Thoughtful Clinical Use of Pharmacogenetics in Child and Adolescent Psychopharmacology.

J Am Acad Child Adolesc Psychiatry. 2020 Aug 26;:

Authors: Ramsey LB, Namerow LB, Bishop JR, Hicks JK, Bousman C, Croarkin PE, Mathews CA, Van Driest SL, Strawn JR

PMID: 32860906 [PubMed - as supplied by publisher]

Multi-site investigation of genetic determinants of warfarin dose variability in Latinos.

Clin Transl Sci. 2020 Aug 29;:

Authors: El Rouby N, Marcatto LR, Claudio K, Tavares LC, Steiner H, Botton MR, Lubitz SA, Fallon EN, Yee K, Kaye J, Scott SA, Karnes J, Santos PCJL, Duconge J, Cavallari LH

Abstract
We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from five institutions in the U.S. (n=411) and Brazil (n=663) were genotyped for VKORC1 c.-1639G>A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β=-0.29, p<2.0x10-16 ; β=-0.21, p=4.7x10-7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β=0.10, p=2x10-4 ; β=0.10, p=0.01, respectively). Associations with VKORC1 (β=-0.14, p=2.0x10-16 ), CYP2C9 (β=-0.07, p=5.6x10-10 ), and CYP4F2 (β=0.03, p=3x10-3 ), but not NQO1*2 (β=0.01, p=0.30), were replicated in the Brazilians, explaining 43%-46% of warfarin dose variability among the cohorts from U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the U.S. and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from U.S. and Brazil.

PMID: 32860733 [PubMed - as supplied by publisher]

Dietary Cholesterol Exacerbates Statin-Induced Hepatic Toxicity in Syrian Golden Hamsters and in Patients in an Observational Cohort Study.

Cardiovasc Drugs Ther. 2020 Aug 29;:

Authors: Yu Q, Ma X, Wang Y, Shi H, An J, Wang Y, Dong Z, Lu Y, Ge J, Liu G, Xian X, Sun A

Abstract
PURPOSE: Statins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which is involved in cholesterol synthesis. The major side effects of statins include muscle- and liver-related toxicity. Muscle toxicity is highly associated with polymorphisms in cytochrome P450 proteins (CYPs), as predicted by pharmacogenomics. However, the mechanisms of hepatotoxicity are not well understood. Due to differences in cholesterol metabolism, statins are well tolerated in mice. In contrast, hamsters exhibit metabolic traits similar to humans and are suitable for studying the hepatotoxicity of statins.
METHODS: We investigated the effect of rosuvastatin (RSV) on liver damage in wild-type (WT) hamsters fed a high-cholesterol diet (HCD) and LDLR knockout (LDLR-/-) hamsters that developed spontaneous hypercholesterolemia. Two cohorts of clinical subjects (clinical registry number: 2017001) taking atorvastatin (ATV) were recruited for direct (assessment of cholesterol intake individually, n = 44) and indirect (celebratory meals/holiday season, n = 1993) examination of dietary cholesterol intake and liver damage, as indicated by elevation of alanine aminotransferase (ALT).
RESULTS: RSV at a dose of 10 mg/kg caused fatal liver damage only in HCD-fed WT hamsters, while LDLR-/- hamsters with the same cholesterol levels were resistant to this toxic effect. In the human studies, we observed that the incidence of hepatic toxicity in patients receiving long-term ATV treatment was higher in patients with greater dietary cholesterol intake and in patients who consumed more food during Chinese holidays.
CONCLUSION: Our results propose, for the first time, that dietary cholesterol significantly contributes to statin-related hepatotoxicity, providing valuable insight into the clinical use of statins.

PMID: 32860619 [PubMed - as supplied by publisher]

Copy Number Alterations in Papillary Thyroid Carcinomas: Does Loss of SESN2 Have a Role in Age-related Different Prognoses?

