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Pharmacogenomics and Personalized... 2022Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in... (Review)
Review
BACKGROUND
Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics.
METHOD
We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction.
RESULTS
The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters rs4149032, rs2306283, rs11045819, and rs1045642 for rifampicin, drug metabolizing enzyme rs1803155 for rifapentine and for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients.
CONCLUSION
The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.
PubMed: 35693129
DOI: 10.2147/PGPM.S363058 -
Therapeutic Advances in Drug Safety 2021Coronavirus disease 2019 (COVID-19) has been observed to cause a high mortality in people with cardiometabolic diseases. Renin-angiotensin-aldosterone system (RAAS)...
BACKGROUND AND AIMS
Coronavirus disease 2019 (COVID-19) has been observed to cause a high mortality in people with cardiometabolic diseases. Renin-angiotensin-aldosterone system (RAAS) blockers enhance the expression of ACE2, the binding receptor of SARS-CoV-2, and can enhance viral infectivity. We aim to provide a pooled estimate of the effect of RAAS blockers on COVID-19 outcomes.
METHODS
A literature search was performed using MEDLINE/PubMed, Google Scholar and preprint servers. All clinical studies analyzing the effect of RAAS blockers on clinical outcomes in COVID-19 patients were included in this study. Newcastle-Ottawa scale was used for quality assessment of studies. MOOSE checklist was followed. Mortality and severity outcomes were recorded as pooled odds ratio (OR) with 95% Confidence Intervals (CIs) and level of heterogeneity ( ). Odds of mortality was the primary outcome. Odds of severity, hospitalization, intensive care unit (ICU) admission, mechanical ventilation (MV), steroid use and acute kidney injury were the secondary outcomes. Severity outcomes were chosen depending upon the definition used by respective authors. Country-specific variations and effects of individual class of RAAS blockers were also explored.
RESULTS
In total 47 published studies were included in the final analysis, with a total of 26,432 patients from 31 studies in mortality analysis and 20,127 patients from 23 studies in severity analysis. No increased risk of mortality [Pooled OR 0.91 (0.65-1.26), = 89%] or severity [Pooled OR 1.08 (0.79-1.46), = 88%] was seen with RAAS blockers. The drug class was protective in hypertension [pooled OR 0.63 (0.46-0.86), = 58%]. Severity of COVID-19 outcomes was high for Europeans [Pooled OR 2.08 (1.52-2.85), = 77%] and US patients [Pooled OR 1.87 (1.62-2.17)]. Nearly 4 times higher risk of hospitalization and 2 times higher risk of ICU admission and MV were observed in US patients. Class-wise, angiotensin receptor blocker use was associated with 1.6 times higher odds of severity, mainly in Europeans.
CONCLUSION
RAAS blockers are not associated with increased mortality in COVID-19 patients and should be continued in hypertensives. US and European patients are at higher risk of severe outcomes. Pharmacogenetic differences may explain the ethnicity-related variations.
PLAIN LANGUAGE SUMMARY
Higher deaths have been observed in COVID-19 patients who have other long-term diseases such as heart disease, diabetes, and high blood pressure. Many of these patients are prescribed a class of medicines called RAAS blockers (ramipril, telmisartan, etc). We studied whether the use of these medicines worsens the course of COVID-19 disease in these patients or causes excess deaths. We conducted a pooled analysis of 47 observational studies on the use of RAAS blocker drugs in COVID-19 patients. We found that RAAS blockers do not cause excess deaths in patients with COVID-19. On the contrary, they have benefits if prescribed to those with high blood pressure. We also found that whereas European and US patients of COVID-19 taking these medicines had higher disease severity, this was not the case for Chinese patients. Theremay be some genetic and other factors responsible for differences by ethnicity.
PubMed: 34035891
DOI: 10.1177/20420986211011345 -
International Journal of Molecular... Nov 2021The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic... (Review)
Review
The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.
Topics: Animals; Antineoplastic Agents; Biomarkers; Cisplatin; Humans; Kidney Diseases; MicroRNAs; Neoplasms
PubMed: 34884570
DOI: 10.3390/ijms222312765 -
Research in Social & Administrative... Nov 2023The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare... (Review)
Review
BACKGROUND
The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare professionals is the most frequently cited barrier to adopting and implementing pharmacogenomics in clinical settings.
OBJECTIVES
This study aimed to critically evaluate and determine the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice.
