Indian J Anaesth. 2023 Sep;67(9):796-801. doi: 10.4103/ija.ija_1033_22. Epub 2023 Sep 6.

ABSTRACT

BACKGROUND AND AIMS: Genetic polymorphisms contribute to patients' variability in pain perception and response to opioid treatment. The present study evaluated the association of calcitonin gene-related peptide (CGRP) 4218T/C polymorphisms with fentanyl consumption over 24 h postoperatively in patients after major abdominal surgery.

METHODS: Eighty-five patients undergoing major abdominal surgery under general anaesthesia were recruited. For postoperative analgesia, epidural fentanyl and intravenous paracetamol were provided. The CGRP 4218T/C genotype was analysed, and the association between the genotype of the patient and the total consumption of fentanyl in the first 24 h after surgery was assessed. The association between different genotypes, the severity of postoperative pain and the side effects of opioids were also studied.

RESULTS: Our study population distribution included 52.9% of the T/T genotype (wild homozygote), 35.3% of the T/C genotype (heterozygote) and 11.8% of the C/C genotype (mutant homozygote). Mean (standard deviation) total fentanyl consumption in the first 24 h was found to be highest in the C/C group (212.0 [7.5] μg), followed by the T/T group (182.8 [9.9] μg) and was the least in the T/C group (159.6 [7.5] μg). The C/C group reported higher pain scores in all the study periods. There was no significant difference in the side effects of opioids, such as nausea, vomiting, sedation among different genotypes of CGRP 4218T/C.

CONCLUSION: The polymorphism of CGRP 4218T/C affects postoperative pain perception and analgesic consumption. Patients with the C/C genotype had higher postoperative fentanyl consumption and pain scores.

PMID:37829781 | PMC:PMC10566653 | DOI:10.4103/ija.ija_1033_22

Lancet Reg Health Am. 2023 Oct 5;26:100611. doi: 10.1016/j.lana.2023.100611. eCollection 2023 Oct.

NO ABSTRACT

PMID:37829195 | PMC:PMC10565760 | DOI:10.1016/j.lana.2023.100611

Nat Commun. 2023 Oct 12;14(1):6156. doi: 10.1038/s41467-023-41876-5.

ABSTRACT

Raynaud's phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p < 5 × 10-8). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 × 10-27) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12-1.22, p < 4.8 × 10-13) as candidate causal genes through integration of gene expression in disease relevant tissues. We further identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG = -0.21; p-value = 2.3 × 10-3), and systematically highlighted drug repurposing opportunities, like the antidepressant mirtazapine. Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of α2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.

PMID:37828025 | PMC:PMC10570309 | DOI:10.1038/s41467-023-41876-5

Cell Chem Biol. 2023 Oct 10:S2451-9456(23)00332-X. doi: 10.1016/j.chembiol.2023.09.013. Online ahead of print.

ABSTRACT

The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence that this drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is >30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.

PMID:37827156 | DOI:10.1016/j.chembiol.2023.09.013

Gen Hosp Psychiatry. 2023 Sep 1;85:71-79. doi: 10.1016/j.genhosppsych.2023.08.011. Online ahead of print.

ABSTRACT

OBJECTIVE: Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment.

METHOD: Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis.

RESULTS: A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs.

CONCLUSION: This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

PMID:37826886 | DOI:10.1016/j.genhosppsych.2023.08.011

Commun Biol. 2023 Oct 12;6(1):1036. doi: 10.1038/s42003-023-05390-0.

ABSTRACT

In vitro biopanning platforms using synthetic phage display antibody libraries have enabled the identification of antibodies against antigens that were once thought to be beyond the scope of immunization. Applying these methods against challenging targets remains a critical challenge. Here, we present a new biopanning pipeline, RAPID (Rare Antibody Phage Isolation and Discrimination), for the identification of rare high-affinity antibodies against challenging targets. RAPID biopanning uses fluorescent labeled phage displayed fragment antigen-binding (Fab) antibody libraries for the isolation of high-affinity binders with fluorescent activated sorting. Subsequently, discriminatory hit screening is performed with a biolayer interferometry (BLI) method, BIAS (Biolayer Interferometry Antibody Screen), where candidate binders are ranked and prioritized according to their estimated kinetic off rates. Previously reported antibodies were used to develop the methodology, and the RAPID biopanning pipeline was applied to three challenging targets (CHIP, Gαq, and CS3D), enabling the identification of high-affinity antibodies.

