Orthop Clin North Am. 2022 Oct;53(4):361-375. doi: 10.1016/j.ocl.2022.06.001. Epub 2022 Sep 14.

ABSTRACT

Pharmacogenomic testing, together with the early detection of drug-drug-gene interactions (DDGI) before initiating opioids, can improve the selection of dosage and reduce the risk of adverse drug interactions and therapeutic failures following Total Joint Arthroplasty. The variants of CYP genes can mediate DDGI. Orthopedic surgeons should become familiar with the genetic aspect of opioid use and abuse, as well as the influence of the patient genetic makeup in opioid selection and response, and polymorphic variants in pain modulation.

PMID:36208880 | DOI:10.1016/j.ocl.2022.06.001

Toxicol Appl Pharmacol. 2022 Oct 5:116256. doi: 10.1016/j.taap.2022.116256. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 μM in HCT-116, and 9.36, 10.77, and 24.57 μM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.

PMID:36208702 | DOI:10.1016/j.taap.2022.116256

Sci Rep. 2022 Oct 7;12(1):16873. doi: 10.1038/s41598-022-21003-y.

ABSTRACT

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

PMID:36207451 | DOI:10.1038/s41598-022-21003-y

Curr Protoc. 2022 Oct;2(10):e534. doi: 10.1002/cpz1.534.

ABSTRACT

Genome sequencing holds the promise for great public health benefits. It is currently being used in the context of rare disease diagnosis and novel gene identification, but also has the potential to identify genetic disease risk factors in healthy individuals. Genome sequencing technologies are currently being used to identify genetic factors that may influence variability in symptom severity and immune response among patients infected by SARS-CoV-2. The GENCOV study aims to look at the relationship between genetic, serological, and biochemical factors and variability of SARS-CoV-2 symptom severity, and to evaluate the utility of returning genome screening results to study participants. Study participants select which results they wish to receive with a decision aid. Medically actionable information for diagnosis, disease risk estimation, disease prevention, and patient management are provided in a comprehensive genome report. Using a combination of bioinformatics software and custom tools, this article describes a pipeline for the analysis and reporting of genetic results to individuals with COVID-19, including HLA genotyping, large-scale continental ancestry estimation, and pharmacogenomic analysis to determine metabolizer status and drug response. In addition, this pipeline includes reporting of medically actionable conditions from comprehensive gene panels for Cardiology, Neurology, Metabolism, Hereditary Cancer, and Hereditary Kidney, and carrier screening for reproductive planning. Incorporated into the genome report are polygenic risk scores for six diseases-coronary artery disease; atrial fibrillation; type-2 diabetes; and breast, prostate, and colon cancer-as well as blood group genotyping analysis for ABO and Rh blood types and genotyping for other antigens of clinical relevance. The genome report summarizes the findings of these analyses in a way that extensively communicates clinically relevant results to patients and their physicians. © 2022 Wiley Periodicals LLC. Basic Protocol 1: HLA genotyping and disease association Basic Protocol 2: Large-scale continental ancestry estimation Basic Protocol 3: Dosage recommendations for pharmacogenomic gene variants associated with drug response Support Protocol: System setup.

PMID:36205462 | DOI:10.1002/cpz1.534

Transplant Direct. 2022 Sep 15;8(10):e1379. doi: 10.1097/TXD.0000000000001379. eCollection 2022 Oct.

ABSTRACT

Pharmacogenetic profiling of transplant recipients demonstrates that the marked variation in the metabolism of immunosuppressive medications, particularly tacrolimus, is related to genetic variants. Patients of African ancestry are less likely to carry loss-of-function (LoF) variants in the CYP3A5 gene and therefore retain a rapid metabolism phenotype and higher clearance of tacrolimus. Patients with this rapid metabolism typically require higher dosing to achieve therapeutic trough concentrations. This study aims to further characterize the impact of CYP3A5 genotype on clinical outcomes and financial expenditure.

