Zhonghua Gan Zang Bing Za Zhi. 2023 Jun 20;31(6):653-658. doi: 10.3760/cma.j.cn501113-20230418-00172.

ABSTRACT

Drug-induced liver injury (DILI) risk prediction, diagnosis establishment, clinical management, and all other aspects are facing great challenges. Although the current understanding of its pathogenesis is still incomplete, research over the past 20 years has shown that genetic susceptibility may play an important role in the occurrence and development of DILI. In recent years, pharmacogenomics studies have further revealed the association between human leukocyte antigen (HLA) genes, some non-HLA genes, and hepatotoxicity from certain drugs. However, due to the lack of well-designed, prospective, large-sample cohort validation and low positive predictive values, there may still be some way to go before the current results can be truly translated into clinical practice for precise prediction and prevention of DILI risk.

PMID:37400394 | DOI:10.3760/cma.j.cn501113-20230418-00172

bioRxiv. 2023 Jun 15:2023.06.14.544860. doi: 10.1101/2023.06.14.544860. Preprint.

ABSTRACT

BACKGROUND: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained.

METHODS: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 μM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial ( ClinicalTrials.gov Identifier: NCT00451828 ). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified ( ZNF335 ), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335 ).

RESULTS: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 ( ZNF335 aka NIF-1 , rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 ( CNOT3 , rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the Zfp335 R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335 R1092W allele(s) exhibited a significantly blunted LDL statin response.

CONCLUSIONS: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.

PMID:37397985 | PMC:PMC10312755 | DOI:10.1101/2023.06.14.544860

JACC CardioOncol. 2023 Mar 28;5(3):360-373. doi: 10.1016/j.jaccao.2022.10.017. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2).

OBJECTIVES: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart.

METHODS: Rbl2-/- mice and Rbl2+/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies.

RESULTS: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors.

CONCLUSIONS: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.

PMID:37397090 | PMC:PMC10308060 | DOI:10.1016/j.jaccao.2022.10.017

Genes Dis. 2022 May 26;10(3):771-785. doi: 10.1016/j.gendis.2022.05.011. eCollection 2023 May.

ABSTRACT

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

PMID:37396555 | PMC:PMC10308135 | DOI:10.1016/j.gendis.2022.05.011

Front Genet. 2023 Jun 15;14:1217049. doi: 10.3389/fgene.2023.1217049. eCollection 2023.

ABSTRACT

Pharmacogenomics (PGx) aims at tailoring drug therapy by considering patient genetic makeup. While drug dosage guidelines have been extensively based on single gene mutations (single nucleotide polymorphisms) over the last decade, polygenic risk scores (PRS) have emerged in the past years as a promising tool to account for the complex interplay and polygenic nature of patients' genetic predisposition affecting drug response. Even though PRS research has demonstrated convincing evidence in disease risk prediction, the clinical utility and its implementation in daily care has yet to be demonstrated, and pharmacogenomics is no exception; usual endpoints include drug efficacy or toxicity. Here, we review the general pipeline in PRS calculation, and we discuss some of the remaining barriers and challenges that must be undertaken to bring PRS research in PGx closer to patient care. Besides the need in following reporting guidelines and larger PGx patient cohorts, PRS integration will require close collaboration between bioinformatician, treating physicians and genetic consultants to ensure a transparent, generalizable, and trustful implementation of PRS results in real-world medical decisions.

PMID:37396043 | PMC:PMC10311496 | DOI:10.3389/fgene.2023.1217049

Pharmacol Ther. 2023 Jun 29:108487. doi: 10.1016/j.pharmthera.2023.108487. Online ahead of print.

ABSTRACT

Protoporphyrin IX (PPIX) is an intermediate in the heme biosynthesis pathway. Abnormal accumulation of PPIX due to certain pathological conditions such as erythropoietic protoporphyria and X-linked protoporphyria causes painful phototoxic reactions of the skin, which can significantly impact daily life. Endothelial cells in the skin have been proposed as the primary target for PPIX-induced phototoxicity through light-triggered generation of reactive oxygen species. Current approaches for the management of PPIX-induced phototoxicity include opaque clothing, sunscreens, phototherapy, blood therapy, antioxidants, bone marrow transplantation, and drugs that increase skin pigmentation. In this review, we discuss the present understanding of PPIX-induced phototoxicity including PPIX production and disposition, conditions that lead to PPIX accumulation, symptoms and individual differences, mechanisms, and therapeutics.

