Genet Res (Camb). 2023 Oct 31;2023:6105320. doi: 10.1155/2023/6105320. eCollection 2023.

ABSTRACT

INTRODUCTION: Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance.

METHODS: We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's p value was higher than 0.1. We used random models when the p value was less than 0.1.

RESULTS: Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations.

CONCLUSION: This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.

PMID:37942082 | PMC:PMC10630013 | DOI:10.1155/2023/6105320

J Crohns Colitis. 2023 Nov 6:jjad182. doi: 10.1093/ecco-jcc/jjad182. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with IBD.

METHODS: We conducted a prospective study including 213 IBD patients and 53 healthy controls; 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination and interval between vaccination and sampling.

RESULTS: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (Geometric Mean Ratio 0.35 [95% CI 0.20-0.60], p=0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p=0.0050) and tofacitinib (0.28 [0.14-0.57], p=0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p=0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p=0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p=0.017) and tofacitinib (0.23 [0.10-0.56], p=0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 (r=0.27; p=0.0004) and H1N1 (r=0.33; p<0.0001).

CONCLUSIONS: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to Influenza/A, similar to COVID-19 vaccine-induced antibody responses.

PMID:37941436 | DOI:10.1093/ecco-jcc/jjad182

Pharmacogenomics J. 2023 Nov 9. doi: 10.1038/s41397-023-00319-6. Online ahead of print.

ABSTRACT

Compound-analgesics containing codeine (CACC) have been a common source of codeine for people seeking opioid replacement therapy (ORT) for codeine use disorder (CUD). Our previous work demonstrated no relationship between pre-treatment CACC and ORT buprenorphine doses; we hypothesised that CYP2D6 activity would partially account for this disconnection. One hundred six participants with CUD were compared to a published population sample of 5408 Australian patients. Mean age of participants with CUD at treatment entry was 35 years, with mean 6.1 years duration of CUD. Mean codeine dose was 660 mg/day (range 40-2700 mg). Mean calculated CYP2D6 activity scores were significantly higher in the codeine group (CUD 1.65 + 0.63 vs. Gen pop 1.39 + 0.65, Wilcoxon W = 347,001, p < 0.001). Pre-treatment CACC dose weakly predicted sublingual buprenorphine doses overall; there was a stronger relationship within ultrarapid metabolisers. While normal and ultrarapid metabolisers of codeine were more likely to have a diagnosis of CUD, poor or intermediate CYP2D6 metaboliser status may protect against CUD.

PMID:37940651 | DOI:10.1038/s41397-023-00319-6

Pharmacogenomics J. 2023 Nov 9. doi: 10.1038/s41397-023-00318-7. Online ahead of print.

ABSTRACT

Codeine is metabolized by the CYP2D6 enzyme, and individuals with certain genetic variations of the CYP2D6 gene may metabolize codeine differently, leading to variable efficacy and toxicity. Drug-drug interactions can also affect the metabolism of codeine. A tool to adjust codeine dose based on these factors does not currently exist. Healthcare providers should use their clinical judgment and reference different established dosing guidelines to determine the appropriate dose of codeine for individual patients. The study provides a tool that assists prescribers in adjusting codeine dose based on CYP2D6 gene-pair polymorphisms and drug-drug interactions. Highlighted is the need to consider pharmacogenetics and drug-drug interactions when determining the appropriate dosing of codeine and provide a framework for implementing individualized dosing based on these factors.

PMID:37940650 | DOI:10.1038/s41397-023-00318-7

Br J Clin Pharmacol. 2023 Nov 8. doi: 10.1111/bcp.15958. Online ahead of print.

ABSTRACT

AIM: The aim of this study was to investigate the association between VKORC1 and CYP2C9 genes polymorphisms and the maintenance dose of warfarin in Peruvian patients.