METHODS: The CYP3A5 phenotype status was identified in 438 adult kidney transplant (KTx) recipients (96% were African American) using 3 LoF alleles (CYP3A5*3, *6 or *7). Individuals were categorized as rapid metabolism phenotype without LoF alleles' intermediate phenotype for 1 LoF allele' and slow phenotype for 2 LoF alleles. KTx outcomes (patient/kidney survival and Medicare spending) were determined using linked transplant registry and claims data.

RESULTS: Among the cohort, 23% had a rapid, 47% intermediate, and 30% a slow metabolism phenotype based on genotype. At 3 y, the rate of death censored graft failure and all cause graft failure was highest in the rapid metabolism phenotype and lowest in the intermediate metabolism phenotype group. First-year Medicare reimbursement differed significantly by genotype (rapid: $79 535, intermediate: $72 796, slow: $79 346, P = 0.03). After adjustment for donor and recipient characteristics, care for patients with intermediate metabolism was $4790 less expensive (P = 0.003).

CONCLUSIONS: Pharmacogenomic assessment of African American KTx recipients may be useful to guide therapy when as CYP3A5 functional variants appear to be associated with differential outcome and spending after transplant.

PMID:36204191 | PMC:PMC9529042 | DOI:10.1097/TXD.0000000000001379

Curr Top Med Chem. 2022 Oct 6. doi: 10.2174/1568026622666221006140825. Online ahead of print.

ABSTRACT

The role of computational tools in the drug discovery and development process is becoming central, thanks to the possibility to analyze large amounts of data. The high throughput and affordability of current omics technologies, allowing quantitative measurements of many putative targets, has exponentially increased the volume of scientific data available. The quality of the data and the speed with which in silico predictions can be validated in vitro is instrumental in accelerating clinical laboratory medicine, significantly and substantially impacting Precision Medicine (PM). PM affords the basis to develop new drugs by providing a wide knowledge of the patient as an essential step towards individualized medicine. It is, therefore, essential to collect as much information and data as possible on each patient to identify the causes of the different responses to drugs from a pharmacogenomics perspective and to identify biological biomarkers capable of accurately describing the risk signals to develop specific diseases. Furthermore, the role of biomarkers in early drug discovery is increasing, as they can significantly reduce the time it takes to develop new drugs. This review article will discuss how Artificial Intelligence fits in the drug discovery pipeline, covering the benefits of an automated, integrated laboratory framework where the application of Machine Learning methodologies to interpret omics-based data can avail the future perspective of Translational Precision Medicine.

PMID:36201265 | DOI:10.2174/1568026622666221006140825

Explor Res Clin Soc Pharm. 2022 Sep 21;8:100182. doi: 10.1016/j.rcsop.2022.100182. eCollection 2022 Dec.

ABSTRACT

BACKGROUND: As pharmacogenomic services begin to emerge in primary care, the insight of the public is crucial for its integration into clinical practice.

OBJECTIVES: To establish perceptions of pharmacogenomics (awareness, understanding, openness to availability, perceived benefits and concerns, willingness to pay, and service setting) and investigate if they differ between those with and without chronic disease(s).

METHODS: An anonymous, online questionnaire generated using Qualtrics® and circulated via social media and posters placed in eight participating community pharmacies was conducted with Irish adults. The questions were designed to consider existing literature on patient perceptions of pharmacogenomics. Descriptive statistics were used to summarize questionnaire responses. Chi-square test was used to compare categorical variables, while independent sample t-test and one-way ANOVA were used to compare the mean values of two (with and without chronic disease) and three groups (multimorbidity (two or more chronic conditions) and polypharmacy (prescribed four or more regular medicines) (MMPP), a single chronic disease, and those without existing medical conditions) respectively Logistic regression was used to evaluate age and gender adjusted associations of chronic disease(s) with responses. A p-value <0.05 was considered statistically significant.

