Clin Exp Allergy. 2021 Jun 15. doi: 10.1111/cea.13965. Online ahead of print.

ABSTRACT

BACKGROUND: The polymorphism Arg16 in β2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27.

OBJECTIVE: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA.

METHODS: The study was undertaken using data from ten independent studies (n = 5,903) of the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analyzed using the inverse variance weighting method assuming random-effects.

RESULTS: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 vs. Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2 = 0.0%) and Arg16/Gln27 vs. Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2 = 0.0%), but not Gly16/Gln27 vs. Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories i.e., as-required short-acting β2 -agonists (n = 973), ICS monotherapy (n = 2,623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686).

CONCLUSION AND CLINICAL RELEVANCE: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.

PMID:34128573 | DOI:10.1111/cea.13965

CNS Spectr. 2021 Apr;26(2):179-180. doi: 10.1017/S1092852920002953.

ABSTRACT

BACKGROUND: There is a plethora of drugs available to psychiatrists for treatment of mental illness, which can vary in efficacy, tolerability, metabolic pathways and drug-drug interactions. Psychotropics are the second most commonly listed therapeutic class mentioned in the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling. Pharmacogenomic (PGx) assays are increasingly used in psychiatry to help select safe and appropriate medication for a variety of mental illnesses. Our commercial laboratory offers PGx expert consultations by PharmDs and PhDs to clinician-users. Our database contains valuable information regarding the treatment of a diverse and challenging population.

METHODS: Genomind offers a PGx assay currently measuring variants of 24 genes relevant for selection of drugs with a mental illness indication. Since 2012 we have analyzed > 250,000 DNA samples. Between 10/18 - 8/20 6,401 reports received a consult. The data contained herein are derived from those consults. Consultants record information on prior meds, reason for failure or intolerability, potential risk-associated or useful drugs based on the genetic variants. Consultants only recommend specific drugs and doses consistent with a published PGx guideline.

RESULTS: The 5 most commonly discussed genes were SLC6A4, MTHFR, CACNA1C, COMT and BDNF. The 3 most commonly discussed drugs were fluoxetine, lithium and duloxetine. The most common reasons for drug failure were inefficacy and drug induced "agitation, irritability and/or anxiety". SSRIs were the most common class of discontinued drug; sertraline, escitalopram and fluoxetine were the three most commonly reported discontinuations and were also the 3 most likely to be associated with "no improvement". Aripiprazole was the most commonly reported discontinued atypical antipsychotic. The providers rated 94% of consultations as extremely or very helpful at the time of consult. An independent validation survey of 128 providers confirmed these ratings, with 96% reporting a rating of "very helpful" or "extremely helpful". In addition, 94% reported that these consults were superior to PGx consults provided through other laboratories. Patient characteristics captured during consults via a Clinical Global Impressions-Severity (CGI-S) scale revealed that the majority of patients were moderately (54%) or markedly ill (23%). The most frequent symptoms reported were depression, anxiety, insomnia and inattentiveness.

DISCUSSION: The large variety of psychotropic drugs available to providers, and their highly variable response rates, tolerability, capacity for drug-drug interactions and metabolic pathways present a challenge for even expert psychopharmacologists. Consultation with experts in PGx provides additional useful information that may improve outcomes and decrease healthcare resource utilization. This database may provide future opportunities for machine learning algorithms to further inform implications of included gene variants.

FUNDING: Genomind, Inc.

PMID:34127140 | DOI:10.1017/S1092852920002953

CNS Spectr. 2021 Apr;26(2):169-170. doi: 10.1017/S1092852920002746.

ABSTRACT

BACKGROUND: Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).

MATERIALS AND METHODS: Patients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.

RESULTS: Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41-2.83) and RR 2.25 (95% CI 1.39-3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15-0.99, p=0.048). No other significant differences in risk were observed at week 8.

CONCLUSION: These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.

FUNDING: Myriad Neuroscience/Assurex Health.

PMID:34127099 | DOI:10.1017/S1092852920002746

J Appl Lab Med. 2021 Jun 14:jfab043. doi: 10.1093/jalm/jfab043. Online ahead of print.

