J Clin Oncol. 2024 Oct 31:JCO2302761. doi: 10.1200/JCO.23.02761. Online ahead of print.

ABSTRACT

PURPOSE: As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service.

METHODS: Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes (DPYD, NUDT15, TPMT, UGT1A1) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected.

RESULTS: We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases.

CONCLUSION: Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.

PMID:39481076 | DOI:10.1200/JCO.23.02761

PLoS One. 2024 Oct 31;19(10):e0309912. doi: 10.1371/journal.pone.0309912. eCollection 2024.

ABSTRACT

OBJECTIVES: Long-term exposure to air pollution has been associated with higher risk of cardiovascular mortality. Less is known about the association of air pollution with initial development of cardiovascular disease. Herein, the association between low-level exposure to air pollutants and subclinical carotid atherosclerosis in adults without known clinical cardiovascular disease was investigated.

DESIGN: Cross-sectional analysis within a prospective cohort study.

SETTING: The Canadian Alliance for Healthy Hearts and Minds Cohort Study; a pan-Canadian cohort of cohorts.

PARTICIPANTS: Canadian adults (n = 6645) recruited between 2014-2018 from the provinces of British Columbia, Alberta, Ontario, Quebec, and Nova Scotia, were studied, for whom averages of exposures to nitrogen dioxide (NO2), ozone (O3), and fine particulate matter (PM2.5) were estimated for the years 2008-2012.

MAIN OUTCOME MEASURE: Carotid vessel wall volume (CWV) measured by magnetic resonance imaging (MRI).

RESULTS: In adjusted linear mixed models, PM2.5 was not consistently associated with CWV (per 5 μg/m3 PM2.5; adjusted estimate = -8.4 mm3; 95% Confidence Intervals (CI) -23.3 to 6.48; p = 0.27). A 5 ppb higher NO2 concentration was associated with 11.8 mm3 lower CWV (95% CI -16.2 to -7.31; p<0.0001). A 3 ppb increase in O3 was associated with 9.34 mm3 higher CWV (95% CI 4.75 to 13.92; p<0.0001). However, the coarse/insufficient O3 resolution (10 km) is a limitation.

CONCLUSIONS: In a cohort of healthy Canadian adults there was no consistent association between PM2.5 or NO2 and increased CWV as a measure of subclinical atherosclerosis by MRI. The reasons for these inconsistent associations warrant further study.

PMID:39480801 | DOI:10.1371/journal.pone.0309912

Exp Ther Med. 2024 Oct 11;28(6):454. doi: 10.3892/etm.2024.12744. eCollection 2024 Dec.

ABSTRACT

Asthma, a common chronic respiratory condition, poses unique challenges in pregnancy, impacting both maternal and fetal health. Of note, 8-13% of pregnant women suffer from asthma, a condition that can worsen, stabilize, or improve during pregnancy. These fluctuations necessitate a nuanced management strategy to ensure the health of both the mother and fetus. Adverse outcomes, such as preeclampsia, gestational diabetes and increased cesarean delivery rates are associated with poorly controlled asthma. From a fetal perspective, the risks include preterm birth and a low birth weight. Physiological changes in pregnancy, such as an increased tidal volume and altered drug metabolism due to increased blood volume, complicate the management of asthma. The safety of asthma medications during pregnancy remains a significant concern, with ongoing research into their teratogenic effects. Recent advancements in treatment include the development of biologics and the increased use of personalized medicine, integrating pharmacogenomics and immunological profiling to tailor treatments to individual needs. Digital health tools have also emerged, enabling improved patient monitoring and management. The present review highlights the complex interplay between asthma management and pregnancy outcomes, advocating for comprehensive care approaches that consider the dynamic physiological changes during pregnancy. It underscores the need for ongoing research into the safety of medication and innovative therapeutic strategies to improve health outcomes for pregnant women with asthma and their babies.

