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The Journal of Antimicrobial... Jul 2024Aminoglycosides (AGs) are important antibiotics in the treatment of Gram-negative sepsis. However, they are associated with the risk of irreversible sensorineural...
BACKGROUND
Aminoglycosides (AGs) are important antibiotics in the treatment of Gram-negative sepsis. However, they are associated with the risk of irreversible sensorineural hearing loss (SNHL). Several genetic variants have been implicated in the development of ototoxicity.
OBJECTIVES
To evaluate the pharmacogenetic determinants of AG-related ototoxicity.
METHODS
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and was registered on Prospero (CRD42022337769). In Dec 2022, PubMed, Cochrane Library, Embase and MEDLINE were searched. Included studies were those reporting original data on the effect of the AG-exposed patient's genome on the development of ototoxicity.
RESULTS
Of 10 202 studies, 31 met the inclusion criteria. Twenty-nine studies focused on the mitochondrial genome, while two studied the nuclear genome. One study of neonates found that 30% of those with the m.1555A > G variant failed hearing screening after AG exposure (level 2 evidence). Seventeen additional studies found the m.1555A > G variant was associated with high penetrance (up to 100%) of SNHL after AG exposure (level 3-4 evidence). Nine studies of m.1494C > T found the penetrance of AG-related SNHL to be up to 40%; however, this variant was also identified in those with SNHL without AG exposure (level 3-4 evidence). The variants m.1005T > C and m.1095T > C may be associated with AG-related SNHL; however, further studies are needed.
CONCLUSIONS
This review found that the m.1555A > G and m.1494C > T variants in the MT-RNR1 gene have the strongest evidence in the development of AG-related SNHL, although study quality was limited (level 2-4). These variants were associated with high penetrance of a SNHL phenotype following AG exposure.
Topics: Humans; Aminoglycosides; Ototoxicity; Anti-Bacterial Agents; Pharmacogenetics; Hearing Loss, Sensorineural
PubMed: 38629462
DOI: 10.1093/jac/dkae106 -
International Journal of Molecular... Mar 2024Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.
Topics: Humans; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Biological Products; Biomarkers
PubMed: 38612528
DOI: 10.3390/ijms25073717 -
Heliyon Apr 2024Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene...
BACKGROUND
Coronary artery disease (CAD) is the most common reason for mortality and disability-adjusted life years (DALYs) lost globally. This study aimed to suggest a new gene list for the treatment of CAD by a systematic review of bioinformatics analyses of pharmacogenomics impacts of potential genes and variants.
METHODS
PubMed search was filtered by the title including Coronary Artery Disease during 2020-2023. To find the genes with pharmacogenetic impact on the CAD, additional filtrations were considered according to the variant annotations. Protein-Protein Interactions (PPIs), Gene-miRNA Interactions (GMIs), Protein-Drug Interactions (PDIs), and variant annotation assessments (VAAs) performed by STRING-MODEL (ver. 12), Cytoscape (ver. 3.10), miRTargetLink.2., NetworkAnalyst (ver 0.3.0), and PharmGKB.
RESULTS
Results revealed 5618 publications, 1290 papers were qualified, and finally, 650 papers were included. 4608 protein-coding genes were extracted, among them, 1432 unique genes were distinguished and 530 evidence-based repeated genes remained. 71 genes showed a pharmacogenetics-related variant annotation in at least (entirely 6331 annotations). Variant annotation assessment (VAA) showed 532 potential variants for the final report, and finally, the concluding PGs list represented 175 variants. Based on the function and MAF, 57 nonsynonymous variants of 29 Pharmacogenomics-related genes were associated with CAD.
CONCLUSION
Conclusively, evaluating circulating miR33a in individuals' plasma with CAD, and genotyping of rs2230806, rs2230808, rs2487032, rs12003906, rs2472507, rs2515629, and rs4149297 (ABCA1 variants) lead to precisely prescribing of well-known drugs. Also, the findings of this review can be used in both whole-genome sequencing (WGS) and whole-exome sequencing (WES) analysis in the prognosis and diagnosis of CAD.