NO ABSTRACT

PMID:34125206 | DOI:10.1093/jalm/jfab043

Front Pharmacol. 2021 May 28;12:648519. doi: 10.3389/fphar.2021.648519. eCollection 2021.

ABSTRACT

Case introduction: In this work we present a female infant patient with epilepsy of infancy with migrating focal seizures (EIMFS). Although many pharmacological schemes were attempted, she developed an encephalopathy with poor response to antiepileptic drugs and progressive cerebral dysfunction. Aim: To present the pharmacological response and therapeutic drug monitoring of a paediatric patient with a severe encephalopathy carrying a genetic variant in KCNT1 gene, whose identification led to include quinidine (QND) in the treatment regimen as an antiepileptic drug. Case report: Patient showed slow rhythmic activity (theta range) over left occipital areas with temporal propagation and oculo-clonic focal seizures and without tonic spasms three months after birth. At the age of 18 months showed severe impairments of motor and intellectual function with poor eye contact. When the patient was 4 years old, a genetic variant in the exon 24 of the KCNT1 gene was found. This led to the diagnosis of EIMFS. Due to antiepileptic treatment failed to control seizures, QND a KCNT1 blocker, was introduced as a therapeutic alternative besides topiramate (200 mg/day) and nitrazepam (2 mg/day). Therapeutic drug monitoring (TDM) of QND plasma levels needed to be implemented to establish individual therapeutic range and avoid toxicity. TDM for dose adjustment was performed to establish the individual therapeutic range of the patient. Seizures were under control with QND levels above 1.5 mcg/ml (65-70 mg/kg q. i.d). In addition, QND levels higher than 4.0 mcg/ml, were related to higher risk of suffering arrhythmia due to prolongation of QT segment. Despite initial intention to withdrawal topiramate completely, QND was no longer effective by itself and failed to maintain seizures control. Due to this necessary interaction between quinidine and topiramate, topiramate was stablished in a maintenance dose of 40 mg/day. Conclusion: The implementation of Precision Medicine by using tools such as Next Generation Sequencing and TDM led to diagnose and select a targeted therapy for the treatment of a KCNT1-related epilepsy in a patient presented with EIMFS in early infancy and poor response to antiepileptic drugs. QND an old antiarrhythmic drug, due to its activity as KCNT1 channel blocker, associated to topiramate resulted in seizures control. Due to high variability observed in QND levels, TDM and pharmacokinetic characterization allowed to optimize drug regimen to maintain QND concentration between the individual therapeutic range and diminish toxicity.

PMID:34122071 | PMC:PMC8194824 | DOI:10.3389/fphar.2021.648519

Clin Transl Sci. 2021 Jun 13. doi: 10.1111/cts.13086. Online ahead of print.

ABSTRACT

Low-dose methotrexate (MTX) is a first-line therapy for the treatment of arthritis. However, there is considerable inter-individual variability in MTX exposure following standard dosing. Polymorphisms in SLCO1B1 significantly effect MTX clearance, altering therapeutic response. One decreased function variant, rs4149056 (c.521T>C, Val174Ala), slows MTX clearance and in vitro uptake of MTX. This phenotype was recapitulated in a mouse model using a knockout (KO) of the murine orthologue, Slco1b2. Our objective was to investigate the impact of this phenotype on the pharmacokinetics and therapeutic outcomes of low-dose MTX in a murine model of collagen-induced arthritis (CIA). We evaluated response to MTX in mice with CIA using wildtype (WT), heterozygous, and KO Slco1b2 mice on a DBA1/J background. Arthritis was macroscopically evaluated daily to quantify disease progression. Mice received 2 mg/kg or a pharmacogenetically-guided MTX dose subcutaneously 3 times a week for 2 weeks. MTX concentrations were collected at the end of the study and exposure (day*µM) was estimated using a two-compartment model. Mice displayed a 7-fold range in MTX exposure and revealed a significant exposure-response relationship (p=0.0027). KO mice receiving the 2 mg/kg dosing regimen had 2.3-fold greater exposure to MTX (p<0.0001) and a 66% reduction in overall disease progression (p=0.011) compared to WT mice. However, exposure and response were equivalent when pharmacogenetically-guided dosing was used. These studies demonstrate that an exposure-response relationship exists for MTX and that Slco1b2 genotype affects MTX exposure and therapeutic response. Such evidence supports the use of SLCO1B1-pharmacogenetic dosing of low-dose methotrexate for patients with arthritis.