Cancer Genomics Proteomics. 2020 Sep-Oct;17(5):643-648

Authors: DE Almeida DCN, DE Souza MPC, Amorim CKN, DA Silva MauÉs JH, DO E Santo Sagica F, Moreira-Nunes CA, DE Oliveira EHC

Abstract
BACKGROUND/AIM: Thyroid cancer is the only tumor in which age is an important prognostic factor. In papillary thyroid carcinomas (PTC), 45 years of age seems to be a key point that divides adult patients into two groups, with different clinical features. The aim of the study was to perform a microarray-based analysis in two groups of patients (<45 and ≥45 years old), in order to verify the occurrence of specific copy number alterations (CNAs) that could be associated to different patient behaviors associated with age.
PATIENTS AND METHODS: In order to search and compare genomic alterations that may be related to age, we evaluated the occurrence of CNAs in the genome of 24 PTC samples, divided in two groups (<45 and ≥45 years old).
RESULTS: We identified only one region showing a statistically significant difference between the groups (p=0.00357): a deletion of approximately 537 kps in 1p35.3., which was more frequent in patients aged 45 years or older. This is the region where, among others, the gene SESN2 is located, which is activated under oxidative stress and plays an antioxidant role, in addition to protecting the genetic material from damage generated by reactive oxygen species (ROS).
CONCLUSION: This is the first time that a CNA involving the deletion of the SESN2 gene is associated with papillary thyroid carcinomas, particularly in patients aged 45 years and older, indicating that this deletion would lead to a more malignant and prominent tumoral behavior associated to a worst prognosis.

PMID: 32859642 [PubMed - as supplied by publisher]

Plasma trimethylamine n-oxide is associated with renal function in patients with heart failure with preserved ejection fraction.

BMC Cardiovasc Disord. 2020 Aug 28;20(1):394

Authors: Guo F, Qiu X, Tan Z, Li Z, Ouyang D

Abstract
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an emerging global health problem with less awareness. Renal dysfunction in HFpEF is associated with worse outcome. However, there is lack of rapid, noninvasive and accurate method for risk stratification in HFpEF and renal dysfunction. This study aimed to explore the utility of plasma trimethylamine n-oxide (TMAO) for evaluation of HFpEF and renal function.
METHODS: Plasma TMAO levels were measured in total 324 subjects comprising 228 HFpEF patients and 96 healthy controls.
RESULTS: TMAO levels were significantly elevated in patients with HFpEF compared with controls (12.65(9.32-18.66) μg/l vs 10.85(6.35-15.58) μg/l, p <  0.01). Subjects in higher TMAO tertile group had more incidences of HFpEF ((78.5%) in tertile 3 vs (73.39%) in tertile 2 vs (59.26%) in tertile 1, p <  0.01). TMAO concentrations were inversely correlated with estimated glomerular filtration rate (eGFR) and HFpEF patients with impaired renal function (eGFR < 60 ml/min/1.73 m2) had higher TMAO than those with normal eGFR (≥ 60 ml/min/1.73 m2) (14.18(10.4-23.06) μg/l vs 10.9(7.48-15.47) μg/l, p < 0.01). Increased TMAO levels were independently associated with higher risk of HFpEF (OR = 3.49, 95% CI: 1.23-9.86, p = 0.02) and renal dysfunction (OR = 9.57, 95% CI: 2.11-43.34, p < 0.01) after adjustment for multiple traditional risk factors. Furthermore, TMAO had good performance at distinguishing HFpEF from controls (AUC = 0.63, p < 0.01), and renal dysfunction from normal renal function in HFpEF (AUC = 0.67, p < 0.01).
CONCLUSION: In this cross-sectional study, HFpEF and renal function were closely related with plasma TMAO levels and TMAO may serve as a diagnostic biomarker for HFpEF and renal function.

PMID: 32859154 [PubMed - as supplied by publisher]

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review.