PubMed: 38601677
DOI: 10.1016/j.heliyon.2024.e28983 -
Antioxidants (Basel, Switzerland) Feb 2024This systematic review extensively investigated the role of the genetic and transcriptomic factors in late complications of type 2 diabetes mellitus (T2DM) and the... (Review)
Review
This systematic review extensively investigated the role of the genetic and transcriptomic factors in late complications of type 2 diabetes mellitus (T2DM) and the current approaches targeting oxidative-stress-related pathways with antioxidant therapies. To cover our broad research area, we have conducted two systematic searches, the first focusing on genetic and transcriptomic factors affecting oxidative stress and the second one focusing on the antioxidant therapies in late complications of T2DM. The final review included 33 genetic and transcriptomic studies and 23 interventional randomized clinical trials. The conducted systematic review highlights the important role of oxidative stress in the development of late complications in T2DM patients. However, the current level of evidence does not support the use of genetic and transcriptomic factors as predictive and prognostic biomarkers for the development of T2DM late complications. Further studies are needed to elucidate the potential of targeting oxidative-stress-related pathways for novel preventative and therapeutic approaches. Additionally, antioxidants both in dietary and supplement form have been shown to improve different metabolic and biochemical parameters in T2DM patients with developed late complications. In recent years, studies have improved in methodological quality despite still mainly focusing on microvascular late complications of T2DM. Furthermore, the observed interventional studies suggest non-homogeneity in the duration of observation. As many studies do not provide post-intervention follow-up testing, it is difficult to assess the long-term health benefits of antioxidant supplementation.
PubMed: 38539811
DOI: 10.3390/antiox13030277 -
Cancers Feb 2024This study investigated the health economic evaluations of predictive biomarker testing in solid tumours treated with immune checkpoint inhibitors (ICIs). Searching... (Review)
Review
This study investigated the health economic evaluations of predictive biomarker testing in solid tumours treated with immune checkpoint inhibitors (ICIs). Searching PubMed, EMBASE, and Web of Science from June 2010 to February 2022, 58 relevant articles were reviewed out of the 730 screened. The focus was predominantly on non-small cell lung cancer (NSCLC) (65%) and other solid tumours (40%). Among the NSCLC studies, 21 out of 35 demonstrated cost-effectiveness, notably for pembrolizumab as first-line treatment when preceded by PD-L1 assessment, cost-effective at a threshold of $100,000/QALY compared to the standard of care. However, for bladder, cervical, and triple-negative breast cancers (TNBCs), no economic evaluations met the affordability threshold of $100,000/QALY. Overall, the review highlights a certain degree of uncertainty about the cost-effectiveness of ICI. In particular, we found PD-L1 expression associated with ICI treatment to be a cost-effective strategy, particularly in NSCLC, urothelial, and renal cell carcinoma. The findings suggest the potential value of predictive biomarker testing, specifically with pembrolizumab in NSCLC, while indicating challenges in achieving cost-effectiveness for certain other solid tumours.
PubMed: 38473355
DOI: 10.3390/cancers16050995 -
International Immunopharmacology Mar 2024Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a...
INTRODUCTION
Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors.
METHODS
We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP.
RESULTS
There were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69-7.87), avelumab (ROR 10.32, 95 % CI 4.91-21.69), durvalumab (ROR 7.91, 95 % CI 4.91-12.75), nivolumab (ROR 9.76, 95 % CI 8.34-11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55-15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP.
CONCLUSION
There is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.
Topics: United States; Humans; Nivolumab; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Purpura, Thrombocytopenic, Idiopathic; Pharmacovigilance; Retrospective Studies; Drug-Related Side Effects and Adverse Reactions; Thrombocytopenia
PubMed: 38359661
DOI: 10.1016/j.intimp.2024.111606 -
Farmacia Hospitalaria : Organo Oficial... Feb 2024Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is... (Review)
Review
INTRODUCTION
Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine.
MATERIALS AND METHODS
A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualizing dosing", "clinical routine", and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis.
RESULTS
49 articles were included for the final analysis following review by 2 investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNFα agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found.
CONCLUSION
The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.
PubMed: 38341366
DOI: 10.1016/j.farma.2023.12.004 -
European Neuropsychopharmacology : the... Apr 2024The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis... (Meta-Analysis)
Meta-Analysis
Current level of evidence for improvement of antidepressant efficacy and tolerability by pharmacogenomic-guided treatment: A Systematic review and meta-analysis of randomized controlled clinical trials.
