therapy in heavy smokers with psychiatric disorders.

Drug Test Anal. 2019 Sep;11(9):1453-1459

Authors: Duflot T, Vasse M, Guillerme J, Schrapp A, Mory C, Imbert L, Djerada Z, Protais Y, Guillin O, Goetz H, Lamoureux F

Abstract
Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (UCNC ) and to determine UCNC thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids. One hundred thirty-two patients with 452 urine samples were included between 2013 and 2017. Urinary cannabinoids and UCNC elimination curves were computed for each patient. Using a mono-exponential mixed effect model with 88 samples from 26 subjects exhibiting at least 3 decreasing UCNC in a row, the average calculated elimination rate constant was 0.0108 ± 0.0026 h-1 , corresponding to a mean elimination half-life of 64 ± 12 hours. The use of UCNC is of particular interest because of a high inter- and intra-individual variability of urinary creatinine concentration (from 0.06 to 3.81 mg/mL). Moreover, UCNC allows for the detection of diluted or concentrated urine specimens that may lead to false positive (FP) or false negative (FN) results. Receiver operator characteristic (ROC) curves were used to assess UCNC thresholds of 32.4 and 124.7 ng/mg that provide a strong discrimination between positive and negative samples for cannabinoids cut-offs of 20 and 50 ng/mL respectively. The developed model and the defined UCNC thresholds allowed for the accurate prediction of the time needed to reach a negative UCNC result that could be used by clinicians to optimize clinical care.

PMID: 31261442 [PubMed - indexed for MEDLINE]

Developmental population pharmacokinetics-pharmacodynamics and dosing optimization of cefoperazone in children.

J Antimicrob Chemother. 2020 Mar 04;:

Authors: Shi HY, Wang K, Wang RH, Wu YE, Tang BH, Li X, Du B, Kan M, Zheng Y, Xu BP, Shen AD, Su LQ, Jacqz-Aigrain E, Huang X, Zhao W

Abstract
OBJECTIVES: To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic-pharmacodynamic approach in order to optimize cefoperazone treatment.
METHODS: A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic-pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344).
RESULTS: A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with '40 mg/kg/day, q8h, IV drip 3 h' would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L.
CONCLUSIONS: For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics-pharmacodynamics. The dose indicated in the instructions (20-160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

PMID: 32129861 [PubMed - as supplied by publisher]

A genome-wide association study of circulating levels of atorvastatin and its major metabolites.

Clin Pharmacol Ther. 2020 Mar 03;:

Authors: Turner RM, Fontana V, Zhang JE, Carr D, Yin P, FitzGerald R, Morris AP, Pirmohamed M

Abstract
Atorvastatin (ATV) is frequently prescribed and generally well tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L) and 2-OH ATV L was performed in 590 patients that had been hospitalised with a non-ST elevation acute coronary syndrome one month earlier and were on high dose ATV (80mg or 40mg daily). The UGT1A locus (lead SNP, rs887829) was strongly associated with both increased 2-OH ATV/ATV (p=7.25x10-16 ) and 2-OH ATV L/ATV L (p=3.95x10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (p=6.18x10-7 ), and SLCO1B1 rs4149056 with increased ATV (p=2.21x10-6 ) and 2-OH ATV (p=1.09x10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalisation (n=149), all of these associations remained, except for 2-OH ATV and rs4149056 (p=0.057). Clinically, rs4149056 was associated with increased muscular symptoms (OR 3.97, 95% CI 1.29-12.27, p=0.016) and ATV intolerance (OR 1.55, 95% CI 1.09-2.19, p=0.014) in patients (n=870) primarily discharged on high dose ATV. In summary, both novel and recognised genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high dose ATV.

PMID: 32128760 [PubMed - as supplied by publisher]

Precision medication: An illustrative case series guiding the clinical application of multi-drug interactions and pharmacogenomics.

Clin Case Rep. 2020 Feb;8(2):305-312

Authors: Bain KT, McGain D, Cicali EJ, Knowlton CH, Michaud V, Turgeon J

Abstract
Precision medication entails selecting the precise medication, dose, and timing of administration. Multi-drug interactions and genetics significantly affect precision medication. In this article, we present two simulated cases for real-world applications of precision medication. Clinicians may need to acquire additional skills to apply the principles illustrated by these cases.

PMID: 32128178 [PubMed]

A new genetic locus for antipsychotic-induced weight gain: A genome-wide study of first-episode psychosis patients using amisulpride (from the OPTiMiSE cohort).