Pharmaceutics. 2020 Aug 26;12(9):

Authors: B Tata E, A Ambele M, S Pepper M

Abstract
Clinical research in high-income countries is increasingly demonstrating the cost- effectiveness of clinical pharmacogenetic (PGx) testing in reducing the incidence of adverse drug reactions and improving overall patient care. Medications are prescribed based on an individual's genotype (pharmacogenes), which underlies a specific phenotypic drug response. The advent of cost-effective high-throughput genotyping techniques coupled with the existence of Clinical Pharmacogenetics Implementation Consortium (CPIC) dosing guidelines for pharmacogenetic "actionable variants" have increased the clinical applicability of PGx testing. The implementation of clinical PGx testing in sub-Saharan African (SSA) countries can significantly improve health care delivery, considering the high incidence of communicable diseases, the increasing incidence of non-communicable diseases, and the high degree of genetic diversity in these populations. However, the implementation of PGx testing has been sluggish in SSA, prompting this review, the aim of which is to document the existing barriers. These include under-resourced clinical care logistics, a paucity of pharmacogenetics clinical trials, scientific and technical barriers to genotyping pharmacogene variants, and socio-cultural as well as ethical issues regarding health-care stakeholders, among other barriers. Investing in large-scale SSA PGx research and governance, establishing biobanks/bio-databases coupled with clinical electronic health systems, and encouraging the uptake of PGx knowledge by health-care stakeholders, will ensure the successful implementation of pharmacogenetically guided treatment in SSA.

PMID: 32858798 [PubMed - as supplied by publisher]

Integration of pharmacogenomics and theranostics with nanotechnology as quality by design (QbD) approach for formulation development of novel dosage forms for effective drug therapy.

J Control Release. 2020 Aug 25;:

Authors: Jhawat V, Gulia M, Gupta S, Maddibonia B, Dutt R

Abstract
To cater to medication needs in the future healthcare system, we need to shift from the conventional system of drug delivery to modern molecular signature-based drug delivery systems. The current drug therapies are either less effective, ineffective, or produce numerous adverse reactions. One scientific principle or discipline cannot adequately address all the problems, so we need an innovative application of the current scientific principles. Here we are proposing a novel concept of nanoformulation based on pharmacogenomics and theranostics for personalized error-free and targeted therapeutic agent delivery. The addition of more knowledge about the human genome opens the new way to study disease-gene, gene-drug, and drug-effect interactions, which is the basis of future medicines. Pharmacogenomics provides information about the disease etiology, role in genes in disease pathophysiology, disease biomarkers, drug targets, drug effects, and the fate of drugs inside the body. Theranostics approach utilizes the above information in diagnosis, treatment, and monitoring of the disease on a real-time basis. Personalized dosage forms can be formulated into a nanoformulation that provides a better therapeutic effect and minimizes adverse drug reactions. The therapeutic system needs to be shifted from the principle of one drug fits all to one drug unique population. In the present manuscript, we tried to conceptualize a modern therapeutic system by combining the three approaches viz. pharmacogenomics, theranostics, and nanotechnology applied in the area of formulation development to produce a multifunctional single tiny entity.

PMID: 32858073 [PubMed - as supplied by publisher]

Escitalopram in Adolescents With Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study.

J Clin Psychiatry. 2020 Aug 25;81(5):

Authors: Strawn JR, Mills JA, Schroeder H, Mossman SA, Varney ST, Ramsey LB, Poweleit EA, Desta Z, Cecil K, DelBello MP

Abstract
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018.
METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes.
RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo.
CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.

PMID: 32857933 [PubMed - as supplied by publisher]

The Association between Trimethylamine N-Oxide and Its Predecessors Choline, L-Carnitine, and Betaine with Coronary Artery Disease and Artery Stenosis.