METHODS: An observational study was conducted on outpatients from the Hospital Grau ESSALUD in Lima, Peru. The participants were selected using non-probabilistic convenience sampling. Inclusion criteria required patients to have been on anticoagulation therapy for more than three months, maintain stable doses of warfarin (consistent dose for at least three outpatient visits), and maintain an INR within the therapeutic range of 2.5-3.5. DNA samples were obtained from peripheral blood for gene analysis.

RESULTS: Seventy patients (mean age of 69.6 ± 13.4 years, 45.7% female) were included in the study. The average weekly warfarin dose was 31.6 ± 15.2 mg. The genotypic frequencies of VKORC1 were as follows: 7.1% (95% CI, 2.4-15.9) for AA, 44.3% (32.4-56.7) for GA, and 48.6% (36.4-60.8) for GG. No deviation from the Hardy-Weinberg equilibrium was observed in the variants studied (p=0.56). The mean weekly warfarin doses for AA, GA, and GG genotypes were 16.5 ± 2.9 mg, 26.5 ± 9.5 mg, and 37.9 ± 17.1 mg, respectively (p<0.001). The genotypic frequencies of CYP2C9 were as follows: 82.8% (72.0-90.8) for CC (*1/*1), 4.3% (1.0-12.0) for CT (*1/*2), and 12.9% (6.1-23.0) for TT (*2/*2). We did not find a significant association between the CYP2C9 gene polymorphism and the dose of Warfarin.

CONCLUSION: The AA genotype of the VKORC1 gene was associated with a lower maintenance dose of warfarin in Peruvian patients.

PMID:37940132 | DOI:10.1111/bcp.15958

Neurol Sci. 2023 Nov 7. doi: 10.1007/s10072-023-07152-6. Online ahead of print.

ABSTRACT

BACKGROUND: While migraine is markedly prevalent in women, gender-related phenotype differences were rarely assessed. For this reason, we investigated, through a multicenter observational cross-sectional study, based on an online questionnaire, gender-related differences in stress factors, emotions, and pain perception in migraine patients and controls and their impact on migraine severity.

METHODS: The study was designed as an online questionnaire. The link was emailed to healthy subjects (C) and migraine patients (MIG) (age 18-75, education ≥ 13 years) recruited during the first visit in 8 Italian Headache Centers adhering to Italian Society for Headache Study (SISC). The questionnaire included personal/social/work information, the Perceived Stress Scale, the Romance Quality Scale, the Emotion Regulation Questionnaire, the Beck Anxiety Inventory, the Body Perception Questionnaire, the pain perception, and a self-assessment of migraine severity in the last 3 months.

RESULTS: 202 MIG and 202 C completed the survey. Independently from gender, migraine was characterized by higher pain sensitivity and more severe partner relationships. The female gender, in MIG, exhibited higher anxiety scores, body awareness, and reduced emotional suppression. Body awareness and emotional suppression were discriminating factors between genders in control and migraine groups without relevant influence on disease features. Perceived perception of migraine severity was similar between genders.

CONCLUSION: Gender-related emotional and stress factors did not contribute to delineate a distinct phenotype in migraine men and women. The possible impact of emotional and stress factors characterizing genders could be considered for a single case-tailored therapeutic approach.

PMID:37936018 | DOI:10.1007/s10072-023-07152-6

Infect Drug Resist. 2023 Nov 1;16:6999-7005. doi: 10.2147/IDR.S431425. eCollection 2023.

ABSTRACT

OBJECTIVE: In this study, we conducted a multi-center research on six common lower respiratory tract pathogens using novel multiplex fluorescence quantitative polymerase chain reaction (PCR), and investigated the additional diagnostic value of this method, to provide a molecular diagnostic basis for clinical practice.

METHODS: From March 2019 to October 2021, a total of 2047 respiratory sputum samples were collected from Hunan Provincial People's Hospital (the First Affiliated Hospital of Hunan Normal University), Hunan Provincial Children's Hospital, Jiangxi Provincial Children's Hospital, and Wuhan Infectious Disease Hospital. The samples were analyzed using a novel multiplex fluorescence quantitative PCR method for Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Legionella pneumophila, and Staphylococcus aureus. The results were compared to the results of bacterial culture and sequencing, as well as the results of third-party kits.

