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Therapeutic Advances in Cardiovascular... 2024Atrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran,... (Review)
Review
Atrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that have been proven to prevent stroke in patients with non-valvular AF. This review summarizes the pharmacokinetics, pharmacodynamics, and drug interactions of DOACs, as well as new data from pharmacogenetic studies of these drugs. This review is aimed at analyzing the scientific literature on the gene polymorphisms involved in the metabolism of DOACs. We searched PubMed, Cochrane, Google Scholar, and CyberLeninka (Russian version) databases with keywords: 'dabigatran', 'apixaban', 'rivaroxaban', 'edoxaban', 'gene polymorphism', 'pharmacogenetics', '', '', '', '', and ''. The articles referred for this review include (1) full-text articles; (2) study design with meta-analysis, an observational study in patients taking DOAC; and (3) data on the single-nucleotide polymorphisms and kinetic parameters of DOACs (plasma concentration), or a particular clinical outcome, published in English and Russian languages during the last 10 years. The ages of the patients ranged from 18 to 75 years. Out of 114 reviewed works, 24 were found eligible. As per the available pharmacogenomic data, polymorphisms affecting DOACs are different. This may aid in developing individual approaches to optimize DOAC pharmacotherapy to reduce the risk of hemorrhagic complications. However, large-scale population studies are required to determine the dosage of the new oral anticoagulants based on genotyping. Information on the genetic effects is limited owing to the lack of large-scale studies. Uncovering the mechanisms of the genetic basis of sensitivity to DOACs helps in developing personalized therapy based on patient-specific genetic variants and improves the efficacy and safety of DOACs in the general population.
Topics: Humans; Atrial Fibrillation; Administration, Oral; Hemorrhage; Pharmacogenomic Variants; Risk Factors; Anticoagulants; Treatment Outcome; Stroke; Risk Assessment; Phenotype; Polymorphism, Single Nucleotide; Vitamin K; Drug Interactions
PubMed: 38801157
DOI: 10.1177/17539447241249886 -
Frontiers in Immunology 2024Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors...
BACKGROUND
Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.
CASE PRESENTATION
We report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.
CONCLUSION
Efficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.
Topics: Humans; Male; Melanoma; Middle Aged; Immune Checkpoint Inhibitors; Immunotherapy; Skin Neoplasms; CTLA-4 Antigen; Treatment Outcome; Programmed Cell Death 1 Receptor
PubMed: 38799429
DOI: 10.3389/fimmu.2024.1369531 -
BMC Psychiatry May 2024Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or...
BACKGROUND
Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses.
METHODS
Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses.
RESULTS
No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects.
CONCLUSIONS
We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.
Topics: Humans; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2C19; Male; Antidepressive Agents; Female; Middle Aged; Adult; Longitudinal Studies; Netherlands; Anxiety Disorders; Depressive Disorder
PubMed: 38797832
DOI: 10.1186/s12888-024-05764-6 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Polypharmacy is a global healthcare concern, especially among the elderly, leading to drug interactions and adverse reactions, which are significant causes of death in...
Polypharmacy is a global healthcare concern, especially among the elderly, leading to drug interactions and adverse reactions, which are significant causes of death in developed nations. However, the integration of pharmacogenetics can help mitigate these risks. In this study, the data from 483 patients, primarily elderly and polymedicated, were analyzed using Eugenomic's personalized prescription software, g-Nomic. The most prescribed drug classes included antihypertensives, platelet aggregation inhibitors, cholesterol-lowering drugs, and gastroprotective medications. Drug-lifestyle interactions primarily involved inhibitions but also included inductions. Interactions were analyzed considering gender. Significant genetic variants identified in the study encompassed , and . To prevent adverse reactions and enhance medication effectiveness, it is strongly recommended to consider pharmacogenetics testing. This approach shows great promise in optimizing medication regimens and ultimately improving patient outcomes.
PubMed: 38794134
DOI: 10.3390/ph17050565 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been...
Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including * and 22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The genotype and a low Tac trough concentration/dose ratio (Tac C/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C/dose ratio ≤ 1.5 ng/mL/mg), assessing genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers ( or genotypes). CYP3A5 expressers had lower C at 48 h (3.7 vs. 6.2 ng/mL, = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.
PubMed: 38794124
DOI: 10.3390/ph17050553 -
Journal of Personalized Medicine Apr 2024The causal effect and pathways of gut microbiota and plasma metabolome on lung cancer have been important topics for personalized medicine; however, the heterogeneity of...