PMID:37392940 | DOI:10.1016/j.pharmthera.2023.108487

Curr Pharm Teach Learn. 2023 Jun 28:S1877-1297(23)00154-5. doi: 10.1016/j.cptl.2023.06.017. Online ahead of print.

ABSTRACT

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US).

METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates.

RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate.

CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

PMID:37391352 | DOI:10.1016/j.cptl.2023.06.017

Kidney Int. 2023 Jun 28:S0085-2538(23)00475-1. doi: 10.1016/j.kint.2023.06.021. Online ahead of print.

ABSTRACT

For three decades, tacrolimus (Tac) dose adjustment in clinical practice has been calculated empirically according to the manufacturer's labeling based on a patient's body weight. Here, we developed and validated a Population pharmacokinetic (PPK) model including pharmacogenetics (cluster CYP3A4/CYP3A5), age, and hematocrit. Our study aimed to assess the clinical applicability of this PPK model in the achievement of Tac Co (therapeutic trough Tac concentration) compared to the manufacturer's labelling dosage. A prospective two-arm, randomized, clinical trial was conducted to determine Tac starting and subsequent dose adjustments in 90 kidney transplant recipients. Patients were randomized to a control group with Tac adjustment according to the manufacturer's labeling or the PPK group adjusted to reach target Co (6-10 ng/ml) after the first steady state (primary endpoint) using a Bayesian prediction model (NONMEM). A significantly higher percentage of patients from the PPK group (54.8%) compared with the control group (20.8%) achieved the therapeutic target fulfilling 30% of the established superiority margin defined. Patients receiving PPK showed significantly less intra-patient variability compared to the control group, reached the Tac Co target sooner (5 days vs 10 days), and required significantly fewer Tac dose modifications compared to the control group within 90 days following kidney transplant. No statistically significant differences occurred in clinical outcomes. Thus, PPK-based Tac dosing offers significant superiority for starting Tac prescription over classical labeling-based dosing according to the body weight, which may optimize Tac-based therapy in the first days following transplantation.

PMID:37391040 | DOI:10.1016/j.kint.2023.06.021

Longhua Chin Med. 2022;5:35. doi: 10.21037/lcm-21-72. Epub 2022 Dec 30.

ABSTRACT

BACKGROUND AND OBJECTIVE: Cancer is a major public health problem in the world, and it dramatically affects the life expectancy of patients and their quality of life. Natural products from botanicals could be beneficial in the prevention or treatment of a variety of cancers. Saffron (the extract of Crocus sativus) includes its major constituent, crocin, have been used as a folk medicine for a long time, and they have shown obvious cancer chemoprevention potential. The objectives of this review are to present the progress of research on the effects of saffron and crocin in cancer management and the underlying mechanisms of action.

METHODS: We searched publications in the English language, published between January 1, 1980 and September 30, 2022, of saffron and crocin on cancer through several search engines, i.e., PubMed, SciFinder and Web of Science.

KEY CONTENT AND FINDINGS: In this article, we first summarize the phytochemical studies of this botanical. Then, we present the anticancer effects of saffron and crocin on different human cancer cells. Saffron and crocin showed obvious antiproliferative effects on human cancer cell lines, including colorectal cancer, breast cancer, lung cancer, prostate cancer, cervical cancer, leukemia, glioblastoma and rhabdomyosarcoma. Finally, the anticancer-related mechanisms of action are summarized, including cell cycle arrest at G0/G1 or G2/M phases, induction of caspase-dependent apoptosis, signaling pathway-linked tumor metabolism regulation, and adaptive immunity regulated inflammation of host immune responses.

CONCLUSIONS: Previous studies related to saffron and crocin in cancer management have been reviewed and reported results have been analyzed. Clinical data suggest that saffron and crocin have beneficial effects to improve quality of life in cancer patients. Thus, saffron and crocin can be considered promising candidates for future clinical cancer studies.

PMID:37389090 | PMC:PMC10309162 | DOI:10.21037/lcm-21-72

Front Genet. 2023 Jun 14;14:1085864. doi: 10.3389/fgene.2023.1085864. eCollection 2023.