RESULTS: Compared to the bacterial culture method, 2047 samples were detected with a sensitivity of 100%, a specificity of 72.22%, and an overall compliance rate of 81.91%. Compared to the sequencing method, the positive agreement percentage was 99.88%, the negative agreement percentage was 97.72%, and the overall agreement rate was 98.84%. Compared to similar control reagents, the positive agreement percentage was 100%, negative agreement percentage was 79.79%, and overall compliance rate was 96.19%.

CONCLUSION: The multiplex fluorescence PCR method has the advantages of simultaneously detecting multiple pathogenic bacteria and reducing the duration of pathogen culture identification. Combined detection can increase the detection rate, which has favorable performance and application prospects.

PMID:37933294 | PMC:PMC10625741 | DOI:10.2147/IDR.S431425

J Asthma. 2023 Nov 6:1-16. doi: 10.1080/02770903.2023.2280917. Online ahead of print.

ABSTRACT

OBJECTIVE: Asthma exacerbations are a frequent reason for pediatric emergency medical services (EMS) encounters. The objective of this study was to examine the implementation of evidence-based treatments for pediatric asthma in a regional consortium of EMS agencies.

METHODS: This retrospective study applied the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) implementation framework to data from an EMS agency consortium in the Cincinnati, Ohio region. The study analyzed one year before an oral systemic corticosteroid (OCS) option was added to the agencies' protocol, and five years after the protocol change. We constructed logistic regression models for the primary outcome of Reach, defined as proportion of pediatric asthma patients who received a systemic corticosteroid. We modeled Maintenance (Reach measured monthly over time) using time series models.

RESULTS: A total of 713 patients were included, 133 pre- and 580 post-protocol change. In terms of Reach, 3% (n = 4) of eligible patients received a systemic corticosteroid pre-OCS versus 20% (n = 116) post-OCS. Multivariable modeling of Reach revealed study period, EMS transport time, months since implementation of OCS, and number of bronchodilators administered by EMS as significant covariates for the administration of a systemic corticosteroid. For Maintenance, it took approximately two-years to reach maximal administration of systemic corticosteroids.

CONCLUSIONS: Indicators of asthma severity and time since the protocol change were significantly associated with EMS administration of systemic corticosteroids to pediatric asthma patients. The two-year time for maximal Reach suggests further work is required to understand how to best implement evidence-based pediatric asthma treatments in EMS.

PMID:37930329 | DOI:10.1080/02770903.2023.2280917

Pharmacogenomics. 2023 Nov 6. doi: 10.2217/pgs-2023-0166. Online ahead of print.

ABSTRACT

Background: CYP2C19 is important in the metabolism of clopidogrel and several antidepressants. This study aimed to characterize the distribution of CYP2C19 star alleles (haplotypes) across diverse African populations compared with global populations. Methods: CYP2C19 star alleles and diplotypes were called from high coverage genomes using the StellarPGx pipeline. Results: CYP2C19*1 (51%), *2 (17%) and *17 (22%) were the most common star alleles across African populations in this study. It was observed that 3% of African participants had potentially novel CYP2C19 haplotypes. Conclusion: This study supports the necessity for CYP2C19 pharmacogenetic testing in African and global clinical settings, as well as the importance of comprehensive star allele characterization in the African context.

PMID:37929326 | DOI:10.2217/pgs-2023-0166

Front Vet Sci. 2023 Oct 19;10:1188633. doi: 10.3389/fvets.2023.1188633. eCollection 2023.

ABSTRACT

INTRODUCTION: Because of their importance as companion animals or as racehorses, horses can be treated with various drugs. Although it is known that drug withdrawal times can vary for each horse, pharmacogenetics for these animals has not been adequately studied and requires further development. Since CYP2D6 is responsible for the metabolism of 25-30% of drugs in humans, including some used to treat horses, a study of the CYP2D family in horses was conducted to define its genetic structure as well as its expression pattern in the liver.