PMID:37828150 | DOI:10.1038/s42003-023-05390-0

J Glob Health. 2023 Oct 13;13:04120. doi: 10.7189/jogh.13.04120.

ABSTRACT

BACKGROUND: The global epidemiological data on congenital hearing loss in children is sparse. We aimed to analyse the trends in the burden of complete hearing loss caused by congenital birth defects in children younger than five years from 1990 to 2030.

METHODS: Using data from the Global Burden of Disease (GBD) Study 2019, we reported the counts and rates of prevalence and years lived with disability (YLD) by age, sex, and sociodemographic index (SDI). We also forecasted the prevalence rates until 2030 through the autoregressive integrated moving average (ARIMA) and Bayesian age-period-cohort (BAPC) models.

RESULTS: We observed a global prevalence rate of 15.4 (95% uncertainty interval (UI) = 5.8 to 33.8) and a YLD rate of 3.3 (95% UI = 1.1 to 7.1) per 100 000 population in 2019, with both showing downward trends from 1990 to 2019. Regionally, Oceania had the highest prevalence (47.2; 95% UI = 18.8 to 96.6) and YLD (10; 95% UI = 3.2 to 22.8) rates, while Central Europe had the lowest rates. Nationally, the prevalence (85.0; 95% UI = 36.8 to 166.8) and YLD (17.9; 95% UI = 6.6 to 36.9) rates were highest in Myanmar and lowest in Peru. Only the United States of America (2.6%; 95% UI = -4.6 to 14.4) and Norway (0.6%; 95% UI = -6.7 to 16.2) showed upward trends. Compared to girls, the prevalence and YLD rates were higher for boys at global, regional, and five SDI quintile levels, except for Eastern Sub-Saharan Africa. At the global level, downward trends were predicted in prevalence rates from 2019 to 2030 between boys and girls.

CONCLUSIONS: Although the global burden of childhood congenital complete hearing loss showed inequalities across locations, sexes, and age groups, we found decreases in the global prevalence rates between 1990 and 2019 and predicted decreases from 2019 to 2030. Better prevention of infectious aetiologies, improving genetic diagnoses, and hearing restoration could alleviate this burden.

PMID:37824170 | DOI:10.7189/jogh.13.04120

Elife. 2023 Oct 12;12:e93330. doi: 10.7554/eLife.93330.

ABSTRACT

An assistant professor and group leader explains how being diagnosed with autism in her early 40s changed her approach to being a scientist.

PMID:37823395 | DOI:10.7554/eLife.93330

Pharm Res. 2023 Oct 11. doi: 10.1007/s11095-023-03614-w. Online ahead of print.

ABSTRACT

BACKGROUND: Dosing regimens of trastuzumab administered by intracerebroventricular (icv) route to patients with HER2-positive brain localizations remain empirical. The objectives of this study were to describe pharmacokinetics (PK) of trastuzumab in human plasma and cerebrospinal fluid (CSF) after simultaneous icv and intravenous (iv) administration using a minimal physiologically-based pharmacokinetic model (mPBPK) and to perform simulations of alternative dosing regimens to achieve therapeutic concentrations in CSF.

METHODS: Plasma and CSF PK data were collected in two patients with HER2-positive brain localizations. A mPBPK model for mAbs consisting of four compartments (tight and leaky tissues, plasma and lymph) was enriched by an additional compartment for ventricular CSF. The comparison between observed and model-predicted concentrations was evaluated using prediction error (PE).

RESULTS: The developed mPBPK model described plasma and CSF trastuzumab concentrations reasonably well with mean PE for plasma and CSF data of 41.8% [interquartile range, IQR = -9.48; 40.6] and 18.3% [-36.7; 60.6], respectively, for patient 1 and 11.4% [-10.8; 28.7] and 22.5% [-27.7; 77.9], respectively, for patient 2. Trastuzumab showed fast clearance from CSF to plasma with Cmin,ss of 0.56 and 0.85 mg/L for 100 and 150 mg q1wk, respectively. Repeated dosing of 100 and 150 mg q3day resulted in Cmin,ss of 10.3 and 15.4 mg/L, respectively. Trastuzumab CSF target concentrations are achieved rapidly and maintained above 60 mg/L from 7 days after a continuous perfusion at 1.0 mg/h.

CONCLUSION: Continuous icv infusion of trastuzumab at 1.0 mg/h could be an alternative dosing regimen to rapidly achieve intraventricular CSF therapeutic concentrations.