Cardiol Res Pract. 2020;2020:5854919

Authors: Guo F, Zhou J, Li Z, Yu Z, Ouyang D

Abstract
Background: Trimethylamine N-oxide (TMAO) and its predecessor products, choline, L-carnitine, and betaine, were reported to be associated with cardiovascular events risk. However, the association of TMAO and its predecessors with extent of artery stenosis in coronary artery disease (CAD) and in different gender is still unknown. Our aim is to investigate the association of plasma TMAO and its predecessors in CAD and extent of artery lesion in different gender.
Methods: 94 CAD patients and 75 healthy controls (CON) were enrolled. Fasting plasma TMAO, choline, L-carnitine, and betaine were detected using liquid chromatography-tandem mass spectrometry.
Results: Elevated plasma TMAO but not choline, L-carnitine, or betaine was observed in CAD (1.46(0.8-2.32) μM) and severe artery stenosis patients (S) (1.62(0.91-2.81) μM) compared with controls and mild artery stenosis (M) (1.18(0.67-1.7) μM in CON; 1.27(0.77-1.82) μM in M, p < 0.05). TMAO was an independent risk factor of CAD and severe artery stenosis (CAD : OR = 1.81, 95%CI: 1.07-3.09, p=0.03; S : OR = 1.36, 95%CI: 1.01-1.84, p=0.04). TMAO was more sensitive in diagnosing CAD and severe artery stenosis from controls in men rather than in women by ROC analysis (AUC for men and women in CAD: 0.64 versus 0.57; AUC for men and women in S: 0.64 versus 0.58), while the combined four metabolites greatly improved diagnostic accuracy in women with CAD and severe artery stenosis (AUC in CAD: 0.64, AUC in S: 0.68).
Conclusion: The associations of TMAO with CAD and severe artery stenosis were sex-related. TMAO alone was more powerful in determining CAD and artery stenosis in men than women, while a combination of TMAO, choline, L-carnitine, and betaine could be potential biomarkers for diagnosing CAD and artery stenosis in both men and women.

PMID: 32855821 [PubMed]

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy.

Mol Cancer. 2020 Aug 27;19(1):133

Authors: Zheng J, Mo J, Zhu T, Zhuo W, Yi Y, Hu S, Yin J, Zhang W, Zhou H, Liu Z

Abstract
Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

PMID: 32854711 [PubMed - in process]

Opioids, Polypharmacy, and Drug Interactions: A Technological Paradigm Shift Is Needed to Ameliorate the Ongoing Opioid Epidemic.

Pharmacy (Basel). 2020 Aug 25;8(3):

Authors: Matos A, Bankes DL, Bain KT, Ballinghoff T, Turgeon J

Abstract
Polypharmacy is a common phenomenon among adults using opioids, which may influence the frequency, severity, and complexity of drug-drug interactions (DDIs) experienced. Clinicians must be able to easily identify and resolve DDIs since opioid-related DDIs are common and can be life-threatening. Given that clinicians often rely on technological aids-such as clinical decision support systems (CDSS) and drug interaction software-to identify and resolve DDIs in patients with complex drug regimens, this narrative review provides an appraisal of the performance of existing technologies. Opioid-specific CDSS have several system- and content-related limitations that need to be overcome. Specifically, we found that these CDSS often analyze DDIs in a pairwise manner, do not account for relevant pharmacogenomic results, and do not integrate well with electronic health records. In the context of polypharmacy, existing systems may encourage inadvertent serious alert dismissal due to the generation of multiple incoherent alerts. Future technological systems should minimize alert fatigue, limit manual input, allow for simultaneous multidrug interaction assessments, incorporate pharmacogenomic data, conduct iterative risk simulations, and integrate seamlessly with normal workflow.

PMID: 32854271 [PubMed]

Pharmacoepigenetics and Pharmacoepigenomics: An Overview.

Curr Drug Discov Technol. 2019;16(4):392-399

Authors: Peedicayil J

Abstract
BACKGROUND: The rapid and major advances being made in epigenetics are impacting pharmacology, giving rise to new sub-disciplines in pharmacology, pharmacoepigenetics, the study of the epigenetic basis of variation in response to drugs; and pharmacoepigenomics, the application of pharmacoepigenetics on a genome-wide scale.
METHODS: This article highlights the following aspects of pharmacoepigenetics and pharmacoepigenomics: epigenetic therapy, the role of epigenetics in pharmacokinetics, the relevance of epigenetics to adverse drug reactions, personalized medicine, drug addiction, and drug resistance, and the use of epigenetic biomarkers in drug therapy.
RESULTS: Epigenetics is having an increasing impact on several areas of pharmacology.
CONCLUSION: Pharmacoepigenetics and pharmacoepigenomics are new sub-disciplines in pharmacology and are likely to have an increasing impact on the use of drugs in clinical practice.

PMID: 29676232 [PubMed - indexed for MEDLINE]

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pharmacogenomics

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14 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 2020/08/28

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.

Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use.

Bosn J Basic Med Sci. 2020 Aug 11;:

Authors: Ramli FF

Abstract
Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of ABCB1 single-nucleotide polymorphism (SNP) 1236C>T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, ABCB1 SNP 1236C>T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and ABCB1 3435C>T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, ABCB1 diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C>T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of CYP2B6 genotypes *4(G/G) and *9(T/T) among Jewish patients, CYP2B6*9 genotype (T/T) and haplotypes (TA/TG); and CYP2C19 (*2/*2,*2/*3, and *3/*3; Han Chinese). Higher methadone dose was observed in CYP2C19*1 allelic carriers (Han Chinese) and CYP2D6 ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in CYP2B6 SNPs, haplotypes TTT, and AGATAA (Han Chinese), CYP2C19 genotype *1/*1 (Han Chinese), allelic carrier *1xN (Caucasian), and CYP3A4 genotype *1/*1 (Caucasian). Carriers of CYP2B6 genotype *6/*6 (Caucasian), CYP2B6 haplotypes ATGCAG and ATGCTG (Han Chinese), and CYP3A4 genotype *1/*1B (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.

PMID: 32841585 [PubMed - as supplied by publisher]

Network Pharmacology to Identify the Pharmacological Mechanisms of a Traditional Chinese Medicine Derived from Trachelospermum jasminoides in Patients with Rheumatoid Arthritis.

Med Sci Monit. 2020 Aug 25;26:e922639

Authors: Jiang T, Kong B, Yan W, Wu C, Jiang M, Xu X, Xi X

Abstract
BACKGROUND This study used a network pharmacology approach to identify the pharmacological mechanisms of a traditional Chinese medicine derived from Trachelospermum jasminoides (Lindl.) Lem. in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS Known compounds of T. jasminoides were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the Shanghai Institute of Organic Chemistry of Chinese Academy of Science, Chemistry (CASC) database, and a literature search. Putative targets of identified compounds were predicted by SwissTargetPrediction. RA-related targets were achieved from the Therapeutic Target database, Drugbank database, Pharmacogenomics Knowledgebase, and Online Mendelian Inheritance in Man database. The protein-protein interaction (PPI) network was built by STRING. CluGO was utilized for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis. RESULTS A total of 354 potential targets were predicted for the 17 bioactive compounds in T. jasminoides; 69 of these targets overlapped with RA-related targets. A PPI network was composed and 2 clusters of 59 and 42 nodes each were excavated. GO and KEGG enrichment analysis of the overlapping targets and the 2 clusters was mainly grouped into immunity, inflammation, estrogen, anxiety, and depression processes. CONCLUSIONS Our study illustrated that T. jasminoides alleviates RA through the interleukin-17 signaling pathway, the tumor necrosis factor signaling pathway, and other immune and inflammatory-related processes. It also may exert effects in regulating cell differentiation and potentially has anti-anxiety, anti-depression, and estrogen-like effects.

PMID: 32840241 [PubMed - in process]

iPSCs-Derived Platform: A Feasible Tool for Probing the Neurotropism of SARS-CoV-2.

ACS Chem Neurosci. 2020 Aug 25;:

Authors: Mao XY, Jin WL

Abstract
Coronavirus Disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a severe public health problem with a high rate of morbidity and mortality. A mounting number of clinical investigations illustrate that COVID-19 patients suffer from neurologic conditions in addition to respiratory symptoms. In a recent article, Yuen and colleagues present the first experimental evidence of SARS-CoV-2 infection in the human central nervous system using induced pluripotent stem cells (iPSCs)-derived platform including human neural progenitor cells, neurospheres, and three-dimensional brain organoids (Yuen, K.Y., and Huang, J.D. et al. (2020) Cell Res. DOI: 10.1038/s41422-020-0390-x).

PMID: 32840109 [PubMed - as supplied by publisher]

Pharmacogenomics and pharmacokinetics of efavirenz 400 or 600 mg in 184 treatment-naive HIV-infected patients in China.