METHODS: Genomic DNA extracted from venous blood and mRNA from fresh liver tissue were amplified and sequenced to analyze the genomic structure, genotype, and expression of the various enzymes that are part of the equine orthologous family for CYP2D6.

RESULTS: Amplification and sequencing of the gDNA of CYP2D50, the major CYP2D6 orthologue identified in previous studies, revealed a novel putative genomic structure for this gene compared with that reported from the EquCab3.0 assembly, including the formation of a hybrid structure similar to what happens in human CYP2D6. At the mRNA level, transcripts from six different members of the equine CYP2D family were detected in horse liver. In addition, genotyping of CYP2D50 and CYP2D82 revealed the presence of several polymorphisms, six of which result in novel, nonsynonymous amino acid changes for each of the two genes.

DISCUSSION: This study aimed to elucidate the pharmacogenetic analysis of the CYP2D family in horses and resulted in the identification of a novel gene structure for CYP2D50, the expression of six different members of the CYP2D family in horse liver, and several novel polymorphisms for CYP2D50 and CYP2D82.

PMID:37929279 | PMC:PMC10620600 | DOI:10.3389/fvets.2023.1188633

JHEP Rep. 2023 Aug 24;5(12):100896. doi: 10.1016/j.jhepr.2023.100896. eCollection 2023 Dec.

ABSTRACT

BACKGROUND & AIMS: Population screening for non-alcoholic fatty liver disease (NAFLD) and associated comorbidities remains an unaddressed clinical need. We aimed to assess the utility of the fatty liver index (FLI) for risk stratification of NAFLD and related comorbidities using the UK Biobank.

METHODS: Electronic health records and liver MRI-proton density fat fraction (PDFF) were used to define NAFLD cases. FLI was calculated and individuals with high alcohol intake and other liver diseases were excluded. Using listwise deletion analysis, the area under receiver-operating characteristic curve (AUROC) of FLI for NAFLD risk was determined. Thereafter, time-dependent covariate-adjusted Cox regression models were used to estimate FLI's risk stratification potential for comorbidities of interest.

RESULTS: FLI was derived for 327,800 individuals with a median age of 58 (IQR 51.5-64.5), of whom 59.8% were females. Using Perspectum Diagnostics and AMRA protocols as references, FLI identified the risk of NAFLD with AUROCs (95% CI, n) of 0.858 (0.848-0.867, n = 7,566) and 0.851 (0.844-0.856, n = 10,777), respectively. Intermediate and high-risk FLI was associated with increased cardiometabolic and malignant disease. In the first 3 years, high-risk FLI conferred an increased risk (adjusted hazard ratio, 95% CI) of ischaemic heart disease (2.14, 1.94-2.36), hypertension (2.84, 2.70-2.98), type 2 diabetes mellitus (4.55, 4.04-5.12), dyslipidaemia (2.48, 2.32-2.64), ischaemic stroke (1.31, 1.20-1.42) and hepatic malignancy (1.69, 1.23-2.30). FLI was not associated with risk of extrahepatic malignancy but was associated with a higher risk of specific cancers (colon, upper gastrointestinal and breast). All-cause mortality was similarly stratified by FLI, independently of non-invasive fibrosis scores.

CONCLUSIONS: FLI identifies NAFLD and holds potential for the risk stratification of cardiometabolic and malignant disease outcomes (including some extrahepatic malignancies), as well as all-cause mortality. Its use in population screening for primary and secondary prevention of NAFLD should be considered.

IMPACT AND IMPLICATIONS: Our analysis using the UK Biobank study shows the potential of the fatty liver index as a risk stratification tool for identifying the risk of developing NAFLD, ischaemic heart disease, ischaemic stroke, type 2 diabetes mellitus, hypertension, hyperlipidaemia, hepatic malignancy, specific metabolism-related malignancies and all-cause mortality. These results suggest that the fatty liver index should be considered as a non-invasive steatosis score that may help guide primary prevention strategies for NAFLD and related outcomes.