ABSTRACT

Advances in genomic research have significantly enhanced modern drug development. However, equitable benefit sharing of the results of scientific advancement has not always been achieved. This paper shows how molecular biology has modified medicines development while also leaving open significant challenges for benefit sharing. Presented here is a conceptual modeling describing the processes in genetic-related medicines development and how these are related to specific ethical considerations. The focus is on three important areas: 1) population genetics and the need for discrimination prevention; 2) pharmacogenomics and the need for inclusive governance; and 3) global health to be achieved in open science frameworks. Benefit sharing is taken as the ethical value that underlies all these aspects. The implementation of benefit sharing requires a value shift in which the outcomes of health science are not viewed simply as trade commodities but also as a "global public good". This approach should lead to genetic science to contribute to promoting the fundamental human right to health to all members of the global community.

PMID:37388927 | PMC:PMC10300349 | DOI:10.3389/fgene.2023.1085864

Asia Pac Allergy. 2023 Jun;13(2):72-76. doi: 10.5415/apallergy.0000000000000101. Epub 2023 Jun 6.

ABSTRACT

Drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are non-immunoglobulin E-mediated severe cutaneous adverse reactions with a high risk of morbidity, mortality, and physical and mental health impact. These are associated with certain high-risk drugs, human leukocyte antigen (HLA)-specific genotypes and ethnicities. HLA class I-restricted oligoclonal CD8 cytotoxic T-cell responses occur at the tissue level in SJS/TEN. Cytotoxic T cells are the T effector cells that result in keratinocyte apoptosis (cell death) mediated by T effector molecules granzyme B, perforin, granulysin, gamma interferon, tumor necrosis factor-alpha, and lipocalin-2. The clinical hallmarks of SJS/TEN include fever, ≥2 mucosal involvements (ocular, oral, and genital), and positive Nikolsky sign with epidermal detachment. Systematic reviews on immunomodulatory treatments remain limited by the paucity of randomized controlled trials, heterogeneity of studies, and non-standardization of outcome measures. Preventive HLA genotype screening before the prescription of carbamazepine and allopurinol may further reduce the incidence of SJS/TEN. The role of immunomodulatory treatments in SJS/TEN is at present not supported by robust evidence from systematic reviews given the lack of randomized controlled trials. The evidence for improved survival with off-label use of corticosteroids plus intravenous immunoglobulins, ciclosporin plus intravenous immunoglobulins, and ciclosporin alone has not been demonstrated by network meta-analyses and meta-regression. In the real-world clinical setting, systemic corticosteroids (in SJS and overlap SJS/TEN), ciclosporin, and etanercept (in TEN) appear to be the off-label treatments currently most widely used.

PMID:37388817 | PMC:PMC10287110 | DOI:10.5415/apallergy.0000000000000101

Br J Haematol. 2023 Jun 30. doi: 10.1111/bjh.18940. Online ahead of print.

ABSTRACT

Since the publication in 2017 of the revised 4th Edition of the World Health Organization (WHO) classification of haematolymphoid tumours, here referred to as WHO-HAEM4, significant clinicopathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining the diagnostic criteria of several diseases, upgrading entities previously defined as provisional and identifying new entities. This process has resulted in two recent classification proposals of lymphoid neoplasms: the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, focusing on T-cell lymphomas and histiocytic/dendritic cell tumours. Moreover, we update the genetic data of the various pathological entities. The main goal is to provide a tool to facilitate the work of the pathologists, haematologists and researchers involved in the diagnosis and treatment of these haematological malignancies.

PMID:37387351 | DOI:10.1111/bjh.18940

Biomed Pharmacother. 2023 Jun 27;165:115058. doi: 10.1016/j.biopha.2023.115058. Online ahead of print.

ABSTRACT

Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower tmax (2.21 h vs 2.88 h, β = 1.19, R2 =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC∞ corrected by dose/weight (AUC∞/DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R2 =0.250, p = 0.044), higher Cmax/DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, β = 0.245, R2 =0.320, p = 0.002), and lower tmax (2.63 vs 3.19 and 4.15 h, β = -0.346, R2 =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC∞ and Cmax. Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance.

PMID:37385211 | DOI:10.1016/j.biopha.2023.115058

Am J Chin Med. 2023 Jun 30:1-20. doi: 10.1142/S0192415X23500507. Online ahead of print.