PMID:34121338 | DOI:10.1111/cts.13086

Clin Transl Sci. 2021 Jun 13. doi: 10.1111/cts.13097. Online ahead of print.

ABSTRACT

The evolution of evidence and availability of Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines have enabled assessment of pharmacogenetic actionability and clinical implementation. However population-level actionability is not well characterized. We leveraged the Alabama Genomic Health Initiative (AGHI) to evaluate population-level pharmacogenetic actionability. Participants (>18 years), representing all 67 Alabama counties, were genotyped using the Illumina Global Screening array. Using CPIC guidelines, actionability was evaluated using (1) genotype data and genetic ancestry, (2) prescribing data, and (3) combined genotype and medication data. Of 6,331 participants, 4,230 had genotype data and 3,386 had genotype and prescription data (76% female; 76% White/18% Black (self-reported)). Genetic ancestry was concordant with self-reported race. For CPIC level A genes, 98.6% had an actionable genotype (99.4% Blacks/African; 98.5% White/European). With the exception of DPYD and CYP2C19, the prevalence of actionable genotypes by gene differed significantly by race. Based on prescribing, actionability was highest for CYP2D6 (70.9%), G6PD (54.1%), CYP2C19 (53.5%), and CYP2C9 (47.5%). Among participants prescribed atenolol, carvedilol, or metoprolol, approximately 50% had an actionable ADRB1 genotype, associated with decreased therapeutic response, with higher actionability among Blacks compared to Whites (62.5% vs 47.4%; p<0.0001). Based on both genotype and prescribing frequencies, no significant differences in actionability were observed between men and women. This statewide effort highlights pharmacogenetics' population-level impact to help optimize pharmacotherapy. Almost all Alabamians harbor an actionable genotype, and a significant proportion are prescribed affected medications. Statewide efforts such as AGHI lay the foundation for translational research and evaluate "real-world" outcomes of pharmacogenetics.

PMID:34121327 | DOI:10.1111/cts.13097

Proc Jpn Acad Ser B Phys Biol Sci. 2021;97(6):324-335. doi: 10.2183/pjab.97.018.

ABSTRACT

As we look so different, our genomic sequences vary enormously. The differences in our genome, genetic variations, have played very significant roles in medical research and have contributed to improvement of medical managements in the last 2-3 decades. Genetic variations include germline variations, somatic mutations, and diversities in receptor genes of rearranged immune cells, T cells and B cells. Germline variants are in some cases causative of genetic diseases, are associated with the risk of various diseases, and also affect drug efficacies or adverse events. Some somatic mutations are causative of tumor development. Recent DNA sequencing technologies allow us to perform single-cell analysis or detailed repertoire analysis of B and T cells. It is critically important to investigate temporal changes in immune environment in various anatomical regions in the next one to two decades. In this review article, we would like to introduce the roles of genetic variations in medical fields in the past, at present and in the future.

PMID:34121043 | DOI:10.2183/pjab.97.018

Pharmacogenomics. 2021 Jun 14. doi: 10.2217/pgs-2020-0090. Online ahead of print.

ABSTRACT

Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.

PMID:34120461 | DOI:10.2217/pgs-2020-0090

Pharmacogenomics. 2021 Jun 14. doi: 10.2217/pgs-2020-0183. Online ahead of print.

ABSTRACT

Aim: The prognosis of resectable pancreatic cancer patients with the same stage of disease is highly variable. The purpose of this study is to establish a scoring system for preoperative screening of resectable patients. Materials & methods: The clinical information and laboratory tests of 105 resectable patients with pancreatic cancer were enrolled and analyzed. Results: The consistency of clinical stage and pathological stage was poor (κ = 0.193; p < 0.003). We performed a comprehensive scoring system with KRAS mutations in circulating tumor DNA (mutKRAS ctDNA) for the resectable patients. Patients with higher scores were more prone to early postoperative recurrence and poorer prognosis. Conclusion: The scoring system can help preoperatively screen out resectable patients who are prone to early postoperative recurrence.

