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Open Heart Nov 2023Clopidogrel is a P2Y inhibitor that has become a mainstay treatment following percutaneous intervention with drug-eluting stent placement to decrease restenosis and its...
INTRODUCTION
Clopidogrel is a P2Y inhibitor that has become a mainstay treatment following percutaneous intervention with drug-eluting stent placement to decrease restenosis and its potential complications, including sudden cardiac death and ischaemic strokes in patients with significant vascular disease.
AREAS COVERED
As a prodrug, the metabolism and efficacy of clopidogrel are contingent on the presence of wild-type CYP450 (CYP2C19) alleles. Genetic polymorphisms and variants are well known to impair its ability to prevent major adverse cardiovascular events in these patients, with inadequate response rates as high as 30% in previous publications. Patterns of allelic frequencies are expected to exhibit similarities between individuals of the same ancestry, ethnic group or geographic region. Accordingly, we seek to further elucidate worldwide prevalence rates for genetic polymorphisms in the CYP2C19-dependent metabolism of clopidogrel and review the potential of personalised CYP2C19 genotyping in clinical practice to mitigate this high treatment resistance and its associated burden on patients.
EXPERTS' COMMENTARY
Our findings support the consideration of genotyping before initiation of therapy to guide adequate dosage or substitutions of other P2Y inhibitors to promote personalised, precision medicine and to prevent adverse events when these therapies may inevitably fail in patients with variants of the CYP450 (CYP2C19) system.
Topics: Humans; Clopidogrel; Platelet Aggregation Inhibitors; Cytochrome P-450 CYP2C19; Drug-Eluting Stents; Polymorphism, Genetic
PubMed: 37963685
DOI: 10.1136/openhrt-2023-002436 -
PloS One 2023The abuse of psychogenic drugs can lead to multiple health-related problems. Genetic and environmental vulnerabilities are factors in the emergence of substance use...
BACKGROUND
The abuse of psychogenic drugs can lead to multiple health-related problems. Genetic and environmental vulnerabilities are factors in the emergence of substance use disorders. Empirical evidence regarding the gene-environment interaction in substance use is mixed. Summaries of the latest findings from a candidate gene approach will be useful for revealing the significance of particular gene contributions. Thus, we aim to identify different gene-environment interactions in patterns of substance use and investigate whether any effects trend notably across different genders and races.
METHODS
We reviewed published studies, until March 1, 2022, on substance use for candidate gene-environment interaction. Basic demographics of the included studies, target genes, environmental factors, main findings, patterns of gene-environment interaction, and other relevant information were collected and summarized.
RESULTS
Among a total of 44 studies, 38 demonstrated at least one significant interaction effect. About 61.5% of studies on the 5-HTTLPR gene, 100% on the MAOA gene, 42.9% on the DRD2 gene, 50% on the DRD4 gene, 50% on the DAT gene, 80% on the CRHR1 gene, 100% on the OPRM1 gene, 100% on the GABRA1 gene, and 50% on the CHRNA gene had a significant gene-environment interaction effect. The diathesis-stress model represents a dominant interaction pattern (89.5%) in the studies with a significant interaction effect; the remaining significant effect on substance use is found in the differential susceptibility model. The social push and swing model were not reported in the included studies.
CONCLUSION
The gene-environment interaction research on substance use behavior is methodologically multidimensional, which causes difficulty in conducting pooled analysis, or stated differently-making it hard to identify single sources of significant influence over maladaptive patterns of drug taking. In decreasing the heterogeneity and facilitating future pooled analysis, researchers must (1) replicate the existing studies with consistent study designs and measures, (2) conduct power calculations to report gene-environment correlations, (3) control for covariates, and (4) generate theory-based hypotheses with factorial based experiments when designing future studies.
Topics: Humans; Male; Female; Gene-Environment Interaction; Substance-Related Disorders
PubMed: 37906564
DOI: 10.1371/journal.pone.0287446 -
BMC Cancer Oct 2023It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combined with epidermal growth factor receptor tyrosine kinase inhibitors... (Meta-Analysis)
Meta-Analysis
First-line treatment with TKI plus brain radiotherapy versus TKI alone in EGFR-mutated non-small cell Lung cancer with brain metastases: a systematic review and meta-analysis.
BACKGROUND
It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone for EGFR-mutated non-small cell lung cancer with newly diagnosed brain metastases (BMs). Therefore, we performed a meta-analysis to address this issue.