PMID:37821769 | DOI:10.1007/s11095-023-03614-w

Asian Biomed (Res Rev News). 2023 Oct 9;17(3):95-114. doi: 10.2478/abm-2023-0050. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Statins are the most widely used lipid-lowering agents for patients with hyperlipidemia. However, interindividual variations in efficacy and risk of adverse drug reactions to statin treatment have been widely reported. Ethnicity is well known to be one of the contributing factors to this variation, particularly among Asians.

OBJECTIVES: To identify genetic variants associated with statin treatment responses among Asian populations with a focus on four commonly prescribed statins: atorvastatin, rosuvastatin, simvastatin, and pravastatin.

METHODS: A literature search was conducted in Medline and Embase databases. Studies published from 2008 to 2021 were included. The title and abstract of each article were screened by two reviewers and verified by another two reviewers. Data charted include information on authors, year of study, study population, statin studied, gene studied, study findings, and data of significant statistical value.

RESULTS: A total of 35 articles were included from the 1,939 original studies related to treatment efficacy and 5 articles out of the 284 original studies related to adverse effects. Genetic variants in transmembrane transporters, cytochrome P450 isoenzymes, and apolipoproteins are the most extensively studied among Asian populations, with a main focus on ethnic Chinese. However, Asia consists of genetically different populations, and the results of this review indicated that there is a paucity of studies on other ethnic groups within Asia.

CONCLUSIONS: Considering the ethnicity of patients could provide a potential value to personalized medicine in statin therapy.

PMID:37818163 | PMC:PMC10561688 | DOI:10.2478/abm-2023-0050

Am J Cancer Res. 2023 Sep 15;13(9):4039-4056. eCollection 2023.

ABSTRACT

This study investigated the cost-effectiveness and quality of life (QoL) within 1 year of receiving mFOLOFX6 with or without a targeted drug (bevacizumab or ramucirumab) as second-line treatment among patients with metastatic colorectal cancer (mCRC) following the failure of FOLFIRI + bevacizumab as first-line treatment. This prospective cohort study included patients who received a diagnosis of mCRC between March 2015 and May 2020. QoL was evaluated before treatment and at 6 months and 1 year posttreatment. All related variables were controlled using the inverse probability of treatment weighting method. Generalized estimating equations with the difference-in-difference method was used to explore changes in QoL. The incremental cost-utility ratio (ICUR) of the two groups was simulated using the annual-cycle Markov decision tree model. Finally, 39 and 76 patients were included in the targeted and nontargeted agent groups, respectively. At 6 months after treatment, QoL of the two groups improved significantly, but the targeted agent group had significantly better QoL than did the nontargeted agent group at 1 year posttreatment (P < 0.05). When the time frame was set to 20 years, the ICUR of the targeted agent group compared with the nontargeted agent group was US$32,052 per quality-adjusted life years. Addition of a targeted drug to the second-line mFOLOFX6 regimen not only improved the patients' QoL but was also more cost effective when the willingness-to-pay threshold was set at US$33,004 (the per capita gross domestic product of Taiwan). These patients should be reimbursed for these targeted agents by the National Health Insurance scheme in Taiwan.

PMID:37818063 | PMC:PMC10560929

Annu Rev Pharmacol Toxicol. 2023 Oct 10. doi: 10.1146/annurev-physiol-090123-010552. Online ahead of print.

ABSTRACT

The reviews in Volume 64 of the Annual Review of Pharmacology and Toxicology cover diverse topics. A common theme in many of the reviews is the interindividual variability in the clinical response to drugs. Highlighted areas include emerging developments in pharmacogenomics that can predict the personal risk for drug inefficacy and/or adverse drug reactions. Other reviews focus on the use of circulating biomarkers to define drug metabolism phenotypes and the effect of circadian regulation on drug response. Another emerging technology, digital twins that model individual patients, is used to generate computational simulations of drug effects and identify optimal personalized treatments. Another variable that may affect clinical outcomes, the nocebo response (an adverse reaction to a placebo), complicates clinical trials. These reviews further document that pharmacological individuality is an essential component of the concepts of personalized medicine and precision medicine and will likely have an important impact on patient care. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37816308 | DOI:10.1146/annurev-physiol-090123-010552

J Clin Pharmacol. 2023 Oct 10. doi: 10.1002/jcph.2367. Online ahead of print.

NO ABSTRACT

PMID:37816218 | DOI:10.1002/jcph.2367

J Transl Med. 2023 Oct 9;21(1):705. doi: 10.1186/s12967-023-04566-w.