PMID:34120460 | DOI:10.2217/pgs-2020-0183

Pharmacogenomics. 2021 Jun 14. doi: 10.2217/pgs-2020-0152. Online ahead of print.

ABSTRACT

Although statins are effective in treating high cholesterol, adverse effects do occur with their use. Efficacy and tolerability vary among statins in different ethnic groups. Indigenous Australians have a high risk for cardiovascular and kidney diseases. Prescribing statins to Indigenous Australians with multi-morbidity requires different strategies to increase efficacy and reduce their toxicity. Previous studies have reported that Indigenous Australians are more susceptible to severe statin-induced myopathies. However, there is a lack of evidence in the underlying genetic factors in this population. This review aims to identify: inter-ethnic differences in the efficacy and safety of statins; major contributing factors accounting for any identified differences; and provide an overview of statin-induced adverse effects in Indigenous Australians.

PMID:34120458 | DOI:10.2217/pgs-2020-0152

Neurochem Res. 2021 Jun 12. doi: 10.1007/s11064-021-03376-0. Online ahead of print.

ABSTRACT

Epilepsy is a related chronic neurological condition of a predisposition for recurrent epileptic seizures, with various manifestations and causes. Although there are antiepileptic drugs, complementary natural therapies are widely used. The purpose of this systematic review was to analyze the antiepileptic/anticonvulsant pharmacological properties of plant-food derived bioactive molecules. In this regard, a systematic review of the PubMed database was made based on the inclusion criteria. Natural compounds/herbs with scientifically proven antiepileptic properties were selected. Experimental pharmacological studies in vitro and in vivo have shown that flavonoids, alkaloids and terpenoids may have anticonvulsant mechanisms similar to the new generation antiepileptic drugs. The relationships of structure-anticonvulsant effect, pharmacological models, seizure-inducing factors and response, effective dose were also analyzed and discussed. The results of in vitro and in vivo pharmacological studies analyzed in this systematic review support the clinical importance of plant-food-derived bioactive molecules for the complementary treatment of epilepsy. Thus, are opened new perspectives to develop new natural anticonvulsant drugs.

PMID:34120291 | DOI:10.1007/s11064-021-03376-0

Clin Chem. 2021 Jun 13:hvab059. doi: 10.1093/clinchem/hvab059. Online ahead of print.

ABSTRACT

BACKGROUND: Multi-gene panel sequencing using next-generation sequencing (NGS) methods is a key tool for genomic medicine. However, with an estimated 140 000 genomic tests available, current system inefficiencies result in high genetic-testing costs. Reduced testing costs are needed to expand the availability of genomic medicine. One solution to improve efficiency and lower costs is to calculate the most cost-effective set of panels for a typical pattern of test requests.

METHODS: We compiled rare diseases, associated genes, point prevalence, and test-order frequencies from a representative laboratory. We then modeled the costs of the relevant steps in the NGS process in detail. Using a simulated annealing-based optimization procedure, we determined panel sets that were more cost-optimal than whole exome sequencing (WES) or clinical exome sequencing (CES). Finally, we repeated this methodology to cost-optimize pharmacogenomics (PGx) testing.

RESULTS: For rare disease testing, we show that an optimal choice of 4-6 panels, uniquely covering genes that comprise 95% of the total prevalence of monogenic diseases, saves $257-304 per sample compared with WES, and $66-135 per sample compared with CES. For PGx, we show that the optimal multipanel solution saves $6-7 (27%-40%) over a single panel covering all relevant gene-drug associations.

CONCLUSIONS: Laboratories can reduce costs using the proposed method to obtain and run a cost-optimal set of panels for specific test requests. In addition, payers can use this method to inform reimbursement policy.

PMID:34120169 | DOI:10.1093/clinchem/hvab059

Lancet Gastroenterol Hepatol. 2021 Jul;6(7):523-524. doi: 10.1016/S2468-1253(21)00194-1.

NO ABSTRACT

PMID:34119033 | DOI:10.1016/S2468-1253(21)00194-1

J Mol Diagn. 2021 Jun 9:S1525-1578(21)00164-1. doi: 10.1016/j.jmoldx.2021.05.013. Online ahead of print.