PMID:37928746 | PMC:PMC10624587 | DOI:10.1016/j.jhepr.2023.100896

Ann Gastroenterol Surg. 2023 Jul 19;7(6):1009-1020. doi: 10.1002/ags3.12713. eCollection 2023 Nov.

ABSTRACT

PURPOSE: Gemcitabine, cisplatin, and S-1 chemotherapy was superior to gemcitabine and cisplatin chemotherapy for progression-free survival and overall survival for unresectable and recurrent biliary tract cancer in a randomized phase III trial (KHBO1401). This study aimed to evaluate the outcome of conversion surgery after chemotherapy in biliary tract cancer patients (ancillary study, KHBO1401-3C).

METHODS: A total of 246 patients were enrolled in KHBO1401. We compared progression-free and overall survivals between the conversion surgery and non-conversion surgery groups.

RESULTS: Eight patients (3.3%) underwent conversion surgery with chemotherapy, seven of whom were diagnosed with unresectable disease and one with recurrence. Six and two patients received gemcitabine, cisplatin, and S-1 chemotherapy as well as gemcitabine and cisplatin chemotherapy, respectively. Three patients in the conversion surgery group who received gemcitabine, cisplatin, and S-1 chemotherapy showed no disease progression and survived without postoperative chemotherapy. Preoperative carbohydrate antigen 19-9 (CA19-9) level was a prognostic factor for conversion surgery. After correcting for immortal time bias, 1-year progression-free survival rates in the conversion surgery and non-conversion surgery groups were 50.0% and 19.0%, respectively (hazard ratio 0.343, 95% confidence interval 0.286-0.843, p = 0.0092). One-year overall survival rates in the conversion surgery and non-conversion surgery groups were 87.5% and 56.0%, respectively (hazard ratio 0.222, 95% confidence interval 0.226-0.877, p = 0.0197).

CONCLUSIONS: Conversion surgery might be an option for the treatment of unresectable and recurrent biliary tract cancer in patients with normal preoperative CA19-9 level.

PMID:37927929 | PMC:PMC10623972 | DOI:10.1002/ags3.12713

Pulm Circ. 2023 Nov 2;13(4):e12304. doi: 10.1002/pul2.12304. eCollection 2023 Oct.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a rare, complex, and deadly cardiopulmonary disease. It is characterized by changes in endothelial cell function and smooth muscle cell proliferation in the pulmonary arteries, causing persistent vasoconstriction, resulting in right heart hypertrophy and failure. There are multiple drug classes specific to PAH treatment, but variation between patients may impact treatment response. A small subset of patients is responsive to pulmonary vasodilators and can be treated with calcium channel blockers, which would be deleterious if prescribed to a typical PAH patient. Little is known about the underlying cause of this important difference in vasoresponsive PAH patients. Sex, race/ethnicity, and pharmacogenomics may also factor into efficacy and safety of PAH-specific drugs. Research has indicated that endothelin receptor antagonists may be more effective in women and there have been some minor differences found in certain races and ethnicities, but these findings are muddled by the impact of socioeconomic factors and a lack of representation of non-White patients in clinical trials. Genetic variants in genes such as CYP3A5, CYP2C9, PTGIS, PTGIR, GNG2, CHST3, and CHST13 may influence the efficacy and safety of certain PAH-specific drugs. PAH research faces many challenges, but there is potential for new methodologies to glean new insights into PAH development and treatment.

PMID:37927610 | PMC:PMC10621006 | DOI:10.1002/pul2.12304

Front Pharmacol. 2023 Oct 20;14:1247088. doi: 10.3389/fphar.2023.1247088. eCollection 2023.