PMID:39478732 | PMC:PMC11523260 | DOI:10.3892/etm.2024.12744

In Vivo. 2024 Nov-Dec;38(6):2853-2863. doi: 10.21873/invivo.13766.

ABSTRACT

BACKGROUND/AIM: SARS-CoV-2 infection presents different severity levels that suggest the influence of genetic factors on the clinical outcome of the disease. In cases of severe COVID-19, the presence of elevated coagulation markers, increased platelet activation and aggregation and the risk of thrombotic complications are described. Given the participation of these cells in several serious viral infections and their negative role when associated with a prothrombotic response, it is important to understand the mechanistic role of SARS-CoV-2 in platelet physiology. This study evaluated the hyperexpression of platelet-activating factor receptor (PTAFR) and platelet factor 4 (PF4) in unvaccinated and hospitalized patients with COVID-19.

PATIENTS AND METHODS: The study included 43 COVID-19 patients stratified according to WHO guidelines. Subsequently, the expression of the PTAFR and PF4 genes were evaluated using the real-time quantitative PCR and their possible correlation with the severity of the disease and clinical variables including hospitalization, outcome, sex, age and laboratory parameters (platelet count, INR and D-dimer).

RESULTS: The analysis demonstrated a significant (p<0.05) hyperexpression of these genes COVID-19 patients (n=43) compared to healthy controls. Expression of these genes in patients was not statistically significant (p>0.05) different between patients stratified according to clinical variables.

CONCLUSION: The expression of PTAFR and PF4 suggests an important molecular pathway in the pathophysiology of the disease and may be valuable platelet biomarkers to indicate increased risk in patients with COVID-19 who require hospital care, contributing to personalized intervention strategies and improving their clinical management.

PMID:39477442 | DOI:10.21873/invivo.13766

World J Psychiatry. 2024 Oct 19;14(10):1573-1582. doi: 10.5498/wjp.v14.i10.1573. eCollection 2024 Oct 19.

ABSTRACT

BACKGROUND: Major depressive disorder (MDD) is a substantial global health concern, and its treatment is complicated by the variability in individual response to antidepressants.

AIM: To consolidate research and clarify the impact of genetic variation on MDD treatment outcomes.

METHODS: Adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search across PubMed, EMBASE, Web of Science, and the Cochrane Library was conducted without date restrictions, utilizing key terms related to MDD, serotonin 1A receptor polymorphism (5-HTR1A), C-1019G polymorphism, and antidepressant response. Studies meeting inclusion criteria were thoroughly screened, and quality assessed using the Newcastle-Ottawa Scale. Statistical analyses, including χ 2 and I² values, were used to evaluate heterogeneity and fixed-effect or random-effect models were applied accordingly.

RESULTS: The initial search yielded 1216 articles, with 11 studies meeting criteria for inclusion. Analysis of various genetic models showed no significant association between the 5-HTR1A C-1019G polymorphism and antidepressant efficacy. The heterogeneity was low to moderate, and no publication bias was detected through funnel plot symmetry and Egger's and Begg's tests.

CONCLUSION: This meta-analysis does not support a significant association between the 5-HTR1A C-1019G polymorphism and the efficacy of antidepressant treatment in MDD. The findings call for further research with larger cohorts to substantiate these results and enhance the understanding of antidepressant pharmacogenetics.

PMID:39474388 | PMC:PMC11514568 | DOI:10.5498/wjp.v14.i10.1573

Vaccine X. 2024 Oct 15;21:100571. doi: 10.1016/j.jvacx.2024.100571. eCollection 2024 Dec.

ABSTRACT

BACKGROUND: During the COVID-19 vaccination campaign in Sweden, pulmonary embolism (PE) was a frequently reported suspected serious adverse drug reaction. The aim was to estimate risk of PE following vaccination for COVID-19 in the Swedish population aged 18 to 84 years.