ABSTRACT

BACKGROUND AND AIMS: The increasing prevalence of metabolic and cardiovascular diseases poses a significant challenge to global healthcare systems. Regular physical activity (PA) is recognized for its positive impact on cardiovascular risk factors. This study aimed to investigate the relationship between moderate-to-vigorous physical activity (MVPA), sedentary behavior (SB), and abdominal aortic calcification (AAC) using data from the National Health and Nutrition Examination Survey (NHANES).

METHODS: The study used data from NHANES participants aged 40 and above during the 2013-2014 cycle. AAC scores were assessed using the Kauppila scoring system, and MVPA and SB were self-reported. Sociodemographic variables were considered, and multivariable linear regression models were used to analyze associations between MVPA, SB, and AAC scores. Subgroup analyses were conducted based on age, sex, BMI, hypertension, and diabetes.

RESULTS: The study included 2843 participants. AAC prevalence was higher in older age groups, smokers, and those with diabetes or hypertension. Lower socioeconomic status was associated with higher AAC prevalence. Individuals engaged in any level of MVPA exhibited lower AAC rates compared to inactive individuals. Not engaging in occupational MVPA (β = 0.46, 95% confidence interval = 0.24‒0.67, p < .001) and prolonged SB (β = 0.28, 95% confidence interval = 0.04‒0.52, p = .023) were associated with higher AAC scores. However, no significant associations were found for transportation and leisure time MVPA. Subgroup analysis revealed age and hypertension as effect modifiers in the MVPA-AAC relationship.

CONCLUSIONS: This study highlights the potential benefits of engaging in occupational MVPA and reducing SB in mitigating AAC scores, particularly among older individuals and those with hypertension.

PMID:37814346 | DOI:10.1186/s12967-023-04566-w

J Transl Med. 2023 Oct 9;21(1):704. doi: 10.1186/s12967-023-04527-3.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated.

METHODS: Differential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking.

RESULTS: F. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC.

CONCLUSIONS: Our study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis.

PMID:37814323 | DOI:10.1186/s12967-023-04527-3

Schizophr Res. 2023 Oct 7:S0920-9964(23)00353-5. doi: 10.1016/j.schres.2023.09.042. Online ahead of print.

ABSTRACT

Schizophrenia is a highly heritable, severe mental illness characterized by hallucinations, delusions, social withdrawal, and cognitive dysfunction present in ∼1% of populations across cultures. There have been recent major advancements in our understanding of the genetic architecture of schizophrenia. Both rare, highly penetrant genetic variants as well as common, low-penetrant genetic variants can predispose individuals to schizophrenia and can impact the way people metabolize psychoactive medications used to treat schizophrenia. However, the impact of these findings on the clinical management of schizophrenia remains limited. This review highlights the few places where genetics currently informs schizophrenia management strategies, discusses major limitations, and reviews promising areas of genetics research that are most likely to impact future schizophrenia care. Specifically, I focuss on psychiatric genetic counseling, genetic testing strategies, pharmacogenetics, polygenic risk, and genetics-guided treatment. Lastly, I emphasize important ethical considerations in the clinical use of genetics for schizophrenia management, including the exacerbation of healthcare inequalities and unintended consequences of new genetic technologies.

PMID:37813777 | DOI:10.1016/j.schres.2023.09.042

Int J Cardiol Cardiovasc Risk Prev. 2023 Sep 16;19:200213. doi: 10.1016/j.ijcrp.2023.200213. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Poor medication adherence leads to poor health outcomes and increased healthcare costs among patients with heart failure (HF). This study aimed to objectively assess medication adherence by measuring carvedilol and enalaprilat plasma concentrations among patients with HF.

METHODS: The present sub-study of the Safety, Tolerability, and Efficacy of Rapid Optimization, helped by NT-proBNP testing, of Heart Failure therapies (STRONG-HF) study involved adult patients with acute HF admitted in two Mozambican and two Nigerian hospitals who were not optimally treated with oral enalapril and carvedilol. Patients in the high-intensity arm of the STRONG-HF study, and those not meeting the biomarker criteria for persistent congestion, were included in the "frequent visit" (FV) arm. In the FV arm, blood for bioanalysis of plasma enalaprilat or/and carvedilol was drawn at the 2,6,12th week post-discharge. Patients in the usual care arm of STRONG-HF were included in the "standard visit" (SV) arm, which followed the usual local practice with blood sampling in week 12.