J Psychopharmacol. 2020 Mar 04;:269881120907972

Authors: Ter Hark SE, Jamain S, Schijven D, Lin BD, Bakker MK, Boland-Auge A, Deleuze JF, Troudet R, Malhotra AK, Gülöksüz S, Vinkers CH, Ebdrup BH, Kahn RS, Leboyer M, Luykx JJ

Abstract
BACKGROUND: Antipsychotic-induced weight gain is a common and debilitating side effect of antipsychotics. Although genome-wide association studies of antipsychotic-induced weight gain have been performed, few genome-wide loci have been discovered. Moreover, these genome-wide association studies have included a wide variety of antipsychotic compounds.
AIMS: We aim to gain more insight in the genomic loci affecting antipsychotic-induced weight gain. Given the variable pharmacological properties of antipsychotics, we hypothesized that targeting a single antipsychotic compound would provide new clues about genomic loci affecting antipsychotic-induced weight gain.
METHODS: All subjects included for this genome-wide association study (n=339) were first-episode schizophrenia spectrum disorder patients treated with amisulpride and were minimally medicated (defined as antipsychotic use <2 weeks in the previous year and/or <6 weeks lifetime). Weight gain was defined as the increase in body mass index from before until approximately 1 month after amisulpride treatment.
RESULTS: Our genome-wide association analyses for antipsychotic-induced weight gain yielded one genome-wide significant hit (rs78310016; β=1.05; p=3.66 × 10-08; n=206) in a locus not previously associated with antipsychotic-induced weight gain or body mass index. Minor allele carriers had an odds ratio of 3.98 (p=1.0 × 10-03) for clinically meaningful antipsychotic-induced weight gain (⩾7% of baseline weight). In silico analysis elucidated a chromatin interaction with 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. In an attempt to replicate single-nucleotide polymorphisms previously associated with antipsychotic-induced weight gain, we found none were associated with amisulpride-induced weight gain.
CONCLUSION: Our findings suggest the involvement of rs78310016 and possibly 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 in antipsychotic-induced weight gain. In line with the unique binding profile of this atypical antipsychotic, our findings furthermore hint that biological mechanisms underlying amisulpride-induced weight gain differ from antipsychotic-induced weight gain by other atypical antipsychotics.

PMID: 32126890 [PubMed - as supplied by publisher]

Are These Cardiomyocytes? Protocol Development Reveals Impact of Sample Preparation on the Accuracy of Identifying Cardiomyocytes by Flow Cytometry.

Stem Cell Reports. 2019 02 12;12(2):395-410

Authors: Waas M, Weerasekera R, Kropp EM, Romero-Tejeda M, Poon EN, Boheler KR, Burridge PW, Gundry RL

Abstract
Several protocols now support efficient differentiation of human pluripotent stem cells to cardiomyocytes (hPSC-CMs) but these still indicate line-to-line variability. As the number of studies implementing this technology expands, accurate assessment of cell identity is paramount to well-defined studies that can be replicated among laboratories. While flow cytometry is apt for routine assessment, a standardized protocol for assessing cardiomyocyte identity has not yet been established. Therefore, the current study leveraged targeted mass spectrometry to confirm the presence of troponin proteins in day 25 hPSC-CMs and systematically evaluated multiple anti-troponin antibodies and sample preparation protocols for their suitability in assessing cardiomyocyte identity. Results demonstrate challenges to interpreting data generated by published methods and inform the development of a robust protocol for routine assessment of hPSC-CMs. The data, workflow for antibody evaluation, and standardized protocol described here should benefit investigators new to this field and those with expertise in hPSC-CM differentiation.

PMID: 30686762 [PubMed - indexed for MEDLINE]

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

Clin Pharmacol Ther. 2019 06;105(6):1477-1491

Authors: Danese E, Raimondi S, Montagnana M, Tagetti A, Langaee T, Borgiani P, Ciccacci C, Carcas AJ, Borobia AM, Tong HY, Dávila-Fajardo C, Rodrigues Botton M, Bourgeois S, Deloukas P, Caldwell MD, Burmester JK, Berg RL, Cavallari LH, Drozda K, Huang M, Zhao LZ, Cen HJ, Gonzalez-Conejero R, Roldan V, Nakamura Y, Mushiroda T, Gong IY, Kim RB, Hirai K, Itoh K, Isaza C, Beltrán L, Jiménez-Varo E, Cañadas-Garre M, Giontella A, Kringen MK, Haug KBF, Gwak HS, Lee KE, Minuz P, Lee MTM, Lubitz SA, Scott S, Mazzaccara C, Sacchetti L, Genç E, Özer M, Pathare A, Krishnamoorthy R, Paldi A, Siguret V, Loriot MA, Kutala VK, Suarez-Kurtz G, Perini J, Denny JC, Ramirez AH, Mittal B, Rathore SS, Sagreiya H, Altman R, Shahin MHA, Khalifa SI, Limdi NA, Rivers C, Shendre A, Dillon C, Suriapranata IM, Zhou HH, Tan SL, Tatarunas V, Lesauskaite V, Zhang Y, Maitland-van der Zee AH, Verhoef TI, de Boer A, Taljaard M, Zambon CF, Pengo V, Zhang JE, Pirmohamed M, Johnson JA, Fava C

Abstract
The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

PMID: 30506689 [PubMed - indexed for MEDLINE]

Racial variations in lacosamide serum concentrations in adult patients with epilepsy.