RESULTS: A total of 421 responses were received, 30% (n = 120) of whom reported having a chronic disease. Overall, respondents reported low awareness (44%, n = 166) and poor knowledge (55%, n = 212) of pharmacogenomics. After explaining pharmacogenomics to respondents, patients with chronic disease(s) were 2.17 times more likely (p < 0.001) to want pharmacogenomic services availability than those without existing conditions, adjusted for age and gender (driven by preferences of those with MMPP than those with single chronic disease). Respondents demonstrated a high level of interest and noted both the potential benefits and downsides of pharmacogenomic testing. Willingness-to-pay was not associated with having a chronic disease and respondents were more positive about primary care (community pharmacy or general practice) rather than hospital-based pharmacogenomics implementation.

CONCLUSION: The Irish public in general and those with chronic disease in particular are strongly supportive of pharmacogenomic testing, highlighting an unmet need for its incorporation in medicines optimization. These data underline the need for more research on the implementation of community-based pharmacogenomics services for MMPP patients and ubiquitous pharmacogenomics education programs.

PMID:36200068 | PMC:PMC9529536 | DOI:10.1016/j.rcsop.2022.100182

Aliment Pharmacol Ther. 2022 Oct 5. doi: 10.1111/apt.17223. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic offered a unique opportunity to understand inflammatory bowel disease (IBD) management during unexpected disruption. This could help to guide practice overall.

AIMS: To compare prescribing behaviour for IBD flares and outcomes during the early pandemic with pre-pandemic findings.

METHODS: We performed an observational cohort study comprising patients who contacted IBD teams for symptomatic flares between March and June 2020 in 60 National Health Service trusts in the United Kingdom. Data were compared with a pre-pandemic cohort after propensity-matching for age and physician global assessment of disease activity.

RESULTS: We included 1864 patients in each of the pandemic and pre-pandemic cohorts. The principal findings were reduced systemic corticosteroid prescription during the pandemic in Crohn's disease (prednisolone: pandemic 26.5% vs. 37.1%; p < 0.001) and ulcerative colitis (UC) (prednisolone: pandemic 33.5% vs. 40.7%, p < 0.001), with increases in poorly bioavailable oral corticosteroids in Crohn's (pandemic 15.6% vs. 6.8%; p < 0.001) and UC (pandemic 11.8% vs. 5.2%; p < 0.001). Ustekinumab (Crohn's and UC) and vedolizumab (UC) treatment also significantly increased. Three-month steroid-free remission in each period was similar in Crohn's (pandemic 28.4% vs. 32.1%; p = 0.17) and UC (pandemic 36.4% vs. 40.2%; p = 0.095). Patients experiencing a flare and suspected COVID-19 were more likely to have moderate-to-severely active disease at 3 months than those with a flare alone.

CONCLUSIONS: Despite treatment adaptations during the pandemic, steroid-free outcomes were comparable with pre-pandemic levels, although concurrent flare and suspected COVID-19 caused worse outcomes. These findings have implications for IBD management during future pandemics and for standard practice.

PMID:36196569 | DOI:10.1111/apt.17223

Eur J Hum Genet. 2022 Oct 4. doi: 10.1038/s41431-022-01192-w. Online ahead of print.

ABSTRACT

Genome sequencing (GS) outperforms other rare disease diagnostics, but standardized approaches to assessing its clinical utility are limited. This study assessed the validity of the Clinician-reported Genetic testing Utility InDEx (C-GUIDE), a novel tool for assessing the utility of genetic testing from a clinician's perspective, for GS. C-GUIDE ratings were completed for patients who received GS results. For each patient, total C-GUIDE and single item global scores were calculated. Construct validity was assessed using linear regression to determine the association between C-GUIDE total and global item scores and measure the effects of potential explanatory variables. Ratings were completed for 67 pediatric and 36 adult patients. GS indications were neurological for 70.9% and results were diagnostic for 28.2%. When the C-GUIDE assessed primary (PV), secondary (SV), and pharmacogenomic (PGx) variants, on average, a one unit increase in the global item score was associated with an increase of 7.3 in the C-GUIDE score (p < 0.05). Diagnostic results were associated with an increase in C-GUIDE score of 5.0 compared to non-diagnostic results (p < 0.05) and an increase of one SV was associated with an increase of 2.5 (p < 0.05). For children, decreased age of one year was associated with an increase in C-GUIDE score of 0.3 (p < 0.05). Findings provide evidence that C-GUIDE measures the construct of clinical utility in pediatric and adult rare disease populations and is sensitive to changes in utility related to variant type. Quantifying the clinical utility of GS using C-GUIDE can inform efforts to optimize its use in patient care.