RESULTS: The study involved 113 (79 FV and 34 SV) participants with a mean age of 48.6 years and a mean left ventricular (LV) ejection fraction of 33.1%. Theenalaprilat below the lower level of quantification (LLOQ) was documented in 7.7%, 11.9%, and 15.6% of participants in FV during the 2,6 and 12th weeks. Carvedilol concentration below LLOQ was documented in 37%, 30%, and 44.4% of participants in the FV arm during the 2,6 and 12th weeks, respectively. For the SV arm, enalaprilat and carvedilol concentrations below LLOQ in the twelfth week were documented in 37.3% and 42.9% of patients, respectively.

CONCLUSION: Up to a third of patients using enalapril and carvedilol did not take any medication during the 12 weeks of follow-up. Non adherence was more common in patients who had less follow up, emphasizing the importance of close follow up to adherence. No adherence was also more common in medications know to have more side effects such as carvedilol.

PMID:37811486 | PMC:PMC10556761 | DOI:10.1016/j.ijcrp.2023.200213

Transl Clin Pharmacol. 2023 Sep;31(3):131-138. doi: 10.12793/tcp.2023.31.e16. Epub 2023 Sep 19.

ABSTRACT

Clinical trials are essential for medical research, but they often face challenges in matching patients to trials and planning. Large language models (LLMs) offer a promising solution, signaling a transformative shift in the field of clinical trials. This review explores the multifaceted applications of LLMs within clinical trials, focusing on five main areas expected to be implemented in the near future: enhancing patient-trial matching, streamlining clinical trial planning, analyzing free text narratives for coding and classification, assisting in technical writing tasks, and providing cognizant consent via LLM-powered chatbots. While the application of LLMs is promising, it poses challenges such as accuracy validation and legal concerns. The convergence of LLMs with clinical trials has the potential to revolutionize the efficiency of clinical trials, paving the way for innovative methodologies and enhancing patient engagement. However, this development requires careful consideration and investment to overcome potential hurdles.

PMID:37810626 | PMC:PMC10551746 | DOI:10.12793/tcp.2023.31.e16

JACC Adv. 2023 Sep;2(7):None. doi: 10.1016/j.jacadv.2023.100573.

ABSTRACT

BACKGROUND: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Prior studies of genetic polymorphisms in CYP2C19 and their relationship with clinical efficacy have not included South Asian populations.

OBJECTIVES: The objective of this study was to assess prevalence of common CYP2C19 genotype polymorphisms in a British-South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel.

METHODS: The Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants were studied. CYP2C19 diplotypes were assessed using array data. Multivariable logistic regression was used to test for association between genetically inferred CYP2C19 metabolizer status and recurrent myocardial infarction, controlling for known cardiovascular disease risk factors, percutaneous coronary intervention, age, sex, and population stratification.

RESULTS: Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss-of-function CYP2C19 allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss-of-function alleles is 13%, which is higher than that in previously studied European (2.4%) and Central/South Asian populations (8.2%). Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019).

CONCLUSIONS: A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry.

PMID:37808344 | PMC:PMC10550831 | DOI:10.1016/j.jacadv.2023.100573

J Adv Pract Oncol. 2023 Sep;14(6):520-532. doi: 10.6004/jadpro.2023.14.6.5. Epub 2023 Sep 1.

ABSTRACT

Cyclophosphamide remains a critical component to haploidentical transplant conditioning regimens. Post-transplant cyclophosphamide (PTCy) emerged as an effective component of graft-vs.-host disease (GVHD) prophylaxis in the nonmyeloablative haploidentical bone marrow transplant setting. The relative ease of administration compared with ex vivo manipulations and efficacy in reducing GVHD has led to increasing PTCy use in transplant centers around the world. The role of PTCy has expanded to haploidentical transplantation with myeloablative conditioning regimens and peripheral blood progenitor cells as the donor source. Moreover, encouraging results in GVHD management have been shown with the use of PTCy alone or in combination with other immunosuppressives in the human leukocyte antigen-matched donor setting. The toxicity profile of cyclophosphamide varies extensively depending on dose, duration, overall drug exposure, and, potentially, pharmacogenetics. This review highlights the pharmacology, pharmacokinetics, and toxic effects of cyclophosphamide and offers practical guidance for clinical application in the post-transplant setting. We summarize data on the management of high-dose cyclophosphamide toxicities and provide insights into the pharmacogenetic implications on drug efficacy and safety data.

PMID:37808076 | PMC:PMC10558021 | DOI:10.6004/jadpro.2023.14.6.5