Allergy Asthma Immunol Res. 2021 Nov;13(6):896-907. doi: 10.4168/aair.2021.13.6.896.

ABSTRACT

PROPOSE: The purpose of this study was to investigate panels of enzyme-linked immunospot assays (ELISpot) to detect drug-specific mediator releasing cells for confirming culprit drugs in severe cutaneous adverse reactions (SCARs).

METHODS: Frequencies of drug-induced interleukin-22 (IL-22)-, interferon-gamma (IFN-γ)-, and granzyme-B (GrB)-releasing cells were measured by incubating peripheral blood mononuclear cells (PBMCs) from SCAR patients with the culprit drugs. Potential immunoadjuvants were supplemented to enhance drug-induced mediator responses.

RESULTS: Twenty-seven patients, including 9 acute generalized exanthematous pustulosis (AGEP), 10 drug reactions with eosinophilia and systemic symptoms, and 8 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) were recruited. The average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells were 35.5±16.3, 33.0±7.1, and 164.8±43.1 cells/million PBMCs, respectively. The sensitivity of combined IFN-γ/IL-22/GrB ELISpot was higher than that of IFN-γ ELISpot alone for culprit drug detection in all SCAR subjects (77.8% vs 51.9%, P < 0.01). The measurement of drug-induced IL-22- and IFN-γ releasing cells confirmed the culprit drugs in 77.8% of AGEP. The measurement of drug-induced IFN-γ- and GrB-releasing cells confirmed the culprit drugs in 62.5% of SJS/TEN. Alpha-galactosylceramide supplementation significantly increased the frequencies of drug-induced IFN-γ releasing cells.

CONCLUSION: The measurement of drug-induced IFN-γ-releasing cells is the key for identifying culprit drugs. The additional measurement of drug-induced IL-22-releasing cells enhances ELISpot sensitivity to identify drug-induced AGEP, while the measurement of drug-induced GrB-releasing cells could have a role in SJS/TEN. ELISpot sensitivity might be improved by supplementary alpha-galactosylceramide.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02574988.

PMID:34734507 | DOI:10.4168/aair.2021.13.6.896

Curr Top Behav Neurosci. 2021 Nov 4. doi: 10.1007/7854_2021_270. Online ahead of print.

ABSTRACT

Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine, and mescaline, and entactogens/empathogens, especially 3,4-methylenedioxymethamphetamine, have received renewed attention in psychiatric research and may be developed into medications for such indications as anxiety, depression, cluster headache, and posttraumatic stress disorder, among others. However, identifying proper doses is crucial. Controlled study data on dosing using well-characterized pharmaceutical formulations of the substances are scarce. The dose equivalence of different substances, dose-response effects, and subjective effects of different doses are of great interest and practically important for their clinical use in psychotherapy. Furthermore, the so-called microdosing of psychedelics has recently gained popularity, and the first placebo-controlled studies of LSD have been published. This chapter discusses different aspects of psychedelic dosing, including pharmaceutical aspects, definitions and characteristics of different doses, including microdoses, aspects of personalized dosing, and non-pharmacological factors, that can influence the response to psychedelics.

PMID:34734392 | DOI:10.1007/7854_2021_270

Ir J Med Sci. 2021 Nov 4. doi: 10.1007/s11845-021-02828-4. Online ahead of print.

ABSTRACT

BACKGROUND: Dietary supplement use has continued to rise. In addition to supplement-drug interactions, it is prudent to consider how dietary supplements may interact with a patient's specific pharmacogenetics. Variations in genes associated with CYP 450 enzymes have evidence of impacting drug metabolism and adverse effects.

AIMS: This research was performed to evaluate CYP P450 enzyme activity of the top 15 dietary supplements used in the USA in order to initiate pharmacogenetic considerations specific to commonly used dietary supplements.

METHODS: The most common dietary supplements used in the USA were obtained from the National Health and Nutrition Examination Survey (NHANES). Primary literature detailing supplement CYP P450 activity was compiled from PubMed using MeSH search terms: supplement name(s), cytochrome P450 enzymes, metabolism, and pharmacokinetics. Additional resources utilized for documented CYP enzyme genotypes were the pharmacogenetic databases from Clinical Pharmacogenetics Implementation Consortium and The Pharmacogenomic Variation Consortium.