PMID:36195708 | DOI:10.1038/s41431-022-01192-w

Respir Investig. 2022 Oct 1:S2212-5345(22)00121-6. doi: 10.1016/j.resinv.2022.09.001. Online ahead of print.

ABSTRACT

BACKGROUND: Cough and sputum are the significant symptoms of nontuberculous mycobacteriosis (NTM) and impair quality of life (QOL). However, the relationship between these symptoms and clinical features is not fully understood. This study aimed to investigate cough-related QOL in NTM patients.

METHODS: The study subjects included 78 patients with NTM at our hospital from October to December 2015. They completed the Leicester Cough Questionnaire (LCQ) and the Cough and Sputum Assessment Questionnaire (CASA-Q) (both questionnaires: the higher, the better); the Frequency Scale for the Symptoms of gastroesophageal reflux disease (GERD) (FSSG), a validated Japanese questionnaire for GERD (the higher, the worse), was also assessed. The FSSG consists of 12 items, including the reflux-related symptoms and dysmotility symptoms domains, each of which is quantified on a scale of 0-4 points, and the cut-off score for GERD is set at 8 points. Associations between these scores and clinical parameters were assessed.

RESULTS: The total LCQ score was reduced-the physical domain was dominant. The total LCQ and CASA-Q scores were reduced, with dominance in the physical and symptoms domains, respectively. The reflux-related symptoms score was higher than the dysmotility symptoms score. A multivariate linear regression analysis revealed that the mean total LCQ score was independently associated with current smoking, fibrocavitary type, bilateral cavitary lesion, and FSSG total score.

CONCLUSIONS: Cough-related QOL was impaired in NTM patients who currently smoked, had radiological characteristics, and had GERD.

PMID:36195550 | DOI:10.1016/j.resinv.2022.09.001

Dtsch Med Wochenschr. 2022 Oct;147(20):1336-1341. doi: 10.1055/a-1924-6646. Epub 2022 Oct 4.

ABSTRACT

Next-generation sequencing is a modern diagnostic high-throughput method (multi-gene analysis) that can be used to better diagnose both hereditary cancers (tumor disposition syndromes, germline diagnostics) and somatic mutations in tumors. The broad usage of this technology in daily clinical practice demonstrates the real interindividual genetic variability. This method has great importance for the investigation of heterogeneous genetic diseases (e. g. tumors, neurodegenerative and neuromuscular diseases). Further indications are pharmacogenetics and non-invasive prenatal diagnosis. It can be expected that this diagnostic tool will find wide clinical application. With the rapid increase and complexity of genetic data information, the correct interpretation and transmission of the results in the human genetic counseling (germline diagnostics) is of great importance. The genetic counseling must be realigned and adapted accordingly in daily clinical practice.

PMID:36195092 | DOI:10.1055/a-1924-6646

Endocrine. 2022 Oct 4. doi: 10.1007/s12020-022-03205-6. Online ahead of print.

ABSTRACT

PURPOSE: The co-occurrence of cyanotic congenital heart disease (CCHD) and PHEO/PGL has been reported, but the role of the hypoxic environment in the pathogenesis of PHEO/PGL remains unclear. Our aim was to compare plasma metanephrine and normetanephrine levels between patients with CCHD and patients with acyanotic congenital heart disease (ACCHD).

METHODS: We performed a cross-sectional study in a prospective cohort of 44 patients with congenital heart disease (CHD) (31 (70.5%) females) with a median age of 37.5 (31.0-55.6) years at the time of evaluation. Thirty-two (73%) patients had CCHD and 12 (27%) patients had ACCHD. Morning blood samples for plasma determination of metanephrine and normetanephrine were collected.