ABSTRACT

With the trend towards promoting personalised medicine (PM), the application of pharmacogenetics and pharmacogenomics (PGx) is of growing importance. For the purposes of clinical trials, the inclusion of PGx is an additional tool that should be considered for improving our knowledge about the effectiveness and safety of new drugs. A search of available clinical trials containing pharmacogenetic and PGx information was conducted on ClinicalTrials.gov. The results show there has been an increase in the number of trials containing PGx information since the 2000 s, with particular relevance in the areas of Oncology (28.43%) and Mental Health (10.66%). Most of the clinical trials focus on treatment as their primary purpose. In those clinical trials entries where the specific genes considered for study are detailed, the most frequently explored genes are CYP2D6 (especially in Mental Health and Pain), CYP2C9 (in Hematology), CYP2C19 (in Cardiology and Mental Health) and ABCB1 and CYP3A5 (particularly prominent in Transplantation and Cardiology), among others. Researchers and clinicans should be trained in pharmacogenetics and PGx in order to be able to make a proper interpretation of this data, contributing to better prescribing decisions and an improvement in patients' care, which would lead to the performance of PM.

PMID:37927590 | PMC:PMC10625420 | DOI:10.3389/fphar.2023.1247088

Front Pharmacol. 2023 Oct 19;14:1292416. doi: 10.3389/fphar.2023.1292416. eCollection 2023.

ABSTRACT

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice.

PMID:37927587 | PMC:PMC10622662 | DOI:10.3389/fphar.2023.1292416

Curr Drug Metab. 2023 Nov 3. doi: 10.2174/0113892002267867231101051310. Online ahead of print.

ABSTRACT

AIMS: To identify single nucleotide polymorphisms (SNPs) of paracetamol-metabolizing enzymes that can predict acute liver injury.

BACKGROUND: Paracetamol is a commonly administered analgesic/antipyretic in critically ill and chronic renal failure patients and several SNPs influence the therapeutic and toxic effects.

OBJECTIVE: To evaluate the role of machine learning algorithms (MLAs) and bioinformatics tools to delineate the predictor SNPs as well as to understand their molecular dynamics.

METHODS: A cross-sectional study was undertaken by recruiting critically ill patients with chronic renal failure and administering intravenous paracetamol as a standard of care. Serum concentrations of paracetamol and the principal metabolites were estimated. Following SNPs were evaluated: CYP2E1*2, CYP2E1_-1295G>C, CYP2D6*10, CYP3A4*1B, CYP3A4*2, CYP1A2*1K, CYP1A2*6, CYP3A4*3, and CYP3A5*7. MLAs were used to identify the predictor genetic variable for acute liver failure. Bioinformatics tools such as Predict SNP2 and molecular docking (MD) were undertaken to evaluate the impact of the above SNPs with binding affinity to paracetamol.

RESULTS: CYP2E1*2 and CYP1A2*1C genotypes were identified by MLAs to significantly predict hepatotoxicity. The predictSNP2 revealed that CYP1A2*3 was highly deleterious in all the tools. MD revealed binding energy of -5.5 Kcal/mol, -6.9 Kcal/mol, and -6.8 Kcal/mol for CYP1A2, CYP1A2*3, and CYP1A2*6 against paracetamol. MD simulations revealed that CYP1A2*3 and CYP1A2*6 missense variants in CYP1A2 affect the binding ability with paracetamol. In-silico techniques found that CYP1A2*2 and CYP1A2*6 are highly harmful. MD simulations revealed CYP3A4*2 (A>G) had decreased binding energy with paracetamol than CYP3A4, and CYP3A4*2 (A>T) and CYP3A4*3 both have greater binding energy with paracetamol.

CONCLUSION: Polymorphisms in CYP2E1, CYP1A2, CYP3A4, and CYP3A5 significantly influence paracetamol's clinical outcomes or binding affinity. Robust clinical studies are needed to identify these polymorphisms' clinical impact on the pharmacokinetics or pharmacodynamics of paracetamol.

PMID:37927072 | DOI:10.2174/0113892002267867231101051310

Neurosci Biobehav Rev. 2023 Nov 3:105451. doi: 10.1016/j.neubiorev.2023.105451. Online ahead of print.