RESULTS: Of the 15 most common dietary supplements used in the USA, 53% (cranberry, echinacea, garlic, ginkgo biloba, ginseng, melatonin, milk thistle, and valerian) exhibit CYP P450 metabolism, with some having possible induction activity as well. Melatonin and garlic are substrates of CYP1A2 and CYP2C19, respectively. Additionally, there is evidence of echinacea having possible CYP3A4 induction activity.

CONCLUSION: CYP P450 activity is an important consideration for any patient but becomes increasingly critical if patients have certain CYP P450 phenotypes that impact metabolism. These popular supplements have the potential for changes in supplement exposure, and adverse effects based on pharmacogenetic profiles. Furthermore, these sites of metabolism are shared with many medications, setting the stage for possibly more profound interactions between medications and supplements. This paper highlights the mechanisms in which dietary supplements may constitute a risk for patients with certain CYP P450 phenotypes. Further research is needed in the area of dietary supplements and their pharmacogenomic implications.

PMID:34734388 | DOI:10.1007/s11845-021-02828-4

BMJ Open. 2021 Nov 3;11(11):e049568. doi: 10.1136/bmjopen-2021-049568.

ABSTRACT

INTRODUCTION: Robust randomised trial data have shown that routine preoperative (pre-op) testing for cataract surgery patients is inappropriate. While guidelines have discouraged testing since 2002, cataract pre-op testing rates have remained unchanged since the 1990s. Given the challenges of reducing low-value care despite strong consensus around the evidence, innovative approaches are needed to promote high-value care. This trial evaluates the impact of an interdisciplinary electronic health record (EHR) intervention that is informed by behavioural economic theory.

METHODS AND ANALYSIS: This pragmatic randomised trial is being conducted at UCLA Health between June 2021 and June 2022 with a 12-month follow-up period. We are randomising all UCLA Health physicians who perform pre-op visits during the study period to one of the three nudge arms or usual care. These three nudge alerts address (1) patient harm, (2) increased out-of-pocket costs for patients and (3) psychological harm to the patients related to pre-op testing. The nudges are triggered when a physician starts to order a pre-op test. We hypothesise that receipt of a nudge will be associated with reduced pre-op testing. The primary outcome will be the change in the percentage of patients undergoing pre-op testing at 12 months. Secondary outcomes will include the percentage of patients undergoing specific categories of pre-op tests (labs, EKGs, chest X-rays (CXRs)), the efficacy of each nudge, same-day surgery cancellations and cost savings.

ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of the University of California, Los Angeles as well as a nominated Data Safety Monitoring Board. If successful, we will have created a tool that can be disseminated rapidly to EHR vendors across the nation to reduce inappropriate testing for the most common low-risk surgical procedures in the country.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT04104256.

PMID:34732478 | DOI:10.1136/bmjopen-2021-049568

BMC Res Notes. 2021 Nov 2;14(1):405. doi: 10.1186/s13104-021-05817-z.

ABSTRACT

There has been an important global interest in Open Science, which include open data and methods, in addition to open access publications. It has been proposed that public availability of raw data increases the value and the possibility of confirmation of scientific findings, in addition to the potential of reducing research waste. Availability of raw data in open repositories facilitates the adequate development of meta-analysis and the cumulative evaluation of evidence for specific topics. In this commentary, we discuss key elements about data sharing in open repositories and we invite researchers around the world to deposit their data in them.

PMID:34727971 | PMC:PMC8561348 | DOI:10.1186/s13104-021-05817-z

Pharmacogenomics. 2021 Nov 3. doi: 10.2217/pgs-2021-0119. Online ahead of print.

ABSTRACT

Poly-(ADP-ribose) polymerase (PARP) inhibitors act in cells with defects in homologous recombination DNA repair (HRR) caused by genomic aberrations such as BRCA mutations. This phenomenon called synthetic lethality is known now to be more common in prostate cancer than previously thought. Olaparib and rucaparib, two PARP inhibitors, were successfully tested in clinical trials for HRR-deficient metastatic castration-resistant prostate cancer. They received a breakthrough US FDA approval in HRR altered metastatic castration-resistant prostate cancer in May 2020. Consequently, the combination of PARP inhibitors with other agents such as androgen receptor pathway inhibitors, immune checkpoint inhibitors or DNA damage inducing chemotherapy are being currently largely studied. In our review, we aim to summarize the key PARP inhibitors published and ongoing trials in prostate cancer.