Pharmacogenomics. 2020 Aug 25;:

Authors: Chen R, Chen J, Xun J, Hu Z, Huang Q, Zhang R, Steinhart C, Shen Y, Liu L, Lu H

Abstract
Background: The pharmacogenomics and pharmacokinetics/pharmacodynamics of 400 mg efavirenz have rarely been reported. Materials & methods: A total of 184 treatment-naive HIV-infected patients were randomly assigned (1:1) to receive a lower dose (tenofovir disoproxil 200 mg, efavirenz 400 mg and lamivudine) or a standard dose regimen. Relationships between pharmacogenomics and efavirenz pharmacokinetics/pharmacodynamics were explored at 48 weeks. Results: There was no relationship between pharmacogenomics and adverse reactions of the central nervous system and antiretoviral efficacy. CYP2B6 516G>T, 785A>G, 18492C>T and ABCB1 3435C>T T/C were associated with higher efavirenz plasma levels in the standard but not the lower-dose group. No relationship was found between pharmacogenomics and antiretoviral efficacy. Patients who were <60 kg had higher efavirenz concentration compared with those with weight ≥60 kg when using 600 mg efavirenz, this was not observed with 400 mg efavirenz. Conclusion: The effect of pharmacogenomics and body weight on the efavirenz concentration was significant in the 600 mg group but not in the 400 mg group.

PMID: 32838647 [PubMed - as supplied by publisher]

HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease.

Aliment Pharmacol Ther. 2020 02;51(3):356-363

Authors: Wilson A, Peel C, Wang Q, Pananos AD, Kim RB

Abstract
BACKGROUND: Anti-drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn's disease (CD).
AIMS: To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD) METHODS: In a retrospective cohort study, infliximab-exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild-type (GG) and variant-carrying (AG or AA) individuals.
RESULTS: Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97-17.191, P = 1.46 × 10-5 ) independent of age, sex, weight, dose and co-immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41-3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46-3.43, P = 2.53 × 10-4 ) although not with infliximab-associated adverse drug events.
CONCLUSIONS: HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype-guided application of combination therapy in IBD.

PMID: 31650614 [PubMed - indexed for MEDLINE]

Incorporation of Gene-Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients.

J Clin Pharmacol. 2019 06;59(6):890-899

Authors: Tang J, Xu J, Zhang YL, Liu R, Liu MZ, Hu YF, Shao MJ, Zhu LJ, Cao S, Xin HW, Feng GW, Shang WJ, Meng XG, Zhang LR, Ming YZ, Zhang W, Zhou G

Abstract
The narrow therapeutic window of tacrolimus necessitates daily monitoring and predictive algorithms based on genetic and nongenetic factors. In this study, we constructed predictive algorithms for tacrolimus stable dose in a retrospective cohort of 1045 Chinese renal transplant recipients. All patients were genotyped for CYP3A4 20230T>C (rs2242480), CYP3A4 T>C (rs4646437), CYP3A5*3 6898A>G (rs776746), ABCB1 129T>C (rs3213619); ABCB1 c.1236C>T (rs01128503), ABCB1 c.2677G>T/A (rs2032582) and ABCB1 c.3435C>T (rs1045642) polymorphisms, and the effects of gene-gene and gene-environment interactions on the predictive accuracy of algorithm were evaluated. In wild-type CYP3A4 rs2242480 (TT) carriers, patients who took calcium channel blockers had lower tacrolimus stable doses than those without the concomitant medications (P < 1 × 10-4 ). In contrast, there was no significant difference in mutant type patients. Similarly, the tacrolimus stable doses in wild-type CYP3A5 rs776746 carriers who had hypertension were higher than those without hypertension (P = 4.10 × 10-3 ). More importantly, dose-predictive algorithms with interaction terms showed higher accuracy and better performance than those without interaction terms. Our finding suggested that wild-type CYP3A4 rs2242480 (TT) carriers should be more cautious to take tacrolimus when they are coadministrated with calcium channel blockers, and CYP3A5 rs776746 (AA) carriers may need higher tacrolimus dosage when they are in combination with hypertension.

PMID: 30861159 [PubMed - indexed for MEDLINE]