METHODS
Four electronic databases were searched: MEDLINE, EMBASE, CENTRAL, and PsycINFO. Studies on pharmacogenomics educational interventions for health care professionals and students with pre- and post-intervention assessments and results were included. No restrictions were placed on time, language, or educational contexts. The educational outcomes measured include both objective and subjective outcomes. The pharmacogenomics competency domains used to judge educational interventions are based on the competency domains listed by the American Association of Colleges of Pharmacies (AACP). The National Heart, Lung, and Blood Institute of the National Institutes of Health was used for the quality assessment of pre-post studies with no control group and the controlled intervention studies. No meta-analysis was conducted; the data were synthesized qualitatively. The systematic review was reported in accordance with the PRISMA statement.
RESULTS
Fifty studies were included in this review. All included studies integrated the AACP pharmacogenomics competency domains into their educational interventions. Most of the studies had educational interventions that integrated clinical cases (n = 44; 88%). Knowledge was the most frequently evaluated outcome (n = 34; 68%) and demonstrated significant improvement after the educational intervention that integrated AACP pharmacogenomics competency domains and employed active learning with clinical case inclusion.
CONCLUSION
This review provided evidence of the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice. Incorporating pharmacogenomics competency domains into education and training, with patient cases for healthcare professionals and students, dramatically improved their pharmacogenomics knowledge, attitudes, and confidence in practice.
Topics: Humans; Pharmacogenetics; Students; Health Personnel; Educational Status; Delivery of Health Care
PubMed: 37586945
DOI: 10.1016/j.sapharm.2023.07.012 -
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 -
Antioxidants (Basel, Switzerland) Aug 2022The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease's progression is not entirely understood, but... (Review)
Review
The coronavirus disease (COVID-19) pandemic is a leading global health and economic challenge. What defines the disease's progression is not entirely understood, but there are strong indications that oxidative stress and the defense against reactive oxygen species are crucial players. A big influx of immune cells to the site of infection is marked by the increase in reactive oxygen and nitrogen species. Our article aims to highlight the critical role of oxidative stress in the emergence and severity of COVID-19 and, more importantly, to shed light on the underlying molecular and genetic mechanisms. We have reviewed the available literature and clinical trials to extract the relevant genetic variants within the oxidative stress pathway associated with COVID-19 and the anti-oxidative therapies currently evaluated in the clinical trials for COVID-19 treatment, in particular clinical trials on glutathione and N-acetylcysteine.
PubMed: 36009328
DOI: 10.3390/antiox11081609 -
Biomedicine & Pharmacotherapy =... Aug 2023Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease, but it is one of the most common inflammatory neuropathies in the population. It is... (Review)
Review
BACKGROUND
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease, but it is one of the most common inflammatory neuropathies in the population. It is particularly common among patients with diabetes mellitus. This raises many problems, both with the differential diagnosis of diabetic and inflammatory neuropathy, as well as the choice of treatment. Intravenous immunoglobulin (IVIG) is one of the therapeutic options. There is evidence for the effectiveness of IVIG in treating about two-thirds of patients. However, no review has been published to date systematising studies evaluating the response to IVIG treatment in patients with CIDP and coexisting diabetes.
METHODS
The present study is based on the PRISMA statement and is registered at PROSPERO (CRD42022356180). The study included searches of the databases of MEDLINE, ERIC, CINAHL Complete, Academic Search Ultimate and Health Source: Nursing/Academic Edition, finally including seven original papers evaluating a total of 534 patients in the review. The main inclusion criteria were the presence of a group of patients with CIDP and comorbid diabetes in the study.
RESULTS
The systematic review showed a lower efficacy of IVIG treatment among patients with coexisting diabetes compared with idiopathic CIDP (61 % vs 71 %). In addition, the presence of conduction blocks on neurography and shorter disease duration proved to be significant factors improving response to treatment.
CONCLUSIONS
Current scientific data do not allow for strong recommendations on the choice of treatment for CIDP. A randomised, multicentre study evaluating the efficacy of different therapeutic approaches to this disease entity needs to be planned.
Topics: Humans; Immunoglobulins, Intravenous; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Infusions, Intravenous; Administration, Intravenous; Diabetes Mellitus; Multicenter Studies as Topic
PubMed: 37290187
DOI: 10.1016/j.biopha.2023.114974 -
British Journal of Cancer Jul 2022Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD)... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.
BACKGROUND
Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant allele carriers versus wild type).
METHODS
A systematic review/meta-analysis of original publications indexed in Ovid Medline, Ovid Embase, and the Cochrane CENTRAL (Wiley) library from inception to 7-Dec-2020. Eligible studies evaluated at least one pre-defined treatment outcome measures (toxicity/hospitalisations/survival/overall response/quality of life).