PMID:34729995 | DOI:10.2217/pgs-2021-0119

Clin Transl Sci. 2021 Nov 2. doi: 10.1111/cts.13176. Online ahead of print.

ABSTRACT

To date, there has been no genomewide association study (GWAS) from the Middle East and North African (MENA) region to identify genetic variants associated with warfarin dose variability using this approach. In this study, we aimed to conduct the first GWAS of warfarin dose requirements in patients from the MENA region. A total of 132 Qatari (discovery) and 50 Egyptians (replication) were genotyped using Illumina Multi-Ethnic Global BeadChip Array. A GWAS was performed on log-transformed weekly warfarin dose in the studied population, adjusting for clinical characteristics and ancestry. The genomewide signals from the discovery cohort were tested in the Egyptian cohort. A GWAS meta-analysis, including the Qatari and Egyptian cohorts, was also performed and the output from this analysis was used in a gene-based analysis. The discovery analysis in Qatari identified five genomewide single-nucleotide polymorphisms (SNPs) in chromosome 16. These signals were replicated in the Egyptian cohort. Combining the two data through a GWAS meta-analysis strengthened the association in chromosome 16 with VKORC1 rs9934438 being the lead genomewide signal (β = -0.17, 6 × 10-15 ). Other SNPs were identified in chromosome 10 at a p value less than 1 × 10-5 . The genetic variants within VKORC1 rs9934438 and CYP2C9 rs4086116 explained 39% and 27% of the variability in the weekly warfarin dose requirement in the Qatari and Egyptians, respectively. This is the first GWAS of warfarin dose variability in the MENA region. It confirms the importance of VKORC1 and CYP2C9 variants in warfarin dose variability among patients from the MENA region.

PMID:34729928 | DOI:10.1111/cts.13176

ERJ Open Res. 2021 Nov 1;7(4):00381-2021. doi: 10.1183/23120541.00381-2021. eCollection 2021 Oct.

ABSTRACT

A digital multidisciplinary European expert meeting took place on the 9 July 2020 to identify the unmet needs of paediatric severe asthma patients, and set the priorities for clinical and research activities ahead https://bit.ly/3CeLBHB.

PMID:34729368 | PMC:PMC8558470 | DOI:10.1183/23120541.00381-2021

Drug Metab Dispos. 2021 Nov 2:DMD-AR-2021-000646. doi: 10.1124/dmd.121.000646. Online ahead of print.

ABSTRACT

Naltrexone (NTX), an opioid antagonist primarily metabolized by Aldo-Keto Reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n=163) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of NTX (0.1, 1 µM). NTX biotransformation was determined by UPLC-MS/MS quantification of the primary metabolite, 6-beta-naltrexol (6βN), and 6βN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0-79 y (mean 16.0{plus minus}18.2 y), 37% (n=60) female, 20% (n=33) heterozygous and 1.2% (n=2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6βN formation (0.37-76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0-18y) suggested that AKR1C4 genetic variation, age and sex explained 36% of the variability in 6βN formation. Although activity increased steadily from birth and peaked in middle childhood (2-5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. NTX biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study NTX responsiveness in children and adults. Significance Statement Biotransformation of the commonly used opioid antagonist, naltrexone, is highly variable and may contribute to reduced therapeutic response. Age, sex and genetic variation in the drug metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.

PMID:34728519 | DOI:10.1124/dmd.121.000646

Expert Rev Clin Pharmacol. 2021 Nov 2. doi: 10.1080/17512433.2022.2000858. Online ahead of print.

ABSTRACT

BACKGROUND: This population pharmacokinetic-pharmacogenetic study aimed to investigate the optimal dose of RTV-boosted ATV (ATV/RTV) for Thai adult HIV-infected patients.