METHODS
We searched PubMed, Embase, Cochrane Library, and Web of Science databases for eligible studies published until February 28, 2023. The primary outcomes of interest were overall survival (OS) and intracranial progression-free survival (iPFS), reported as hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS
Twenty-four retrospective studies with 3184 patients were included. First- or second-generation EGFR-TKIs were used in each study. Upfront brain RT plus EGFR-TKIs significantly prolonged OS (HR = 0.75, 95% CI: 0.64-0.88) and iPFS (HR = 0.61, 95% CI: 0.52-0.72) compared to EGFR-TKIs alone. There were no significant differences in OS and iPFS benefits from the combination therapy between asymptomatic and symptomatic patients, patients with exon 19 and 21 mutations, patients with 1-3 and > 3 BMs, and males and females, respectively (HRs interaction, P > 0.05 for each subgroup comparison).
CONCLUSIONS
First-line treatment with upfront brain RT plus EGFR-TKIs is likely to be more effective than EGFR-TKIs alone. The benefits of combination therapy did not appear to be significantly affected by BM-related symptoms, EGFR mutation subtype, number of BMs, or sex.
Topics: Female; Humans; Male; Brain; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 37904083
DOI: 10.1186/s12885-023-11548-0 -
Pharmaceutics Oct 2023The clinical outcomes of antiretroviral drugs may be modified through drug interactions; thus, it is important to update the drug interactions in people living with HIV... (Review)
Review
BACKGROUND
The clinical outcomes of antiretroviral drugs may be modified through drug interactions; thus, it is important to update the drug interactions in people living with HIV (PLHIV).
AIM
To update clinically relevant drug interactions in PLHIV on antiretroviral therapy with novel drug interactions published from 2017 to 2022.
METHODS
A systematic review in Medline/PubMed database from July 2017 to December 2022 using the Mesh terms antiretroviral agents and drug interactions or herb-drug interactions or food-drug interactions. Publications with drug interactions in humans, in English or Spanish, and with full-text access were retrieved. The clinical relevance of drug interactions was grouped into five levels according to the gravity and probability of occurrence.
RESULTS
A total of 366 articles were identified, with 219 (including 87 citation lists) were included, which allowed for the identification of 471 drug interaction pairs; among them, 291 were systematically reported for the first time. In total 42 (14.4%) and 137 (47.1%) were level one and two, respectively, and 233 (80.1%) pairs were explained with the pharmacokinetic mechanism. Among these 291 pairs, protease inhibitors (PIs) and ritonavir/cobicistat-boosted PIs, as well as integrase strand transfer inhibitors (InSTIs), with 70 (24.1%) and 65 (22.3%) drug interaction pairs of levels one and two, respectively, were more frequent.
CONCLUSIONS
In PLHIV on antiretroviral therapy, we identify 291 drug interaction pairs systematically reported for the first time, with 179 (61.5%) being assessed as clinically relevant (levels one and two). The pharmacokinetic mechanism was the most frequently identified. PIs, ritonavir/cobicistat-boosted PIs, and InSTIs were the antiretroviral groups with the highest number of clinically relevant drug interaction pairs (levels one and two).
PubMed: 37896248
DOI: 10.3390/pharmaceutics15102488 -
Exploratory Research in Clinical and... Dec 2023Type 2 diabetes mellitus (T2DM) is one of the non-communicable diseases which continues to rise in prevalence and mortality rate throughout the years. Drug-related... (Review)
Review
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is one of the non-communicable diseases which continues to rise in prevalence and mortality rate throughout the years. Drug-related problems (DRPs) are more prevalent among T2DM patients especially those with co-morbidities.
OBJECTIVE
The objective of this study was to review and assess the prevalence and characteristics of DRPs among hospitalized type 2 diabetes mellitus patients.
METHODS
The systematic review of the literature was carried out using five online databases: PubMed, Scopus, Google Scholar, Web of Science, and Cochrane Library from the inception of the database until June 2022. Studies included in the review were published in English or Malay language. The data were extracted and assessed using the Joanna Briggs Institute (JBI) critical appraisal tools.
RESULTS
A total of 939 studies were identified with 20 studies that met inclusion criteria and were included in this systematic review. The overall prevalence of DRPs in all 20 studies ranged from 7% to 94%. The most common DRPs included drug-drug interaction (DDI), adverse drug reaction (ADR), therapeutic effectiveness problems, and inappropriate medication use.
CONCLUSION
The most common drug classes involved were antidiabetics (metformin), antihypertensives, antiplatelets and antibiotics. The risk factors contributing to DRPs included the presence of comorbidities, the number of medications, and polypharmacy. To conclude, the rate of DRPs incidence in hospitalized T2DM patients was observed to be high. Further future studies with appropriate study designs and methods of detecting DRPs will be necessary to reduce and prevent DRPs occurrences.