RESULTS
Of 1090 identified publications, 17 met predefined eligibility criteria. The meta-analysis observed reduced incidence of grade 3/4 overall toxicity (Risk Ratio [RR] 0.32 [95% Cl 0.27-0.39], p < 0.00001) and grade 3/4 diarrhoea (RR 0.38 [95% Cl 0.24-0.61], p < 0.0001) among PGD versus non-PGD cohorts. Within PGD cohorts, there was no statistical differences for overall response rates (complete/partial) (RR 1.31 [95% Cl 0.93-1.85], p = 0.12). Similar results were found with stable disease (RR 1.27 [95% Cl 0.66-2.44], p = 0.47).
CONCLUSION
PGD improves patient outcomes in terms of grade 3/4 toxicity, in particular overall toxicity and diarrhoea, without impacting on treatment response.
REGISTRATION NUMBER
The study is registered with PROSPERO, registration number CRD42020223768.
Topics: Capecitabine; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Fluorouracil; Humans; Pharmacogenetics; Quality of Life; Standard of Care; Treatment Outcome
PubMed: 35306539
DOI: 10.1038/s41416-022-01779-6 -
International Journal of Molecular... Feb 2022Mesothelioma is a rare tumor, frequently associated with asbestos exposure, arising from pleura and peritoneum. Traditionally, diagnosis and treatment have been...
Mesothelioma is a rare tumor, frequently associated with asbestos exposure, arising from pleura and peritoneum. Traditionally, diagnosis and treatment have been difficult in a clinical setting. The treatment is based on a trimodal approach involving surgery, chemotherapy, and radiotherapy. The introduction of chemotherapy improved the overall survival. However, the regimen of pemetrexed/cisplatin doublet has not been changed as a standard treatment since 2004. Novel combinations of ipilimumab and nivolumab have only been approved for clinical use in late 2020. The aim of this review was to systematically summarize findings on novel treatment options in mesothelioma. We searched available medical databases online, such as PubMed and Clinicaltrials.gov, to systematically review the literature on novel approaches in immunotherapy, vaccines, and Chimeric Antigen Receptor (CAR)-T cell therapy in mesothelioma. We manually screened 1127 articles on PubMed and 450 trials on ClinicalTrials.gov, and 24 papers and 12 clinical trials published in the last ten years were included in this review. Immunotherapy that was swiftly introduced to treat other thoracic malignancies was slow to reach desirable survival endpoints in mesothelioma, possibly due to limited patient numbers. Novel treatment approaches, such as CAR-T cell therapy, are being investigated. As the incidence of mesothelioma is still rising globally, novel treatment options based on a better understanding of the tumor microenvironment and the genetic drivers that modulate it are needed to support future precision-based therapies.
Topics: Animals; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Humans; Immunotherapy; Mesothelioma; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 35216091
DOI: 10.3390/ijms23041975 -
Journal of Clinical Medicine Jul 2020(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome...
(1) Background: The use of corticosteroids in critical coronavirus infections, including severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS), or Coronavirus disease 2019 (COVID-19), has been controversial. However, a meta-analysis on the efficacy of steroids in treating these coronavirus infections is lacking. (2) Purpose: We assessed a methodological criticism on the quality of previous published meta-analyses and the risk of misleading conclusions with important therapeutic consequences. We also examined the evidence of the efficacy of corticosteroids in reducing mortality in SARS, MERS and COVID-19. (3) Methods: PubMed, MEDLINE, Embase, and Web of Science were used to identify studies published until 25 April 2020, that reported associations between steroid use and mortality in treating SARS/MERS/COVID-19. Two investigators screened and extracted data independently. Searches were restricted to studies on humans, and articles that did not report the exact number of patients in each group or data on mortality were excluded. We calculated odds ratios (ORs) or hazard ratios (HRs) under the fixed- and random-effect model. (4) Results: Eight articles (4051 patients) were eligible for inclusion. Among these selected studies, 3416 patients were diagnosed with SARS, 360 patients with MERS, and 275 with COVID-19; 60.3% patients were administered steroids. The meta-analyses including all studies showed no differences overall in terms of mortality (OR 1.152, 95% CI 0.631-2.101 in the random effects model, = 0.645). However, this conclusion might be biased, because, in some studies, the patients in the steroid group had more severe symptoms than those in the control group. In contrast, when the meta-analysis was performed restricting only to studies that used appropriate adjustment (e.g., time, disease severity), there was a significant difference between the two groups (HR 0.378, 95% CI 0.221-0.646 in the random effects model, < 0.0001). Although there was no difference in mortality when steroids were used in severe cases, there was a difference among the group with more underlying diseases (OR 3.133, 95% CI 1.670-5.877, < 0.001). (5) Conclusions: To our knowledge, this study is the first comprehensive systematic review and meta-analysis providing the most accurate evidence on the effect of steroids in coronavirus infections. If not contraindicated, and in the absence of side effects, the use of steroids should be considered in coronavirus infection including COVID-19.
PubMed: 32726951
DOI: 10.3390/jcm9082392