METHODS: A total of 1460 concentrations of ATV and RTV from 544 patients receiving an ATV/RTV-based regimen were analyzed. The CYP3A5 6986A>G, ABCB1 3435C>T, ABCB1 2677G>T, SLCO1B1 521T>C and NR1I2 63396C>T were genotyped. A population pharmacokinetic model was performed using a nonlinear mixed-effect model (NONMEM®). Monte Carlo simulations were conducted to compare the percentages of patients achieving the therapeutic range of ATV trough concentrations (Ctrough).

RESULTS: The apparent oral clearance of ATV (CL/FATV) without RTV was 7.69 L/h with interindividual variability (IIV) of 28.7%. Patients with CYP3A5 6986 GG had a 7.1% lower CL/FATV than those with AA or AG genotype. The CL/FATV decreased by 10.8% for females compared with males. Simulation results showed higher percentages (~70%) of patient receiving doses of 200/100 or 200/50 mg achieved the ATV Ctrough of 0.15-0.85 mg/L, while more patients (~40%) receiving a standard dose (300/100 mg) had ATV Ctrough above this target.

CONCLUSIONS: Both CYP3A5 6986A>G and female decreased CL/FATV in Thai HIV-infected patients. Simulations supported that the reduced dose of ATV/RTV was sufficient to achieve the target concentration for Thai population.

PMID:34727835 | DOI:10.1080/17512433.2022.2000858

Expert Opin Drug Metab Toxicol. 2021 Nov 3. doi: 10.1080/17425255.2021.1998455. Online ahead of print.

ABSTRACT

Adverse drug reactions (ADRs) are among the leading causes of death, and frequently associated with drug-gene interactions (DGIs). In addition to pharmacogenomic programs for implementation of genetic preemptive testing into clinical practice, mathematical modeling can help to understand, quantify and predict the effects of DGIs in vivo. Moreover, modeling can contribute to optimize prospective clinical drug trial activities and to reduce DGI-related ADRs.Areas covered: Approaches and challenges of mechanistical DGI implementation and model parameterization are discussed for population pharmacokinetic and physiologically based pharmacokinetic models. The broad spectrum of published DGI models and their applications is presented, focusing on the investigation of DGI effects on pharmacology and model-based dose adaptations.Expert opinion: Mathematical modeling provides an opportunity to investigate complex DGI scenarios and can facilitate the development process of safe and efficient personalized dosing regimens. However, reliable DGI model input data from in vivo and in vitro measurements are crucial. For this, collaboration among pharmacometricians, laboratory scientists and clinicians is important to provide homogeneous datasets and unambiguous model parameters. For a broad adaptation of validated DGI models in clinical practice, interdisciplinary cooperation should be promoted and qualification toolchains must be established.

PMID:34727800 | DOI:10.1080/17425255.2021.1998455

Clin Chem Lab Med. 2021 Oct 21;59(s1):s698-s704. doi: 10.1515/cclm-2021-5032.

NO ABSTRACT

PMID:34727632 | DOI:10.1515/cclm-2021-5032

Sci Rep. 2021 Nov 1;11(1):21354. doi: 10.1038/s41598-021-98642-0.

ABSTRACT

Anchorage-independent growth of cancer cells in vitro is correlated to metastasis formation in vivo. Metformin use is associated with decreased breast cancer incidence and currently evaluated in cancer clinical trials. The combined treatment with metformin and 2-deoxy-D-glucose (2DG) in vitro induces detachment of viable MDA-MB-231 breast cancer cells that retain their proliferation capacity. This might be important for cell detachment from primary tumors, but the metabolic changes involved are unknown. We performed LC/MS metabolic profiling on separated attached and detached MDA-MB-231 cells treated with metformin and/or 2DG. High 2DG and metformin plus 2DG altered the metabolic profile similarly to metformin, inferring that metabolic changes are necessary but not sufficient while the specific effects of 2DG are crucial for detachment. Detached cells had higher NADPH levels and lower fatty acids and glutamine levels compared to attached cells, supporting the role of AMPK activation and reductive carboxylation in supporting anchorage-independent survival. Surprisingly, the metabolic profile of detached cells was closer to untreated control cells than attached treated cells, suggesting detachment might help cells adapt to energy stress. Metformin treated cells had higher fatty and amino acid levels with lower purine nucleotide levels, which is relevant for understanding the anticancer mechanisms of metformin.