RESULTS: Plasma normetanephrine levels were significantly higher in patients with CCHD compared to ACCHD (p = 0.002). Ten (31.3%) patients with CCHD had plasma normetanephrine levels elevated above the reference range, while all ACCHD patients had normal levels. Patients with lower oxygen saturation and higher proBNP had significantly higher normetanephrine levels (ρ = -0.444, p = 0.003 and ρ = 0.449, p = 0.002, respectively). No chromaffin cell tumors were detected.

CONCLUSION: Increased plasma normetanephrine levels in patients with CCHD can be explained by the effect of hypoxia. Future research is needed to better understand the impact of chronic hypoxia in CCHD on increased sympathetic outflow, hyperplastic response of chromaffin tissue, and the role of somatic mutations in CCHD-PHEO/PGL pathogenesis related to hypoxia.

PMID:36194345 | DOI:10.1007/s12020-022-03205-6

Pharmacogenomics. 2022 Oct 4. doi: 10.2217/pgs-2022-0098. Online ahead of print.

ABSTRACT

Aim: To evaluate the association between SLCO1B1 polymorphisms and elimination/toxicities of high-dose methotrexate (MTX). Methods: SLCO1B1 rs11045879 and rs4149056 polymorphisms were retrospectively genotyped in 301 children with newly diagnosed acute lymphoblastic leukemia. MTX concentration, doses of leucovorin rescue and toxicities were recorded. Results: SLCO1B1 rs11045879C carriers (CC + CT) had higher plasma MTX levels at 96 hr, and longer MTX elimination time. The number of leucovorin rescue doses in rs4149056C carriers (CC + CT) was more than those in TT ones. Moreover, SLCO1B1 polymorphisms were associated with HDMTX toxicities including thrombocytopenia, renal toxicity and anal mucositis, but not associated with MTX level at other time points or delayed elimination. Conclusions: Our data demonstrate that genotyping of SLCO1B1 might be useful to optimize MTX therapy.

PMID:36193736 | DOI:10.2217/pgs-2022-0098

Parasitol Res. 2022 Oct 4. doi: 10.1007/s00436-022-07685-3. Online ahead of print.

ABSTRACT

Human babesiosis is caused by Babesia duncani that is transmitted through tick bites, blood transfusions, and transplacental transmission. Despite its health burden, diagnostic assays for this pathogen are either unsuitable for clinical applications or have a low detection efficiency; therefore, it remains undetected during transfusion and utilization of blood and blood-component transfusions. This study used a molecular approach via nested quantitative polymerase chain reaction (qPCR) by designing primers and probes corresponding to the variable regions of B. duncani 18S rRNA gene to specifically detect B. duncani DNA in experimentally infected LVG Golden Syrian hamster (n = 70) and human (n = 492; tick bite patients from Gansu Province, China) blood samples. Moreover, comparative analyses of this technique with previously reported nested PCR and microscopy were conducted. The newly optimized diagnostic technique exhibited no cross-reactivity with genomic DNA or plasmids containing the 18S rRNA gene of other zoonotically important Babesia spp., including B. microti, B. divergens, B. crassa, and B. motasi Hebei. The detection limit of nested qPCR was approximately one plasmid copy in 20 μL or one infected red blood cell in 200 μL whole blood. The specificity and sensitivity of the method were 100% and 98.6%, respectively. Comparative analyses revealed that nested qPCR detected B. duncani had relatively higher efficacy and specificity than microscopic examination and nested PCR. The 492 human blood samples were negative for B. duncani infection. Thus, the present study provides an improved diagnostic assay for the efficient and effective detection and analysis of B. duncani infections and its prevalence in infection-prone areas.

PMID:36192649 | DOI:10.1007/s00436-022-07685-3

Crit Rev Oncol Hematol. 2022 Sep 30:103826. doi: 10.1016/j.critrevonc.2022.103826. Online ahead of print.