The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.
Topics: Humans; Pharmacogenetics; Antidepressive Agents
PubMed: 38340605
DOI: 10.1016/j.euroneuro.2024.01.005 -
American Journal of Pharmaceutical... Mar 2024Poor knowledge and confidence in pharmacogenomics are key barriers to implementation. Education of future health care professionals is required to enhance appropriate... (Review)
Review
OBJECTIVES
Poor knowledge and confidence in pharmacogenomics are key barriers to implementation. Education of future health care professionals is required to enhance appropriate use of pharmacogenomics; however, the optimal education approach is unclear. This systematic scoping review evaluates pharmacogenomic educational interventions to improve knowledge and confidence.
FINDINGS
A total of 24 studies were included. Most (90%) studies delivered pharmacogenomic education to pharmacy students and consisted of didactic lectures and workshops with case studies. To supplement case studies, self or class aggregated (52%, 12 of 23), mock (43%, 10 of 23) or faculty member provided (4%, 1 of 23) pharmacogenomic data were used in the case scenarios. All studies used quantitative methods, including student assessments and scaled surveys to assess the impact of the educational intervention on knowledge and/or confidence in pharmacogenomics. On average, the educational interventions improved knowledge acquisition by 21%, confidence in pharmacogenomic data interpretation by 37%, confidence in communication of pharmacogenomic information to patients by 41% and to health care professionals by 44%. Improvement in communication with other health care professionals was greater in students involved in interprofessional learning compared to self-pharmacogenomic testing.
SUMMARY
The measures used to determine the effect of educational interventions on student knowledge and confidence varied. Innovative pedagogy, specifically interactive case-based learning and simulation such as interprofessional learning, enhances the knowledge and confidence of students in pharmacogenomics. Course-embedded self-pharmacogenomic testing may offer a supplementary, interactive component to case-based learning by using real-life reports as the foundation of knowledge and confidence acquisition.
Topics: Humans; Pharmacogenetics; Education, Pharmacy; Learning; Health Personnel; Students, Pharmacy
PubMed: 38331197
DOI: 10.1016/j.ajpe.2024.100668 -
Health Science Reports Jan 2024Pharmacists have been recognized as one of the most qualified healthcare professionals in the clinical implementation of pharmacogenomics, yet its widespread...
BACKGROUND AND AIMS
Pharmacists have been recognized as one of the most qualified healthcare professionals in the clinical implementation of pharmacogenomics, yet its widespread implementation in clinical pharmacy practice has remained limited. The review aims to systematically investigate knowledge, perceptions, and attitudes toward pharmacogenomics among pharmacists and pharmacy students to inform the future delivery of pharmacogenomics education programs.
METHODS
PubMed, MEDLINE, Embase, Scopus, and the International Pharmaceutical Abstracts were searched up to May 17, 2022. Studies were selected if they included data on pharmacists' or pharmacy students' knowledge, perception, or attitude about pharmacogenomics and were published in a peer-reviewed, English-language journal with full-text availability. Any published study not deemed original research was excluded. All included studies were critically appraised using the Center for Evidence-Based Management's critical appraisal tools. The data were descriptively analyzed and presented based on pharmacists' and pharmacy students' knowledge/awareness, perception/attitudes toward pharmacogenomic (PGx), confidence in using or interpreting PGx testing results, and their desire to get further PGx education or their most preferred method of further education.
RESULTS
A combined total of 12,430 pharmacists and pharmacy students from 26 countries are represented in the 52 included studies. Despite overwhelmingly positive attitudes and perceptions toward pharmacogenomics among pharmacists and pharmacy students, an overall lack of adequate knowledge and confidence was found. The review also found a strong desire for further pharmacogenomics education among pharmacists and pharmacy students.
CONCLUSION
Pharmacists and pharmacy students have positive perceptions and attitudes toward pharmacogenomics, which is hindered by a lack of knowledge and confidence. However, inadequate control for confounders, limited representativeness of the studied population or region, and small sample sizes diminish the generalizability of the review results. Knowledge and confidence could be improved through enhanced delivery of pharmacogenomic courses within the pharmacy curriculum and continuing education programs.
PubMed: 38274140
DOI: 10.1002/hsr2.1844