PMID:34725457 | DOI:10.1038/s41598-021-98642-0

NPJ Genom Med. 2021 Nov 1;6(1):90. doi: 10.1038/s41525-021-00253-1.

ABSTRACT

Within an institutional pharmacogenomics implementation program, we surveyed 463 outpatients completing preemptive pharmacogenomic testing whose genetic results were available to providers for guiding medication treatment. We compared views and experiences from self-reported White and Black patients, including education level as a covariate across analyses. Black patients were less confident about whether their providers made personalized treatment decisions, and overwhelmingly wanted a greater role for their genetic information in clinical care. Both groups similarly reported that providers asked their opinions regarding medication changes, but White patients were more likely (59% vs. 49%, P = 0.005) to discuss the impact of personal/genetic makeup on medication response with providers, and Black patients reported initiating such discussions much less frequently (4% vs. 15%, P = 0.037). Opportunities exist for enhanced communication with underrepresented patients around personalized care. Tailored communication strategies and development of support tools employed in diverse healthcare settings may facilitate pharmacogenomically guided medication treatment that equitably benefits minority patient populations.

PMID:34725343 | DOI:10.1038/s41525-021-00253-1

Sci Immunol. 2021 Jun 15;6(60):eaba8426. doi: 10.1126/sciimmunol.aba8426.

ABSTRACT

Radiotherapy (RT) is an important anti-cancer treatment modality that activates innate and adaptive immune responses. When all-trans retinoic acid (RA) was administered with radiation, we observed superior antitumor responses compared to ionizing radiation (IR) alone or RA alone. The superior antitumor effects of combination treatment were accompanied by a dramatic increase of TNF-α- and inducible nitric oxide synthase (iNOS)-producing inflammatory macrophages in local and distal non-irradiated (distal) tumors. Inflammatory macrophages are essential for the therapeutic efficacy of combination treatment by inducing effector T cell infiltration and enhancing the effector T cell to regulatory T cell ratio in local and distal tumors. T cells and T cell-derived IFN-γ are crucial for increasing inflammatory macrophage levels in IR and RA treated tumors. Notably, whereas CD8+ T cells are required for the antitumor response to IR, CD4+ T cells are required for the effectiveness of the IR and RA combination. Combination treatment with RA enhanced the abscopal response when radiation and PD-L1 blockade were used together. The synergistic positive feedback loop of inflammatory macrophages and adaptive immunity is required for the antitumor efficacy of IR plus RA combination treatment. Our findings provide a translational and relatively nontoxic strategy for enhancing the local and systemic antitumor effects of IR.

PMID:34723044 | PMC:PMC8550472 | DOI:10.1126/sciimmunol.aba8426

J Clin Transl Hepatol. 2021 Oct 28;9(5):731-737. doi: 10.14218/JCTH.2020.00091. Epub 2021 Sep 14.

ABSTRACT

Metabolic dysfunction-associated fatty liver disease (commonly known as MAFLD) impacts global health in epidemic proportions, and the resulting morbidity, mortality and economic burden is enormous. While much attention has been given to metabolic syndrome and obesity as offending factors, a growing incidence of polypharmacy, especially in the elderly, has greatly increased the risk of drug-induced liver injury (DILI) in general, and drug-induced fatty liver disease (DIFLD) in particular. This review focuses on the contribution of DIFLD to DILI in terms of epidemiology, pathophysiology, the most common drugs associated with DIFLD, and treatment strategies.

PMID:34722188 | PMC:PMC8516847 | DOI:10.14218/JCTH.2020.00091

Front Pharmacol. 2021 Oct 15;12:735278. doi: 10.3389/fphar.2021.735278. eCollection 2021.