J Neurol Sci. 2020 Feb 19;412:116742

Authors: Zutshi D, Yarraguntla K, Mahulikar A, Seraji-Bozorgzad N, Shah AK, Basha MM

Abstract
Lacosamide (LCM) is a third-generation anti-epileptic drug (AED) for partial-onset epilepsy with minimal hepatic metabolism and drug-drug interactions. The impact of individual patient variables such as race on drug metabolism have been under-reported in AEDs and LCM has not been specifically investigated. Our aim was to assess the role race plays on serum LCM levels in the management of epilepsy. Thus, we retrospectively reviewed patients with focal seizures who received LCM and had LCM levels as part of their routine clinical care in our Level IV Epilepsy Center. Variables including age, race, gender, LCM serum levels, LCM daily dose, and concomitant AEDs were collected and analyzed. A total of 93 patients with 1-3 clinic visits yielded 122 LCM serum levels. African Americans (AA) comprised 62.3% of our serum samples. Daily LCM doses averaged 350 mg/day (range 50-1000 mg/day). Eighty-nine percent of patients took 1-2 other AEDs. Overall, AA patients had lower LCM levels (mean 6.8 μg/mL) compared to White patients (mean of 7.1 μg/mL) (p = .017) even when considering for the daily dose effect (p = .007). Analysis of co-variables did not have significant effect on LCM levels. Overall, AA patients had a weaker relationship between LCM daily dose (adjusted for weight) and serum levels as compared to White patients and require a higher LCM dose per weight to achieve similar levels. Differences in pharmacogenetics may play an important role in these findings and focus on how these variations impact seizure burden.

PMID: 32126366 [PubMed - as supplied by publisher]

A review of clinical pharmacogenetics Studies in African populations.

Per Med. 2020 Mar 03;:

Authors: Radouani F, Zass L, Hamdi Y, Rocha JD, Sallam R, Abdelhak S, Ahmed S, Azzouzi M, Benamri I, Benkahla A, Bouhaouala-Zahar B, Chaouch M, Jmel H, Kefi R, Ksouri A, Kumuthini J, Masilela P, Masimirembwa C, Othman H, Panji S, Romdhane L, Samtal C, Sibira R, Ghedira K, Fadlelmola F, Kassim SK, Mulder N

Abstract
Effective interventions and treatments for complex diseases have been implemented globally, however, coverage in Africa has been comparatively lower due to lack of capacity, clinical applicability and knowledge on the genetic contribution to disease and treatment. Currently, there is a scarcity of genetic data on African populations, which have enormous genetic diversity. Pharmacogenomics studies have the potential to revolutionise treatment of diseases, therefore, African populations are likely to benefit from these approaches to identify likely responders, reduce adverse side effects and optimise drug dosing. This review discusses clinical pharmacogenetics studies conducted in African populations, focusing on studies that examined drug response in complex diseases relevant to healthcare. Several pharmacogenetics associations have emerged from African studies, as have gaps in knowledge.

PMID: 32125935 [PubMed - as supplied by publisher]

Clinical application of thiopurine pharmacogenomics in pediatrics.

Curr Drug Metab. 2020 Mar 02;:

Authors: Pavlovic S, Kotur N, Stankovic B, Gasic V, Lucafo M, Decorti G, Zukic B

Abstract
BACKGROUND: Thiopurine drugs are used for treatment of pediatric diseases. Inter-individual differences in metabolism of these drugs greatly influence the risk of thiopurine induced toxicity and therapy failure. These differences are the consequence of genomic, epigenomic and transcriptomic variability among patients. Pharmacogenomics aims to individualize therapy according to specific genetic signature of a patient. Treatment protocols based on thiopurine drugs have already been improved by applying pharmacogenomics in pediatric clinical practice.
OBJECTIVE: The aim of this review is to summarize the application of thiopurine pharmacogenomics in pediatric patients suffering from acute leukemias, different types of autoimmune and inflammatory diseases, as well as in post-transplant care.
METHOD: We searched PubMed/Medline database to identify thiopurine pharmacogenomic markers clinically relevant in pediatric diseases.
RESULTS: TPMT and NUDT15 pharmacogenomic testing is already in place in pediatric care, contributing to the reduction of thiopurine induced toxicity. Data on numerous novel potential pharmacogenomic markers relevant for optimization of thiopurine treatment are still controversial (ITPA, ABCC4, NT5C2, PRPS1, GSTM1, FTO gene variants). Majority of evidences regarding thiopurine pharmacogenomics in pediatrics have been acquired by studying acute lymphoblastic leukemia and inflammatory bowel disease. For other pediatric diseases, namely acute myeloid leukemia, non-Hodgkin lymphoma, juvenile idiopathic arthritis, atopic dermatitis, juvenile autoimmune hepatitis and renal allograft transplantation, data are still scarce.
CONCLUSION: Thiopurine pharmacogenomics has shown to be one of the best examples of successful application of pharmacogenomics in pediatrics.