ABSTRACT

Non-Alzheimer's dementia (NAD) accounts for 30% of all neurodegenerative conditions and is characterized by cognitive decline beyond mere memory dysfunction. Diagnosing NAD remains challenging due to the lack of established biomarkers. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological tool that enables the investigation of cortical excitability in the human brain. Paired-pulse TMS paradigms include short- and long-interval intracortical inhibition (SICI/LICI), intracortical facilitation (ICF), and short-latency afferent inhibition (SAI), which can assess neurophysiological functions of GABAergic, glutamatergic, and cholinergic neural circuits, respectively. We conducted the first systematic review and meta-analysis to compare these TMS indices among patients with NAD and healthy controls. Our meta-analyses indicated that TMS neurophysiological examinations revealed decreased glutamatergic function in patients with frontotemporal dementia (FTD) and decreased GABAergic function in patients with FTD, progressive supranuclear palsy, Huntington's disease, cortico-basal syndrome, and multiple system atrophy-parkinsonian type. In addition, decreased cholinergic function was found in dementia with Lewy body and vascular dementia. These results suggest the potential of TMS as an additional diagnostic tool to differentiate NAD.

PMID:37926239 | DOI:10.1016/j.neubiorev.2023.105451

Neurol Sci. 2023 Nov 6. doi: 10.1007/s10072-023-07167-z. Online ahead of print.

ABSTRACT

OBJECTIVE: To explore the rate of hypertension incoming in patients treated with monoclonal antibodies against the calcitonin gene-related peptide.

BACKGROUND: The monoclonal antibodies blocking the calcitonin gene-related peptide are unquestionable effective in the prevention of migraine. Despite this, the development of hypertension has been detected in some patients.

METHODS: This was a retrospective study conducted at the University Hospital of Modena. Patients were visited quarterly up to 1 year.

RESULTS: Globally, no significant increase in the blood pressure was detected. The 5.7% of the patients developed a significant increase in their blood pressure. In particular, patients with a pre-existing hypertension were more likely to have a significant increase in the blood pressure.

CONCLUSION: The risk of developing hypertension during a treatment with anti-calcitonin gene-related peptide monoclonal antibodies seems low. Anyway, patients with a pre-existing hypertension should be cautiously monitored because they are more likely to develop hypertension.

PMID:37926748 | DOI:10.1007/s10072-023-07167-z

Br J Clin Pharmacol. 2023 Nov 5. doi: 10.1111/bcp.15956. Online ahead of print.

ABSTRACT

Adverse drug reactions (ADRs) account for a large proportion of hospitalizations among adults, and are more common in multimorbid patients, worsening clinical outcomes and burdening healthcare resources. Over the past decade, pharmacogenomics has been developed as a practical tool for optimizing treatment outcomes by mitigating the risk of ADRs. Some single-gene reactive tests are already used in clinical practice, including the DPYD test for fluoropyrimidines, which demonstrates how integrating pharmacogenomic data into routine care can improve patient safety in a cost-effective manner. The evolution from reactive single-gene testing to comprehensive preemptive genotyping panels holds great potential for refining drug prescribing practices. Several implementation projects have been conducted to test the feasibility of applying different genetic panels in clinical practice. Recently, the results of a large prospective randomized trial in Europe (Ubiquitous Pharmacogenomics-PREPARE study) have provided the first evidence that prospective application of a preemptive pharmacogenomic test panel in clinical practice, in seven European healthcare systems, is feasible and yielded a 30% reduction in the risk of developing clinically relevant toxicities. Nevertheless, some important questions remain unanswered, and will hopefully be addressed by future dedicated studies. These issues include the cost-effectiveness of applying a preemptive genotyping panel, the role of multiple co-medications, the transferability of currently tested pharmacogenetic guidelines among patients of non-European origin, and the impact of rare pharmacogenetic variants that are not detected by currently used genotyping approaches.

PMID:37926674 | DOI:10.1111/bcp.15956

Pharmacogenomics J. 2023 Nov 4. doi: 10.1038/s41397-023-00320-z. Online ahead of print.

ABSTRACT

CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.

PMID:37925536 | DOI:10.1038/s41397-023-00320-z