PubMed: 37885436
DOI: 10.1016/j.rcsop.2023.100348 -
Journal of Medical Internet Research Oct 2023Reddit's (Reddit Inc) large user base, diverse communities, and anonymity make it a useful platform for substance use research. Despite a growing body of literature on... (Review)
Review
BACKGROUND
Reddit's (Reddit Inc) large user base, diverse communities, and anonymity make it a useful platform for substance use research. Despite a growing body of literature on substance use on Reddit, challenges and limitations must be carefully considered. However, no systematic scoping review has been conducted on the use of Reddit as a data source for substance use research.
OBJECTIVE
This review aims to investigate the use of Reddit for studying substance use by examining previous studies' objectives, reasons, limitations, and methods for using Reddit. In addition, we discuss the implications and contributions of previous studies and identify gaps in the literature that require further attention.
METHODS
A total of 7 databases were searched using keyword combinations including Reddit and substance-related keywords in April 2022. The initial search resulted in 456 articles, and 227 articles remained after removing duplicates. All included studies were peer reviewed, empirical, available in full text, and pertinent to Reddit and substance use, and they were all written in English. After screening, 60 articles met the eligibility criteria for the review, with 57 articles identified from the initial database search and 3 from the ancestry search. A codebook was developed, and qualitative content analysis was performed to extract relevant evidence related to the research questions.
RESULTS
The use of Reddit for studying substance use has grown steadily since 2015, with a sharp increase in 2021. The primary objective was to identify tendencies and patterns in various types of substance use discussions (52/60, 87%). Reddit was also used to explore unique user experiences, propose methodologies, investigate user interactions, and develop interventions. A total of 9 reasons for using Reddit to study substance use were identified, such as the platform's anonymity, its widespread popularity, and the explicit topics of subreddits. However, 7 limitations were noted, including the platform's low representativeness of the general population with substance use and the lack of demographic information. Most studies use application programming interfaces for data collection and quantitative approaches for analysis, with few using qualitative approaches. Machine learning algorithms are commonly used for natural language processing tasks. The theoretical, methodological, and practical implications and contributions of the included articles are summarized and discussed. The most prevalent practical implications are investigating prevailing topics in Reddit discussions, providing recommendations for clinical practices and policies, and comparing Reddit discussions on substance use across various sources.
CONCLUSIONS
This systematic scoping review provides an overview of Reddit's use as a data source for substance use research. Although the limitations of Reddit data must be considered, analyzing them can be useful for understanding patterns and user experiences related to substance use. Our review also highlights gaps in the literature and suggests avenues for future research.
Topics: Humans; Algorithms; Data Collection; Databases, Factual; Language; Substance-Related Disorders
PubMed: 37878361
DOI: 10.2196/48905 -
Frontiers in Medicine 2023The core idea behind precision medicine is to pinpoint the subpopulations that differ from one another in terms of disease risk, drug responsiveness, and treatment...
The core idea behind precision medicine is to pinpoint the subpopulations that differ from one another in terms of disease risk, drug responsiveness, and treatment outcomes due to differences in biology and other traits. Biomarkers are found through genomic sequencing. Multi-dimensional clinical and biological data are created using these biomarkers. Better analytic methods are needed for these multidimensional data, which can be accomplished by using artificial intelligence (AI). An updated review of 80 latest original publications is presented on four main fronts-preventive medicine, medication development, treatment outcomes, and diagnostic medicine-All these studies effectively illustrated the significance of AI in precision medicine. Artificial intelligence (AI) has revolutionized precision medicine by swiftly analyzing vast amounts of data to provide tailored treatments and predictive diagnostics. Through machine learning algorithms and high-resolution imaging, AI assists in precise diagnoses and early disease detection. AI's ability to decode complex biological factors aids in identifying novel therapeutic targets, allowing personalized interventions and optimizing treatment outcomes. Furthermore, AI accelerates drug discovery by navigating chemical structures and predicting drug-target interactions, expediting the development of life-saving medications. With its unrivaled capacity to comprehend and interpret data, AI stands as an invaluable tool in the pursuit of enhanced patient care and improved health outcomes. It's evident that AI can open a new horizon for precision medicine by translating complex data into actionable information. To get better results in this regard and to fully exploit the great potential of AI, further research is required on this pressing subject.
PubMed: 37849490
DOI: 10.3389/fmed.2023.1227168 -
JAMA Oct 2023There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension. (Comparative Study)
Comparative Study Meta-Analysis
IMPORTANCE
There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension.
OBJECTIVE
To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension.
DATA SOURCES
Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022.
STUDY SELECTION
Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments.
DATA EXTRACTION AND SYNTHESIS
Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach.
MAIN OUTCOMES AND MEASURES
Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less.