ABSTRACT

The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and determine a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations for a minimum panel of variant alleles ("Tier 1") and an extended panel of variant alleles ("Tier 2") that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document will focus on clinical CYP2D6 PGx testing that may be applied to all CYP2D6-related medications. These recommendations are not to be interpreted as prescriptive but to provide a reference guide to clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform.

PMID:34118403 | DOI:10.1016/j.jmoldx.2021.05.013

Sci Rep. 2021 Jun 11;11(1):12343. doi: 10.1038/s41598-021-90969-y.

ABSTRACT

Prior knowledge of allele frequencies of cytochrome P450 polymorphisms in a population is crucial for the revision and optimization of existing medication choices and doses. In the current study, the frequency of the CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP2C19*6, CYP2C19*17, and CYP3A4 (rs4646437) alleles in a Thai population across different regions of Thailand was examined. Tests for polymorphisms of CYP2C9 and CYP3A4 were performed using TaqMan SNP genotyping assay and CYP2C19 was performed using two different methods; TaqMan SNP genotyping assay and Luminex x Tag V3. The blood samples were collected from 1205 unrelated healthy individuals across different regions within Thailand. Polymorphisms of CYP2C9 and CYP2C19 were transformed into phenotypes, which included normal metabolizer (NM), intermediate metabolizer (IM), poor metabolizer (PM), and rapid metabolizers (RM). The CYP2C9 allele frequencies among the Thai population were 0.08% and 5.27% for the CYP2C9*2 and CYP2C9*3 alleles, respectively. The CYP2C19 allele frequencies among the Thai population were 25.60%, 2.50%, 0.10%, and 1.80% for the CYP2C19*2, CYP2C19*3, CYP2C19*6, and CYP2C19*17 alleles, respectively. The allele frequency of the CYP3A4 (rs4646437) variant allele was 28.50% in the Thai population. The frequency of the CYP2C9*3 allele was significantly lower among the Northern Thai population (P < 0.001). The frequency of the CYP2C19*17 allele was significantly higher in the Southern Thai population (P < 0.001). Our results may provide an understanding of the ethnic differences in drug responses and support for the utilization of pharmacogenomics testing in clinical practice.

PMID:34117307 | DOI:10.1038/s41598-021-90969-y

Clin J Am Soc Nephrol. 2021 Jun;16(6):916-925. doi: 10.2215/CJN.15841020. Epub 2021 Jun 11.

ABSTRACT

BACKGROUND AND OBJECTIVES: Patients with kidney failure have a high risk of cardiovascular disease due to cardiac remodeling, left ventricular fibrosis, and hyperaldosteronism, all of which can be potentially mitigated by mineralocorticoid receptor antagonists. However, because of the fear of hyperkalemia, the use of mineralocorticoid receptor antagonists in patients with kidney failure is limited in current clinical practice, and few studies have investigated the efficacy and safety. Thus, we aimed to determine the benefits and side effects of mineralocorticoid receptor antagonists in patients with kidney failure treated with dialysis.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a systematic review and meta-analysis of randomized controlled trials published from 2005 to 2020 that compared the effect of mineralocorticoid receptor antagonists with either placebo or no treatment in patients with kidney failure. Two reviewers independently searched the PubMed, EMBASE, and Cochrane databases for all published studies, extracted data, assessed the risk of bias, and rated the quality of evidence. A meta-analysis was conducted on 14 eligible randomized controlled trials, and a total of 1309 patients were included.

RESULTS: High-quality evidence suggested that mineralocorticoid receptor antagonists are associated with lower cardiovascular mortality (relative risk, 0.41; 95% confidence interval, 0.24 to 0.70; P=0.001) and all-cause mortality (relative risk, 0.44; 95% confidence interval, 0.30 to 0.66; P<0.001), and the risk of hyperkalemia was comparable with that of control group (relative risk, 1.12; 95% confidence interval, 0.91 to 1.36; P=0.29). However, no significant decrease in nonfatal cardiovascular events and stroke was observed, and there was no significant improvement in BP or cardiac performance parameters, including left ventricular ejection fraction and left ventricular mass index.

CONCLUSIONS: Our meta-analysis suggests that mineralocorticoid receptor antagonists might improve clinical outcomes of patients with kidney failure without significant increase in the risk of hyperkalemia.