ABSTRACT

Corticosteroids (CSs) are widely used in oncology, presenting several different indications. They are useful for induction of apoptosis in hematological neoplasms, for management of anaphylaxis and cytokine release/hypersensitivity reaction and for the symptomatic treatment of many tumour- and treatment-related complications. If the employment of CSs in the oncological setting results in several benefits for patients and satisfaction for clinicians, on the other hand, many potential adverse events (AEs), both during treatment and after withdrawal of CSs, as well as the duality of the effects of these compounds in oncology, recommend being cautious in clinical practice. To date, several gray zones remain about indications, contraindications, dose, and duration of treatment. In this article, a panel of experts provides a critical review on CSs therapy in oncology, focusing on mechanisms of action and pharmacological characteristics, current and emerging therapeutic indications/contraindications, AEs related to CSs treatment, and the impact on patient outcome.

PMID:36191821 | DOI:10.1016/j.critrevonc.2022.103826

Ther Drug Monit. 2022 Oct 1. doi: 10.1097/FTD.0000000000001049. Online ahead of print.

ABSTRACT

PURPOSE: Trazodone hydrochloride is an antidepressant used in clinical practice. As a substrate of cytochrome P450 enzymes that is vulnerable to P-glycoprotein transport, several factors can alter its plasma concentration, and hence, dose adjustment may be required. The aim of this scoping review was to identify genetic polymorphisms that influence the pharmacokinetics of trazodone hydrochloride.

METHODS: A literature search was performed using PubMed, PubMed Central, BVS/BIREME, EBSCOhost, Web of Science, Embase, Cochrane Library, and Medline databases for studies published until August 2021. The search strategy was based on the following keywords: Trazodone OR "m-chlorophenyl piperazine" AND "Pharmacogenetics" OR "Genetics" OR "Cytochrome P-450 Enzyme System" OR "Polymorphism, Single Nucleotide" OR "Polymorphism, Genetic."

RESULTS: The search retrieved 684 candidate articles; 307 duplicates were eliminated. In total, 377 articles were eligible for the first screen. However, only four met the eligibility criteria, and 12 polymorphisms in five different genes (CYP2D6, CYP1A2, CYP3A4, CYP3A5, and ABCB1). Notably, only C3435T ABCB1 influenced the pharmacokinetics of trazodone hydrochloride. Individuals with the T/T genotype had lower area under the curve, half-life, and maximum concentration values with a higher clearance rate.

CONCLUSIONS: Polymorphisms in CYP450 do not appear to directly influence the pharmacokinetics of trazodone hydrochloride or its metabolites. Genetic polymorphisms in ABCB1, in contrast, seem to have an important effect on the pharmacokinetics of trazodone hydrochloride by enhancing drug metabolism and elimination.

PMID:36191287 | DOI:10.1097/FTD.0000000000001049

Genet Mol Biol. 2022 Sep 30;45(3 Suppl 1):e20220120. doi: 10.1590/1678-4685-GMB-2022-0120. eCollection 2022.

ABSTRACT

The use of combined antiretroviral therapy (cART) has resulted in a remarkable reduction in morbidity and mortality of people living with HIV worldwide. Nevertheless, interindividual variations in drug response often impose a challenge to cART effectiveness. Although personalized therapeutic regimens may help overcome incidence of adverse reactions and therapeutic failure attributed to host factors, pharmacogenetic studies are often restricted to a few populations. Latin American countries accounted for 2.1 million people living with HIV and 1.4 million undergoing cART in 2020-21. The present review describes the state of art of HIV pharmacogenetics in this region and highlights that such analyses remain to be given the required relevance. A broad analysis of pharmacogenetic markers in Latin America could not only provide a better understanding of genetic structure of these populations, but might also be crucial to develop more informative dosing algorithms, applicable to non-European populations.