RESULTS
The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension (P = .16 for interaction of treatment with baseline standing hypotension).
CONCLUSIONS AND RELEVANCE
In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.
Topics: Aged; Female; Humans; Male; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Hypertension; Hypotension, Orthostatic; Middle Aged
PubMed: 37847274
DOI: 10.1001/jama.2023.18497 -
The World Allergy Organization Journal Sep 2023Beta-lactams (BLs) are the most prescribed antibiotics, being the most frequent cause of drug allergy. However, the association between BL allergy and genetic variations...
IMPORTANCE
Beta-lactams (BLs) are the most prescribed antibiotics, being the most frequent cause of drug allergy. However, the association between BL allergy and genetic variations is still unclear.
OBJECTIVE
This systematic review and meta-analysis aimed to summarize the genetic effects of BL-induced hypersensitivity using existing evidence.
METHODS
We searched PubMed, Medline, Scopus, EMBASE, CINAHL, and Cochrane Library from inception to September 15, 2022 with no language restriction. Genetic association studies investigating genetic variant/polymorphism and risk of drug-induced hypersensitivity reactions among individuals receiving BL-antibiotics were included. We excluded studies of acute interstitial nephritis, drug-induced liver injury, serum sickness, and isolated drug fever. Data were comprehensively synthesized and quality of study were assessed using STrengthening the Reporting of Genetic Association Studies (STREGA). The record screening, extraction and quality assessment were performed by two reviewers and discussions were made to resolve discrepancies. The effects of each variant were pooled and evaluated by modified Venice criteria.
RESULTS
A total of 9276 records were identified, and 31 studies were eligible for inclusion. Twenty-seven were candidate-gene association studies (5416 cases and 5939 controls), while the others were next-generation sequencing (NGS) or genome-wide association studies (GWASs) (119 838 cases and 1 487 111 controls). Forty-nine polymorphisms were identified and most of them located in allergic reaction pathways. Meta-analyses of 15 candidate variants in a mixture of both immediate and non-immediate reactions revealed weak genetic effects of rs1801275 (8 studies; n = 1,560; odd ratio 0.73; 95%CI: 0.57-0.93) and rs20541 (4 studies; n = 1,482; odd ratio 1.34; 95%CI: 1.07-1.68) in and , respectively. Results from GWASs and NGS identified, and confirmed associations in HLA regions including and .
CONCLUSION
Our study summarized genetic evidence influencing BL-induced hypersensitivity and estimated effects of potential variants. We postulated that the genomic studies provide better insights to the mechanism of reactions and suggest potential effects of HLA Class II variants. However, results were inconsistent and unable to generalize in different settings. Further high-throughput studies with a well-defined function, epigenetic interaction, incorporated with clinical factors, would be beneficial for risk identification in BL-induced hypersensitivity.
PubMed: 37780578
DOI: 10.1016/j.waojou.2023.100816 -
Antibiotics (Basel, Switzerland) Sep 2023Cephalexin is a first-generation β-lactam antibiotic used in adults and pediatrics to treat various streptococcal and staphylococcal infections. This review aims to... (Review)
Review
Cephalexin is a first-generation β-lactam antibiotic used in adults and pediatrics to treat various streptococcal and staphylococcal infections. This review aims to summarize and evaluate all the pharmacokinetic (PK) data on cephalexin by screening out all pertinent studies in human beings following the per oral (PO) route. By employing different online search engines such as Google Scholar, PubMed, Cochrane Central, and Science Direct, 23 studies were retrieved, among which nine were in healthy subjects, five in diseased ones, and the remaining were drug-drug, drug-food, and bioequivalence-related. These studies were included only based on the presence of plasma concentration-time profiles or PK parameters, i.e., maximum plasma concentration (C), half-life (t) area under the curve from time 0-infinity (AUC and clearance (CL/F). A dose-proportional increase in AUC and C can be portrayed in different studies conducted in the healthy population. In comparison to cefaclor, C was recorded to be 0.5 folds higher for cephalexin in the case of renal impairment. An increase in AUC was seen in cephalexin on administration with probenecid, i.e., 117 µg.h/mL vs. 68.1 µg.h/mL. Moreover, drug-drug interactions with omeprazole, ranitidine, zinc sulfate, and drug-food interactions for cephalexin and other cephalosporins have also been depicted in different studies with significant changes in all PK parameters. This current review has reported all accessible studies containing PK variables in healthy and diseased populations (renal, dental, and osteoarticular infections, continuous ambulatory peritoneal dialysis) that may be favorable for health practitioners in optimizing doses among the latter.
PubMed: 37760698
DOI: 10.3390/antibiotics12091402