METHODS: Population-based cohort study using the CoVacSafe-SE established platform including national registers. PE-case definition: Individuals discharged from inpatient-care or visiting specialized outpatient-care with a main diagnosis of PE occurring between 27-Dec-2020 and 31-Dec-2022 without simultaneous diagnosis of COVID-19 infection. Time-to-event analysis was performed using multi-variable Cox' proportional hazard's models. Hazard Ratios (HR) adjusted for age, sex and co-morbidities were modelled.The vaccines were BNT162b2/Comirnaty®, mRNA1273/Spikevax® and ChAdOx1 nCoV-19/Vaxzevria® without regard to variants. Doses number one to five were studied.

RESULTS: Eighty percent of the study-population (≈6.1 million people) received at least two doses of COVID-19 vaccine. A total of 12,456 cases of PE were identified. Twenty-eight days after vaccinations we observed 99 cases after 701,455 1st doses of ChAdOx1 nCoV-19, HRadj, 1.29 (95%-CI, 1.05-1.59). Corresponding for BNT162b2 was 361 cases after 4,708,284 1st doses of BNT162b2 HRadj of 1.19 (95%-CI, 1.06-1.34) driven by age group 65-84; HR adj, 1.24 (95%-CI, 1.07-1.44). No increased risks were observed for mRNA1273.

CONCLUSION: In this nation-wide study, no strong associations were found between COVID-19 vaccinations and pulmonary embolism. Small increases in relative risk for the earliest doses of vaccines may be associated with prioritizing the frailest groups of people in the vaccination campaign, thus selection bias or unmeasured residual confounding is possible.

PMID:39474208 | PMC:PMC11513630 | DOI:10.1016/j.jvacx.2024.100571

Br J Clin Pharmacol. 2024 Oct 29. doi: 10.1111/bcp.16320. Online ahead of print.

ABSTRACT

AIMS: Therapeutic drug monitoring for astronauts faces limitations in conventional blood sampling and sample management onboard the international space station. Here, we explore the feasibility of dried blood spot (DBS) collection during parabolic flights (PF) to overcome these constraints.

METHODS: We assessed the feasibility of blood deposition on blotting paper for preanalytical aspects in a PF using synthetic blood. Subsequently, DBS sampling validation was carried out in another PF campaign. Twenty volunteers participated in a pharmacokinetic study on caffeine and its metabolite, paraxanthine, conducted during parabolic flights. After >18 h caffeine washout, coffee (115 mg), tea (30 mg) or dark chocolate (11 mg) were ingested by the participants. DBS samples were collected at baseline, during weightlessness and post-flight. Caffeine and paraxanthine were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Genotyping for cytochrome P450-1A2 (CYP1A2) was performed and a metabolic ratio by area under the curve for caffeine and paraxanthine (AUCPAX/AUCCAF) for CYP1A2 was determined. A user experience survey was also conducted.

RESULTS: Full in-flight pharmacokinetic study was feasible in seventeen volunteers with three unable to perform the sampling due to motion sickness. Nineteen participants (twelve males and seven females) completed pharmacokinetic profiles, with repeated pharmacokinetic studies for six participants. CYP1A2 genotyping resulted in eight ultrarapid, eleven intermediate, and one poor metabolizer. Among the women, four were on oestrogen contraceptives, a known inhibitor of CYP1A2, and were considered as poor metabolizers. Expected differences in kinetic profiles, consistent with consumption habits, the ingested dose and the genotypic/phenotypic information, were observed. The mean caffeine AUC for coffee, tea and chocolate were 9419 ng.h.mL-1 (95% confidence interval [CI]: 6222-12 616, n = 10), 6917 ng.h.mL-1 (95% CI: 2729-11 105), n = 7) and 3039 ng.h.mL-1 (95% CI: 1614-4142, n = 12), respectively. The mean paraxanthine AUC were 10 566 ng.h.mL-1 (95% CI: 6242-14 890, n = 10), 4011 ng.h.mL-1 (95% CI: 2305-5716, n = 7) and 3638 ng.h.mL-1 (95% CI: 1589-40 859, n = 12), respectively. The mean metabolic ratio in oestrogen-treated women was 0.53 (95% CI: 0.35-0.71) compared to 1.19 (95% CI: 0.99-1.33) in others. The mean metabolic ratio was 1.02 (95% CI: 0.81-1.23, n = 15) on the ground and 1.10 (95% CI: 0.70-1.41, n = 13) during the parabolic flights, with no significant difference observed between the two conditions. Overall participants were satisfied with the usability of the method.