PMID:34117083 | DOI:10.2215/CJN.15841020

Pharmacogenet Genomics. 2021 Jun 9. doi: 10.1097/FPC.0000000000000438. Online ahead of print.

ABSTRACT

OBJECTIVE: The implementation of pharmacogenetics (PGx) in clinical practice is an essential tool for personalized medicine. However, clinical laboratories must validate their procedures before being used to perform PGx studies in patients, in order to confirm that they are adequate for the intended purposes.

METHODS: We designed a validation process for our in-house pharmacogenetic PCR-based method assay.

RESULTS: The concordance to reference, repeatability and reproducibility was 100%. Sensitivity and specificity were 100% for the detection of variant diplotypes in CYP2C9, CYP3A5, TPMT, DPYD and UGT1A1 genes. The sensitivity was lower in the detection of CYP2C19 variants due to a limitation in the design that prevents the detection of CYP2C19 *2/*10 diplotype.

CONCLUSIONS: The success of implementing clinical pharmacogenetic testing into routine clinical practice is dependent on the precision of genotyping. Limitations must be bearing in mind to guarantee the quality of PGx assays in clinical laboratory practice. We provided objective evidence that the necessary requirements in our laboratory-development assay were fulfilled.

PMID:34116532 | DOI:10.1097/FPC.0000000000000438

AIDS. 2021 Jun 9. doi: 10.1097/QAD.0000000000002984. Online ahead of print.

ABSTRACT

OBJECTIVE: Efavirenz use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms (SNPs) in genes that contribute to efavirenz pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance.

DESIGN: Cross-sectional study where adults with HIV (PWH) receiving 600 mg efavirenz for at least two months were recruited and paired hair and dried blood spots (DBS) samples collected.

METHODS: Participants (N = 93, 70.3% female) were genotyped for 7 SNPs in CYP2B6, NRII3 and ABCB1 using DBS. Efavirenz was quantified in DBS and hair using validated liquid-chromatography-tandem-mass-spectrometry methods, with plasma efavirenz concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (7 domains) that assessed total neurocognitive functioning.

RESULTS: Strong correlation (r = 0.66, P < 0.001) was observed between plasma and hair efavirenz concentrations. The median (IQR) hair efavirenz concentration was 6.85ng/mg (4.56-10.93). CYP2B6 516G > T, (P < 0.001) and CYP2B6 983T > C (P = 0.001) were each associated with hair efavirenz concentrations. Similarly, 516G > T (P < 0.001) and 983T > C (P = 0.009) were significantly associated with plasma efavirenz concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma efavirenz concentrations (r = 0.23, P = 0.043) and 983T > C genotype (r = 0.38, P < 0.0005).

CONCLUSION: This study demonstrated approximately 3-fold and 2-fold higher efavirenz plasma and hair concentrations, respectively, among CYP2B6 516TT compared to 516GG. Higher efavirenz concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.

PMID:34115651 | DOI:10.1097/QAD.0000000000002984

Annu Rev Nutr. 2021 Jun 11. doi: 10.1146/annurev-nutr-043020-090216. Online ahead of print.

ABSTRACT

The endocannabinoid system is involved in signal transduction in mammals. It comprises principally G protein-coupled cannabinoid receptors and their endogenous agonists, called endocannabinoids, as well as the enzymes and transporters responsible for the metabolism of endocannabinoids. Two arachidonic acid-containing lipid molecules, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, function as endocannabinoids. N-acylethanolamines and monoacylglycerols, in which the arachidonic acid chain is replaced with a saturated or monounsaturated fatty acid, are not directly involved in the endocannabinoid system but exhibit agonistic activities for other receptors. These endocannabinoid-like molecules include palmitoylethanolamide, oleoylethanolamide (OEA), and 2-oleoylglycerol. Endocannabinoids stimulate feeding behavior and the anabolism of lipids and glucose, while OEA suppresses appetite. Both central and peripheral systems are included in these nutritional and metabolic contexts. Therefore, they have potential in the treatment and prevention of obesity. We outline the structure, metabolism, and biological activities of endocannabinoids and related molecules, and focus on their involvement in energy homeostasis and metabolic regulation. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:34115519 | DOI:10.1146/annurev-nutr-043020-090216