PMID:36190287 | DOI:10.1590/1678-4685-GMB-2022-0120

Antimicrob Agents Chemother. 2022 Oct 3:e0056522. doi: 10.1128/aac.00565-22. Online ahead of print.

ABSTRACT

Clofazimine [N,5-bis(4-chlorophenyl)-3-[(propane-2-yl)rimino]-3,5-dihydrophenazin-2-amine] is an antimycobacterial agent used as a second-line antituberculosis (anti-TB) drug. Nonetheless, little information is known about the metabolic routes of clofazimine, and the enzymes involved in metabolism. This study aimed to characterize the metabolic pathways and enzymes responsible for the metabolism of clofazimine in human liver microsomes. Eight metabolites, including four oxidative metabolites, three glucuronide conjugates, and one sulfate conjugate were identified, and their structures were deduced based on tandem mass spectrometry (MS/MS) spectra. Hydroxylated clofazimine and hydrated clofazimine was generated even in the absence of the NADPH generating system presumably via a nonenzymatic pathway. Hydrolytic-dehalogenated clofazimine was catalyzed mainly by CYP1A2 whereas hydrolytic-deaminated clofazimine was formed by CYP3A4/A5. In case of glucuronide conjugates, UGT1A1, UGT1A3, and UGT1A9 showed catalytic activity toward hydroxylated and hydrated clofazimine glucuronide whereas hydrolytic-deaminated clofazimine glucuronide was catalyzed by UGT1A4, UGT1A9, UGT1A3, and UGT2B4. Our results suggested that CYP1A2 and CYP3A are involved in the formation of oxidative metabolites while UGT1A1, 1A3, 1A4, 1A9, and 2B4 are involved in the formation of glucuronide conjugates of oxidative metabolites of clofazimine.

PMID:36190267 | DOI:10.1128/aac.00565-22

Front Pharmacol. 2022 Sep 15;13:926607. doi: 10.3389/fphar.2022.926607. eCollection 2022.

ABSTRACT

Neuropsychiatric diseases are a group of disorders that cause significant morbidity and disability. The symptoms of psychiatric disorders include anxiety, depression, eating disorders, autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder, and conduct disorder. Various medicinal plants are frequently used as therapeutics in traditional medicine in different parts of the world. Nowadays, using medicinal plants as an alternative medication has been considered due to their biological safety. Despite the wide range of medications, many patients are unable to tolerate the side effects and eventually lose their response. By considering the therapeutic advantages of medicinal plants in the case of side effects, patients may prefer to use them instead of chemical drugs. Today, the use of medicinal plants in traditional medicine is diverse and increasing, and these plants are a precious heritage for humanity. Investigation about traditional medicine continues, and several studies have indicated the basic pharmacology and clinical efficacy of herbal medicine. In this article, we discuss five of the most important and common psychiatric illnesses investigated in various studies along with conventional therapies and their pharmacological therapies. For this comprehensive review, data were obtained from electronic databases such as MedLine/PubMed, Science Direct, Web of Science, EMBASE, DynaMed Plus, ScienceDirect, and TRIP database. Preclinical pharmacology studies have confirmed that some bioactive compounds may have beneficial therapeutic effects in some common psychiatric disorders. The mechanisms of action of the analyzed biocompounds are presented in detail. The bioactive compounds analyzed in this review are promising phytochemicals for adjuvant and complementary drug candidates in the pharmacotherapy of neuropsychiatric diseases. Although comparative studies have been carefully reviewed in the preclinical pharmacology field, no clinical studies have been found to confirm the efficacy of herbal medicines compared to FDA-approved medicines for the treatment of mental disorders. Therefore, future clinical studies are needed to accelerate the potential use of natural compounds in the management of these diseases.

PMID:36188551 | PMC:PMC9521271 | DOI:10.3389/fphar.2022.926607

Front Genet. 2022 Sep 14;13:982955. doi: 10.3389/fgene.2022.982955. eCollection 2022.

ABSTRACT

Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59-243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.

PMID:36186466 | PMC:PMC9515473 | DOI:10.3389/fgene.2022.982955