CONCLUSIONS: DBS collection was safe, stable, feasible and well accepted in weightlessness. This method would offer valuable insights into human metabolism adaptation during long-term spaceflight, addressing space pharmacology challenges.

PMID:39473131 | DOI:10.1111/bcp.16320

Life Sci. 2024 Oct 27:123186. doi: 10.1016/j.lfs.2024.123186. Online ahead of print.

ABSTRACT

Personalized medicine has transformed the treatment of cystic fibrosis (CF), providing customized therapeutic approaches based on individual genetic profiles. This review explores the genetic foundations of CF, focusing on mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and their implications for the development of the disease. The advent of genetic testing has enabled the association of specific mutations to disease severity, leading to the development of CFTR modulators like Ivacaftor, Lumacaftor, and Tezacaftor. Beyond CFTR mutations, genetic modifiers, including gene replacement therapy, genetic manipulation, lentivirus, and non-viral gene therapy formulations, along with environmental factors, play critical roles in influencing disease expression and outcomes. The identification of these modifiers is essential for optimizing therapeutic strategies. Emerging biomarkers, including inflammatory markers and pulmonary function indicators, aid in early disease detection and monitoring progression. Omics technologies are uncovering novel biomarkers, enabling more precise disease management. Pharmacogenomics has become integral to CF care, allowing for personalized approaches that consider genetic variations influencing drug metabolism, especially in antibiotics and anti-inflammatory therapies. The future of CF treatment lies in precision therapies, including CFTR modulators and cutting-edge techniques like gene therapy and CRISPR-Cas9 for mutation correction. As research evolves, these advances can improve patient outcomes while minimizing adverse effects. Ethical considerations and regulatory challenges remain critical as personalized medicine advances, ensuring equitable access and the long-term effectiveness of these innovative therapies.

PMID:39471902 | DOI:10.1016/j.lfs.2024.123186

Pharmacogenet Genomics. 2024 Oct 29. doi: 10.1097/FPC.0000000000000549. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomic testing can optimize drug efficacy and minimize adverse effects. CYP3A5 polymorphisms affect the metabolism of tacrolimus. We sought to estimate the budget impact of preemptive pharmacogenomic testing for CYP3A5 in pediatric heart transplantation patients from an institutional perspective.

METHODS: A decision tree was constructed to estimate the budget impact of pediatric heart transplant patients (age ≤18 years) initiated on tacrolimus with and without CYP3A5 pharmacogenomic testing. The budget impact of preemptive pharmacogenomic testing versus no pharmacogenomic testing was calculated. One-way sensitivity analysis and alternative analyses were conducted to assess the robustness of results to changes in model parameters.

RESULTS: CYP3A5 genotype-guided dosing provided savings of up to $17 225 per patient compared to standard dosing. These savings decreased to $11 759 when using another institution's data for the standard-dosing group. The time to achieve therapeutic concentration in the poor metabolizer genotype-guided dosing group had the largest impact on cost savings while the cost of the pharmacogenetic test had the smallest impact on cost savings.

CONCLUSION: Implementing CYP3A5 testing could save $17 225 per pediatric heart transplant patient receiving tacrolimus. As pharmacogenomic testing becomes more widespread, institutions should track resource requirements and outcomes to determine the best implementation policies going forward.