ABSTRACT

Ginseng is a very commonly used natural product in the world, and its two main species are Asian ginseng and American ginseng. Ginseng is an adaptogenic botanical that reportedly protects the body against stress, stabilizes physiological processes, and restores homeostasis. Previously, different animal models and contemporary research methodologies have been used to reveal ginseng's biomedical activities in different body systems and the linked mechanisms of actions. However, human clinical observation data on ginseng effects have attracted more attention from the general public and medical community. In this paper, after an introduction of the phytochemistry of ginseng species, we review positive ginseng clinical studies, mainly conducted in developed countries, performed over the past 20 years. The reported effects of ginseng are presented in several sections, and conditions impacted by ginseng include diabetes; cardiovascular disorders; cognition, memory, and mood; the common cold and flu; cancer fatigue and well-being; quality of life and social functioning, etc. Administration of ginseng demonstrated a good safety record in humans. Although encouraging beneficial effects obtained from clinical data, using the study treatment regimen, the reported ginseng effects in general only ranged from mild to moderate. Nonetheless, these beneficial effects of ginseng could be a valuable add-on therapy for patients receiving standard drug treatments. Additionally, as a dietary supplement, ginseng possesses an important role in maintaining and promoting human health. We believe that the quality of future ginseng trials should be improved, particularly by providing detailed herbal phytochemistry and quality control information. With solid effectiveness data obtained from a well-designed, carefully executed ginseng clinical trial, this meritoriously herbal medicine will be widely used by consumers and patients.

PMID:37385964 | DOI:10.1142/S0192415X23500507

Front Cell Dev Biol. 2023 Jun 13;11:1088057. doi: 10.3389/fcell.2023.1088057. eCollection 2023.

ABSTRACT

Colorectal adenocarcinoma (COREAD) is the second most deadly cancer and third most frequently encountered malignancy worldwide. Despite efforts in molecular subtyping and subsequent personalized COREAD treatments, multidisciplinary evidence suggests separating COREAD into colon cancer (COAD) and rectal cancer (READ). This new perspective could improve diagnosis and treatment of both carcinomas. RNA-binding proteins (RBPs), as critical regulators of every hallmark of cancer, could fulfill the need to identify sensitive biomarkers for COAD and READ separately. To detect new RBPs involved in COAD and READ progression, here we used a multidata integration strategy to prioritize tumorigenic RBPs. We analyzed and integrated 1) RBPs genomic and transcriptomic alterations from 488 COAD and 155 READ patients, 2) ∼ 10,000 raw associations between RBPs and cancer genes, 3) ∼ 15,000 immunostainings, and 4) loss-of-function screens performed in 102 COREAD cell lines. Thus, we unraveled new putative roles of NOP56, RBM12, NAT10, FKBP1A, EMG1, and CSE1L in COAD and READ progression. Interestingly, FKBP1A and EMG1 have never been related with any of these carcinomas but presented tumorigenic features in other cancer types. Subsequent survival analyses highlighted the clinical relevance of FKBP1A, NOP56, and NAT10 mRNA expression to predict poor prognosis in COREAD and COAD patients. Further research should be performed to validate their clinical potential and to elucidate their molecular mechanisms underlying these malignancies.

PMID:37384253 | PMC:PMC10293682 | DOI:10.3389/fcell.2023.1088057

Front Pharmacol. 2023 Jun 13;14:1234219. doi: 10.3389/fphar.2023.1234219. eCollection 2023.

NO ABSTRACT

PMID:37383722 | PMC:PMC10299726 | DOI:10.3389/fphar.2023.1234219

Pharmgenomics Pers Med. 2023 Jun 23;16:645-664. doi: 10.2147/PGPM.S371994. eCollection 2023.

ABSTRACT

Proton pump inhibitors (PPIs) are commonly used medications to treat acid-related conditions, including gastro-esophageal reflux disease (GERD). Gastroenterology guidelines mention the importance of CYP2C19 in PPI metabolism and the influence of CYP2C19 genetic variations on variable responses to PPIs, but do not currently recommend the genotyping of CYP2C19 prior to prescribing PPIs. There are strong data to support the influence of CYP2C19 genetic variations on the pharmacokinetics of PPIs and clinical outcomes. Existing pharmacogenetic guideline recommendations for dose increases focus on H. pylori and erosive esophagitis indications, but PPIs are also the main therapy for treating GERD. Recent data suggest GERD patients being treated with a PPI may also benefit from genotype-guided dosing. We summarize the literature supporting this contention and highlight future directions for improved management of patients with GERD through precision medicine approaches.