ABSTRACT

Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, despite the development of novel OVs with improved efficacy and tumor selectivity, their limited efficacy as monotherapeutic agents remains a significant challenge. This study extended our previously observed combination effects of propranolol, a nonselective β-blocker, and the T1012G oncolytic virus into colorectal cancer models. A cell viability assay showed that cotreatment could induce synergistic killing effects on human and murine colorectal cell lines. Moreover, cotreatment caused sustained tumor regression compared with T1012G monotherapy or propranolol monotherapy in human HCT116 and murine MC38 tumor models. The propranolol activity was not via a direct effect on viral replication in vitro or in vivo. Western blotting showed that cotreatment significantly enhanced the expression of cleaved caspase-3 in HCT116 and MC38 cells compared with the propranolol or T1012G alone. In addition, propranolol or T1012G treatment induced a 35.06% ± 0.53% or 35.49% ± 2.68% reduction in VEGF secretion in HUVECs (p < 0.01/p < 0.01). Cotreatment further inhibited VEGF secretion compared with the monotherapies (compared with propranolol treatment: 75.06% ± 1.50% decrease, compared with T1012G treatment: 74.91% ± 0.68%; p＜0.001, p < 0.001). Consistent with the in vitro results, in vivo data showed that cotreatment could reduce Ki67 and enhance cleaved caspase 3 and CD31 expression in human HCT116 and murine MC38 xenografts. In summary, β-blockers could improve the therapeutic potential of OVs by enhancing oncolytic virus-mediated killing of colorectal cancer cells and colorectal tumors.

PMID:34721024 | PMC:PMC8554205 | DOI:10.3389/fphar.2021.735278

Front Pharmacol. 2021 Oct 15;12:723940. doi: 10.3389/fphar.2021.723940. eCollection 2021.

ABSTRACT

Drug-induced liver injury (DILI) has become one of the major challenges of drug safety all over the word. So far, about 1,100 commonly used drugs including the medications used regularly, herbal and/or dietary supplements, have been reported to induce liver injury. Moreover, DILI is the main cause of the interruption of new drugs development and drugs withdrawn from the pharmaceutical market. Acute DILI may evolve into chronic DILI or even worse, commonly lead to life-threatening acute liver failure in Western countries. It is generally considered to have a close relationship to genetic factors, environmental risk factors, and host immunity, through the drug itself or its metabolites, leading to a series of cellular events, such as haptenization and immune response activation. Despite many researches on DILI, the specific biomarkers about it are not applicable to clinical diagnosis, which still relies on the exclusion of other causes of liver disease in clinical practice as before. Additionally, circumstantial evidence has suggested that DILI is mediated by the immune system. Here, we review the underlying mechanisms of the immune response to DILI and provide guidance for the future development of biomarkers for the early detection, prediction, and diagnosis of DILI.

PMID:34721020 | PMC:PMC8554067 | DOI:10.3389/fphar.2021.723940

Front Pharmacol. 2021 Apr 28;12:634016. doi: 10.3389/fphar.2021.634016. eCollection 2021.

ABSTRACT

Introduction: Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterized in European and Asian populations, but data from African populations are under-studied-which has implications for drug safety and effective use in Africa. Results: We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations. Discussion: The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.

PMID:34721006 | PMC:PMC8549571 | DOI:10.3389/fphar.2021.634016

Hosp Pharm. 2021 Oct;56(5):592-596. doi: 10.1177/0018578720931756. Epub 2020 Jun 2.

ABSTRACT

Background: Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS), which includes the symptoms of anxiety, fear, and emotional tension. However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions, reducing the efficacy of therapy. Aim: The purpose of our study was to investigate the effects of CYP2C19*17 genetic polymorphisms on the steady-state concentration of diazepam in patients with AWS. Materials and Methods: The study was conducted on 50 Russian male patients suffering from the AWS. For the therapy of psychomotor agitation, anxiety, fear, and emotional tension, patients received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Therapeutic drug monitoring (TDM) was performed using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. Results: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 -806C>T genotypes: (*1/*1) -12.0 [-15.0; -8.0], (*1/*17+*17/*17) -7.0 [-14.0; -5.0], P < .001, as well as the results of TDM: (CC) 250.70 [213.34; 308.53] ng/mL (*1/*17+*17/*17) 89.12 [53.26; 178.07] ng/mL, P < .001. Conclusion: Thus, our study enrolling 50 patients with AWS, showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant difference in the levels of plasma steady-state concentrations of diazepam in patients carrying different genotypes.

PMID:34720165 | PMC:PMC8554590 | DOI:10.1177/0018578720931756