PMID:39470413 | DOI:10.1097/FPC.0000000000000549

Pharmacogenet Genomics. 2024 Oct 15. doi: 10.1097/FPC.0000000000000552. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic polymorphisms have been associated with risk of antituberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.

METHODS: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015 and 2019, and who were eligible for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24-month follow-up. Analyses included 43 polymorphisms in 20 genes related to antituberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.

RESULTS: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment-related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A, and the genes METTL17 and PRSS57, but none achieved genome-wide significance.

CONCLUSION: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations, particularly regarding risk of treatment failure/recurrence.

PMID:39470346 | DOI:10.1097/FPC.0000000000000552

Pharmacogenet Genomics. 2024 Oct 16. doi: 10.1097/FPC.0000000000000550. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective.

METHODS: A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results.

RESULTS: Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model.

CONCLUSION: Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.

PMID:39470342 | DOI:10.1097/FPC.0000000000000550

Ann Hum Genet. 2024 Oct 29. doi: 10.1111/ahg.12582. Online ahead of print.

ABSTRACT

INTRODUCTION: An ethics-guided decision-making framework was developed for applying pathology-supported genetic testing, a multifaceted pharmacodiagnostic approach that translates population risk stratification into clinical utility. We introduce this service, supported by the Open Genome Project, which aligns with the beneficence principle in personalized medicine.

METHODS: Genetic testing of six noncommunicable disease pathways was conducted as part of a pilot program, benchmarked against a readiness checklist for implementation of genomic medicine in Africa. Patient referral criteria were determined using healthcare funder claims data, employing the Adjusted Clinical Groupers and Resource Utilization Band risk rating structure to identify potential nonresponders to treatment.

RESULTS: Three of the 135 doctors (2.2%) invited expressed immediate disinterest in the pilot, while 24 (17.8%) actively participated. Inherited, lifestyle-triggered, and therapy-related pathologies were simultaneously assessed in case reports, with special medical scheme reimbursement tariff codes applied to 25 patient referrals. The findings were used by the participating genetic counselor to select three patients for whole exome sequencing, utilizing a novel, level-up data processing algorithm for adaptive reporting.

CONCLUSION: This study demonstrated the implementation of genomics into an evolving workflow for patients with a history of frequent clinic visits. Eliminating the cost barrier provided valuable insights to guide future reimbursement policy decisions.

PMID:39470271 | DOI:10.1111/ahg.12582

J Pharm Policy Pract. 2024 Oct 25;17(1):2410197. doi: 10.1080/20523211.2024.2410197. eCollection 2024.

ABSTRACT

BACKGROUND: Pharmacogenetic testing improves the efficacy and safety of antidepressant pharmacotherapy for moderate-severe major depressive disorder by identifying genetic variations that influence medication metabolism, and adjusting treatment regimens accordingly. This study aims to assess the cost-effectiveness of implementing a pharmacogenetic testing approach to guide the prescription of antidepressants.

METHODS: From the public hospital perspective, we developed a two-stage decision tree diagram of a short-term 6-week follow up, and a lifetime Markov model with 3-month cycles. The analysis compared the current standard of care with the alternative strategy of Pharmacogenetic-guided (multi-gene panel) testing in adult patients with moderate-severe major depressive disorder. Clinical outcomes and utilities were obtained from published studies, while healthcare costs were locally available. The short-term incremental cost-effectiveness ratio was against treatment response without side effects and without relapse, and against treatment response with/without side effects and without relapse. The long-term incremental cost-effectiveness ratio was against the quality-adjusted life year gained and years of life saved.