PMID:37383676 | PMC:PMC10296543 | DOI:10.2147/PGPM.S371994

Breathe (Sheff). 2023 Jun;19(2):220267. doi: 10.1183/20734735.0267-2022. Epub 2023 Jun 13.

ABSTRACT

Pharmacological management of airway obstructive diseases is a fast-evolving field. Several advances in unravelling disease mechanisms as well as intracellular and molecular pathways of drug action have been accomplished. While the clinical translation and implementation of in vitro results to the bedside remains challenging, advances in comprehending the mechanisms of respiratory medication are expected to assist clinicians and scientists in identifying meaningful read-outs and designing clinical studies. This European Respiratory Society Research Seminar, held in Naples, Italy, 5-6 May 2022, focused on current and future developments of the drugs used to treat asthma and COPD; on mechanisms of drug action, steroid resistance, comorbidities and drug interactions; on prognostic and therapeutic biomarkers; on developing novel drug targets based on tissue remodelling and regeneration; and on pharmacogenomics and emerging biosimilars. Related European Medicines Agency regulations are also discussed, as well as the seminar's position on the above aspects.

PMID:37377851 | PMC:PMC10292790 | DOI:10.1183/20734735.0267-2022

Front Genet. 2023 Jun 9;14:1199549. doi: 10.3389/fgene.2023.1199549. eCollection 2023.

ABSTRACT

Background and Aims: Various publications suggested that there is an association between CYP7A1 single nucleotide polymorphisms (SNP) and a reduced response to statin therapy, but the results were inconsistent. This study aimed to collectively review these publications to appraise the effect of statins on cholesterol control in carriers of CYP7A1 variant alleles. Methods: PUBMED, Cochrane and EMBASE were searched systematically to identify reported studies on the lipid responses to statin treatment between carriers of the variant allele versus the non-variant allele of CYP7A1 SNPs. The change from baseline in lipid responses for all included studies were calculated using weighted mean differences (WMD) (with 95% confidence interval (CI)). A meta-analysis was conducted to pool results using either the random-effects model or the fixed effects model. Results: A total of 6 publications comprising of 1,686 subjects for the assessment of total cholesterol, LDL-C and HDL-C and 1,156 subjects for the assessment of triglycerides were included in the meta-analyses. Subjects who were non-carriers of a CYP7A1 SNP (-204 A/C (rs3808607), -278 A/C (rs3808607) and rs8192875) had a greater reduction in total cholesterol (overall WMD -0.17, 95% CI -0.29, -0.06) and LDL-C levels (overall WMD -0.16, 95% CI -0.26, -0.05) as compared with subjects who borne the variant allele of CYP7A1 SNPs when administered a statin. Conclusion: The presence of variant allele of CYP7A1 SNPs may result in suboptimal control of total cholesterol and LDL-C levels as compared with individuals who do not carry the variant allele, when administered an equivalent dose of statin.

PMID:37377593 | PMC:PMC10292746 | DOI:10.3389/fgene.2023.1199549

Viruses. 2023 May 30;15(6):1286. doi: 10.3390/v15061286.

ABSTRACT

Cytomegalovirus (CMV) infection is a serious complication in hematopoietic cell transplantation (HCT) recipients. Drug-resistant strains make it more challenging to treat CMV infection. This study aimed to identify variants associated with CMV drug resistance in HCT recipients and assess their clinical significance. A total of 123 patients with refractory CMV DNAemia out of 2271 HCT patients at the Catholic Hematology Hospital between April 2016 and November 2021 were analyzed, which accounted for 8.6% of the 1428 patients who received pre-emptive therapy. Real-time PCR was used to monitor CMV infection. Direct sequencing was performed to identify drug-resistant variants in UL97 and UL54. Resistance variants were found in 10 (8.1%) patients, and variants of uncertain significance (VUS) were found in 48 (39.0%) patients. Patients with resistance variants had a significantly higher peak CMV viral load than those without (p = 0.015). Patients with any variants had a higher risk of severe graft-versus-host disease and lower one-year survival rates than those without (p = 0.003 and p = 0.044, respectively). Interestingly, the presence of variants reduced the rate of CMV clearance, particularly in patients who did not modify their initial antiviral regimen. However, it had no apparent impact on individuals whose antiviral regimens were changed due to refractoriness. This study highlights the importance of identifying genetic variants associated with CMV drug resistance in HCT recipients for providing appropriate antiviral treatment and predicting patient outcomes.

PMID:37376586 | DOI:10.3390/v15061286