PMID: 32124692 [PubMed - as supplied by publisher]

PHARMIP: An insilico method to predict genetics that underpin adverse drug reactions.

MethodsX. 2020;7:100775

Authors: Zidan AM, Saad EA, Ibrahim NE, Mahmoud A, Hashem MH, Hemeida AA

Abstract
Pharmacovigilance is the pharmacological science that focuses on the safe and appropriate use of drugs.Variability in response to drug therapy in both terms of safety and efficacy is highly related to patient's personal genomics. Hence, pharmacovigilance considers pharmacogenomics methodologies in the evaluation of medicinal products. The aim of this work is to introduce the pharmacovigilance/ pharmacogenomics insilico pipeline (PHARMIP) that uses the drug (or drug candidate) digital structure and the advances in bioinformatics tools and databases to figure-out the genetic factors underlying the drug reported adverse reactions (ADRs).PHARMIP uses user-friendly freely available bioinformatics resources to help pharmacovigilance and pharmacogenomics scientists with minimal bioinformatics experience to retrieve helpful information for their daily basis activities. Also, PHARMIP could help the advances in precision medicine in a drug-centric approach as it can be used to reveal genetic risk factors for certain drug ADRs. Domperidone was used as an example to the application of PHARMIP as the pipeline was initially developed during the insilico exploration of domperidone cardiotoxic ADRs. Method is composed of 3 main steps: •Preparing the drug off-label targets (OLT) list.•Retrieving the related diseases/ adverse reactions (DA) list.•Analysis of DA list to get answers.

PMID: 32123669 [PubMed]

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury.

Acta Pharmacol Sin. 2020 Mar 02;:

Authors: Rao T, Liu YT, Zeng XC, Li CP, Ou-Yang DS

Abstract
Herbal and dietary supplements (HDS)-induced liver injury has been a great concern all over the world. Polygonum multiflorum Thunb., a well-known Chinese herbal medicine, is recently drawn increasing attention because of its hepatotoxicity. According to the clinical and experimental studies, P. multiflorum-induced liver injury (PM-DILI) is considered to be immune-mediated idiosyncratic liver injury, but the role of immune response and the underlying mechanisms are not completely elucidated. Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury (DILI). However, most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury. The aim of this review is to assess current epidemiological, clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P. multiflorum. The potential effects of factors associated with immune tolerance, including immune checkpoint molecules and regulatory immune cells on the individual's susceptibility to PM-DILI are also discussed. We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.

PMID: 32123300 [PubMed - as supplied by publisher]

Association of MICA-129Met/Val polymorphism with clinical outcome of anti-TNF therapy and MICA serum levels in patients with rheumatoid arthritis.

Pharmacogenomics J. 2020 Mar 03;:

Authors: Iwaszko M, Świerkot J, Dratwa M, Wysoczańska B, Korman L, Bugaj B, Kolossa K, Jeka S, Wiland P, Bogunia-Kubik K

Abstract
MHC class I polypeptide-related sequence A (MICA) is a stress-induced protein involved in activation of NK and T cells through interaction with NKG2D receptor. These molecules are atypically expressed in synovium of patients diagnosed with rheumatoid arthritis (RA). A total of 279 patients with RA, qualified to TNF-blockade therapy, were genotyped for MICA rs1051792 SNP. The effectiveness of anti-TNF agents was assessed with European League Against Rheumatism criteria. Significant relationship between MICA rs1051792 and outcome of TNF-blockade therapy has been found. The MICA rs1051792 GG genotype was overrepresented in patients non-responsive to anti-TNF drugs in comparison with other genotypes (p = 0.010). On the other hand, beneficial therapeutic response was more frequently detected among RA subjects possessing heterozygous genotype than those with homozygous genotypes (p = 0.003). Furthermore, increased MICA concentrations in serum were observed in patients possessing MICA rs1051792 GG genotype as compared with those with GA or AA genotypes (p = 1.8 × 10-5). The results from this study indicate the potential influence of MICA rs1051792 polymorphism on modulation of therapeutic response to TNF-blockade treatment in RA.

PMID: 32123296 [PubMed - as supplied by publisher]