RESULTS: Adopting the pharmacogenetic-guided therapy for adult patients with moderate-severe major depressive disorder in Qatar resulted in cost savings of Qatari Riyal 2,289 (95% confidence interval, -22,654-26,340) for the health system. In the short term, the pharmacogenetic-guided testing was associated with higher response rates without side effects and without relapse (mean difference 0.10, 95% confidence interval 0.09-0.15) and higher response rates with or without side effects and without relapse (mean difference 0.05, 95% confidence interval 0.04-0.06). For long term, the pharmacogenetic-guided testing resulted in 0.13 years of life saved and 0.06 quality-adjusted life year gained, per person, along with cost savings of Qatari Riyal 46,215 (95% confidence interval-15,744-101,758). The sensitivity analyses confirmed the robustness of the model results.

CONCLUSION: Implementing pharmacogenetic testing to guide antidepressant use was found to improve population health outcomes, while also significantly reducing health system costs.

PMID:39469318 | PMC:PMC11514395 | DOI:10.1080/20523211.2024.2410197

Sci Rep. 2024 Oct 28;14(1):25780. doi: 10.1038/s41598-024-76157-8.

NO ABSTRACT

PMID:39468203 | DOI:10.1038/s41598-024-76157-8

Ann Ital Chir. 2024;95(5):788-800. doi: 10.62713/aic.3625.

ABSTRACT

AIM: The administration of anticoagulation therapy during major orthopedic surgeries is a clinical challenge due to the risk of thrombotic events and bleeding complications. This review aims to evaluate the current strategies and emerging developments in perioperative anticoagulation reversal.

METHODS: We conducted a literature review on the management of perioperative anticoagulant therapy, which included the current status of anticoagulant reversal agents, as well as personalized medicine, pharmacogenomics, artificial intelligence (AI), and novel drug delivery systems.

RESULTS: The review indicates that reversal agents such as idarucizumab and andexanet alfa are crucial in managing bleeding associated with direct oral anticoagulants (DOACs). Personalized medicine, guided by pharmacogenomics, allows for tailored anticoagulation regimens. AI and machine learning (ML) algorithms can enhance the predictive capabilities for bleeding and thrombotic risks. Additionally, nanotechnology and biomarkers offer innovative approaches to drug delivery and personalized treatment.

CONCLUSIONS: Integrating evidence-based guidelines with innovative reversal agents, personalized medicine, AI and nanotechnology opens a new era in perioperative anticoagulation management. These advancements can ensure patient safety, minimize bleeding risks, and improve surgical outcomes. Future research should focus on the clinical validation of these strategies to ensure their effectiveness across diverse patient populations.

PMID:39467789 | DOI:10.62713/aic.3625

Hosp Pharm. 2024 Dec;59(6):666-676. doi: 10.1177/00185787241269111. Epub 2024 Aug 7.

ABSTRACT

Objective: Upper gastrointestinal bleeding (UGIB) has been identified as a potential adverse drug reaction associated with the use of low-dose aspirin (LDA). This study aimed to investigate the relationship between variants in the TBXA2R gene, which is involved in platelet aggregation, and the risk of UGIB in patients with cardiovascular diseases treated with LDA. Methods: A case-control study was conducted at a Brazilian hospital complex. Three groups were defined: (1) case group (n = 50): patients with cardiovascular disease who used LDA and were diagnosed with UGIB of non-variceal etiology, (2) LDA control group (n = 50): patients with cardiovascular disease who used LDA without developing UGIB, and (3) healthy control group (n = 189). Data were collected through face-to-face interviews, and blood samples were collected for the analysis of Helicobacter pylori infection and genotyping of 3 genetic variants [rs2238631 (C > T), rs4807491 (A > G), and rs1131882 (A > G)]. Results: The case group had a significantly higher frequency of carriers of the rs4807491.G allele compared to the control group of LDA users (P-value = .004). No significant difference was observed in the proportion of carriers of the rs2238631.T and 1131882.G variants between the studied groups. Carriers of rs2238631.T (OR: 4.515, 95% CI: 1.37-14.89) and rs4807491.G allele (OR: 3.232, 95% CI: 1.12-9.37) exhibited a higher risk of UGIB. Conclusion: These findings suggest that the presence of the rs2238631 and rs4807491 variant alleles is associates with a 3- to 4-fold increased risk of UGIB in patients with cardiovascular diseases treated with LDA. Future studies with larger sample sizes should confirm these results and to better identify individuals who may benefit from chronic LDA use.

PMID:39465093 | PMC:PMC11500220 | DOI:10.1177/00185787241269111

J Multidiscip Healthc. 2024 Oct 23;17:4863-4874. doi: 10.2147/JMDH.S458564. eCollection 2024.

ABSTRACT

Pharmacogenetics is a promising approach in future personalized medicine. This field holds excellent prospects for healthcare quality acceleration. It promotes the transition to the precision medicine era, whereby a health treatment is driven by a deeper understanding of individual characteristics by interpreting the underlying genomic variation. Pharmacogenetics has been developing rapidly since the human genome project. Many pharmacogenetics studies have shown the association between genetic variants and therapy outcomes. Several pharmacogenetics working groups have recommended guidelines for the clinical application of pharmacogenetics. However, the development of pharmacogenetics in low- and middle-income countries (LMICs) is still retarded behind. The problems mainly include clinical evidence, technology, policy and regulation, and human resources. Currently, available genome and drug effect data in LMICs are scarce. Pharmacogenetics development should be escalated with evidence proof through research collaboration across countries. The challenges of pharmacogenetics implementation are discussed comprehensively in this article, along with the prospect of pharmacogenetics-guided personalized medicine in developed countries. Stepwise is expected to help the researchers and stakeholders define the problem that hindered the pharmacogenetics application.

PMID:39464786 | PMC:PMC11512769 | DOI:10.2147/JMDH.S458564

Front Pharmacol. 2024 Oct 11;15:1423636. doi: 10.3389/fphar.2024.1423636. eCollection 2024.

ABSTRACT

Objective: This study explores the frequency of human leukocyte antigen (HLA) genes, particularly HLA-B alleles, within the Kuwaiti population. We aim to identify alleles with known associations to adverse drug reactions (ADRs) based on existing literature. We focus on the HLA-B gene due to its well-documented associations with severe cutaneous adverse reactions and the extensive pharmacogenetic research supporting its clinical relevance.

METHODS: We utilized the HLA-HD tool to extract, annotate, and analyse HLA-B alleles from the exome data of 561 Kuwaiti individuals, sequenced on the Illumina HiSeq platform. HLA typing was conducted using the HLA-HD tool with a reference panel from the IPD-IMGT/HLA database. The major HLA-B pharmacogenetic markers were obtained from the HLA Adverse Drug Reaction Database, focusing on alleles with significant ADR associations in published literature.

RESULTS: The distribution of HLA-B alleles in the Kuwaiti population revealed that the most frequent alleles were HLA-B*50:01 (10.52%), HLA-B*51:01 (9.89%), HLA-B*08:01 (6.06%), HLA-B*52:01 (4.55%), HLA-B*18:01 (3.92%), and HLA-B*41:01 (3.65%). Notably, alleles HLA-B*13:01, HLA-B*13:02, HLA-B*15:02, HLA-B*15:13, HLA-B*35:02, HLA-B*35:05, HLA-B*38:01, HLA-B*40:02, HLA-B*44:03, HLA-B*51:01, HLA-B*57:01 and HLA-B*58:01 were identified with known associations to various ADRs. For example, HLA-B*51:01 was associated with clindamycin, phenobarbital, and phenytoin, and was found in 18% of individuals.

CONCLUSION: Our study enriches the regional genetic landscape by delineating HLA-B allele variations within Kuwait and across the Arabian Peninsula. This genetic insight, along with the identification of markers previously linked to drug hypersensitivity, provides a foundation for future pharmacogenetic research and potential personalized medicine strategies in the region.

PMID:39464636 | PMC:PMC11502445 | DOI:10.3389/fphar.2024.1423636

ACS Omega. 2024 Oct 11;9(42):43252-43263. doi: 10.1021/acsomega.4c08194. eCollection 2024 Oct 22.

ABSTRACT

Cancer resistance to drugs and chemotherapy is a problem faced by public health systems worldwide. Repositioning antimicrobial peptides could be an efficient strategy to overcome that problem. This study aimed at repurposing antimicrobial peptides PepGAT and PepKAA for cancer treatment. After screening against several cancers, PepGAT and PepKAA presented IC50 values of 125.42 and 40.51 μM at 72 h toward colorectal cancer (CRC) cells. The mechanisms of action revealed that both peptides induced cell cycle arrest in G2/M and drove HCT-116 cells to death by triggering apoptosis. qPCR analysis revealed that peptides modulated gene expression in apoptosis, corroborating the data from caspase 3/7 and flow cytometry experiments. Yet, peptides induced ROS overaccumulation and increased membrane permeabilization, pore formation, and loss of internal content, leading to death. Additionally, peptides were able to inhibit cell invasion. Previous studies from the same group attested to no toxicity to normal human cells. Thus, PepGAT and PepKAA have great potential as anticancer molecules.

PMID:39464451 | PMC:PMC11500374 | DOI:10.1021/acsomega.4c08194

BMC Geriatr. 2024 Oct 26;24(1):881. doi: 10.1186/s12877-024-05471-7.

ABSTRACT

BACKGROUND: Older patients with coronary artery disease (CAD) are particularly vulnerable to the efficacy and adverse drug reactions, and may therefore particularly benefit from personalized medication. Drug-gene interactions (DGIs) occur when an individual's genotype affects the pharmacokinetics and/or pharmacodynamics of a victim drug.

OBJECTIVES: This study aimed to investigate the impact of cardiovascular-related DGIs on the clinical efficacy and safety outcomes in older patients with CAD.

METHODS: Hospitalized older patients (≥ 65 years old) with CAD were consecutively recruited from August 2018 to May 2022. Eligible patients were genotyped for the actionable pharmacogenetic variants of CYP2C9, CYP2C19, CYP2D6, CYP3A5, and SLCO1B1, which had clinical annotations or implementation guidelines for cardiovascular drugs. Allele frequencies and DGIs were determined in the cohort for the 5 actionable PGx genes and the prescribed cardiovascular drugs. All patients were followed up for at least 1 year. The influence of DGIs on the cardiovascular drug-related efficacy outcomes (all-cause mortality and/or major cardiovascular events, MACEs) and drug response phenotypes of "drug-stop" and "dose-decrease" were evaluated.

RESULTS: A total of 1,017 eligible older patients with CAD were included, among whom 63.2% were male, with an average age of 80.8 years old, and 87.6% were administrated with polypharmacy (≥ 5 medications). After genotyping, we found that 96.0% of the older patients with CAD patients had at least one allele of the 5 pharmacogenes associated with a therapeutic change, indicating a need for a therapeutic change in a mean of 1.32 drugs of the 19 cardiovascular-related drugs. We also identified that 79.5% of the patients had at least one DGI (range 0-6). The median follow-up interval was 39 months. Independent of age, negative association could be found between the number of DGIs and all-cause mortality (adjusted HR: 0.84, 95% CI: 0.73-0.96, P = 0.008), and MACEs (adjusted HR: 0.84, 95% CI: 0.72-0.98, P = 0.023), but positive association could be found between the number of DGIs and drug response phenotypes (adjusted OR: 1.24, 95% CI: 1.05-1.45, P = 0.011) in the elderly patients with CAD.

CONCLUSIONS: The association between cardiovascular DGIs and the clinical outcomes emphasized the necessity for the integration of genetic and clinical data to enhance the optimization of cardiovascular polypharmacy in older patients with CAD. The causal relationship between DGIs and the clinical outcomes should be established in the large scale prospectively designed cohort study.

PMID:39462319 | DOI:10.1186/s12877-024-05471-7