The causal effect and pathways of gut microbiota and plasma metabolome on lung cancer have been important topics for personalized medicine; however, the heterogeneity of lung cancer subtypes has not gained enough attention in previous studies. This study sought to employ a Mendelian randomization analysis to screen the specific gut microbiota and plasma metabolome, which may have a causal effect on lung cancer. We further extended our analysis to estimate the effects of these exposures on various pathological subtypes of lung cancer. Furthermore, a mediation analysis was performed to identify the potential pathway underlying the influence of microbiota and metabolites. Our study identified 13 taxa and 15 metabolites with a causal association with the overall risk of lung cancer. Furthermore, we found 8 taxa and 14 plasma metabolites with a causal effect on lung adenocarcinoma, 4 taxa and 10 metabolites with a causal effect on squamous cell lung carcinoma, and 7 taxa and 16 metabolites with a causal effect on SCLC. We also identified seven mediation pathways that could potentially elucidate the influence of these microbiota and metabolites on overall lung cancer or special subtypes. Our study highlighted the heterogeneity of the gut microbiome and plasma metabolome in a lung cancer subtype and elucidated the potential underlying mechanisms. This could pave the way for more personalized lung cancer prevention and treatment.
PubMed: 38793035
DOI: 10.3390/jpm14050453 -
Journal of Clinical Medicine May 2024: The balance between regulatory and Th17 cells plays an important role in maintaining the immune tolerance after kidney transplantation (KTx) which is essential for...
: The balance between regulatory and Th17 cells plays an important role in maintaining the immune tolerance after kidney transplantation (KTx) which is essential for transplantation success, defined as a long graft survival and an absence of organ rejection. The present study aimed to assess whether the pretransplant characteristics of IL-17A and IL-17F, their receptors, as well as miR-146a-5p, an miRNA associated with IL-17A/F regulation, can predict KTx outcomes. : A group of 108 pre-KTx dialysis patients and 125 healthy controls were investigated for single nucleotide substitutions within genes coding for , , their / receptors, and . Genotyping was performed using LightSNiP assays. In addition, IL17-A/F serum concentrations were determined using ELISA while miR-146a-5p expression was analyzed by RT-PCR. : The (rs763780) allele prevailed in KTx recipients as compared to healthy individuals (OR = 23.59, < 0.0001) and was associated with a higher IL-17F serum level ( = 0.0381) prior to transplantation. Higher miR-146a-5p expression before KTx was more frequently detected in recipients with an increased IL-17A serum concentration ( = 0.0177). Moreover, (rs2275913) homozygosity was found to be associated with an increased incidence of deaths before KTx (OR = 4.17, = 0.0307). T-cell or acute rejection episodes were more frequently observed among patients with the allele of (rs2910164) (OR = 5.38, = 0.0531). genetic variants ( < 0.05) seem to be associated with eGFR values. : These results imply that (rs763780) polymorphism is associated with the serum level of this cytokine and may be related to the risk of renal disease and transplant rejection together with (rs2910164), while the (rs2275913) genotype may affect patients' survival before KTx.
PubMed: 38792460
DOI: 10.3390/jcm13102920 -
International Journal of Molecular... May 2024The most common type of periodontal disease is chronic periodontitis, an inflammatory condition caused by pathogenic bacteria in subgingival plaque. The aim of our study...
The most common type of periodontal disease is chronic periodontitis, an inflammatory condition caused by pathogenic bacteria in subgingival plaque. The aim of our study was the development of a real-time PCR test as a diagnostic tool for the detection and differentiation of five periodontopathogenic bacteria, , , , , and , in patients with periodontitis. We compared the results of our in-house method with the micro-IDent semiquantitative commercially available test based on the PCR hybridization method. DNA was isolated from subgingival plaque samples taken from 50 patients and then analyzed by both methods. Comparing the results of the two methods, they show a specificity of 100% for all bacteria. The sensitivity for was 97.5%, for 96.88%, and for 95.24%. The sensitivity for and was 100%. The Spearman correlation factor of two different measurements was 0.976 for , 0.967 for , 0.949 for , 0.966 for , and 0.917 for . In conclusion, the in-house real-time PCR method developed in our laboratory can provide information about relative amount of five bacterial species present in subgingival plaque in patients with periodontitis. It is likely that such a test could be used in dental diagnostics in assessing the efficacy of any treatment to reduce the bacterial burden.
Topics: Humans; Real-Time Polymerase Chain Reaction; Periodontitis; Porphyromonas gingivalis; Aggregatibacter actinomycetemcomitans; Treponema denticola; Male; Female; Tannerella forsythia; Sensitivity and Specificity; Prevotella intermedia; Middle Aged; Adult; DNA, Bacterial; Dental Plaque; Bacteria
PubMed: 38791137
DOI: 10.3390/ijms25105097 -
Biomedicines May 2024The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review... (Review)
Review
The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review demonstrated the variability in allelic frequencies of low-functioning and non-functional single nucleotide variants in genes encoding key isoenzymes of valproic acid P-oxidation in the liver across different ethnic/racial groups. The sensitivity and specificity of pharmacogenetic testing panels for predicting the rate of metabolism of valproic acid by P-oxidation can be increased by prioritizing the inclusion of the most common risk allele characteristic of a particular population (country).
PubMed: 38790997
DOI: 10.3390/biomedicines12051036 -
Antioxidants (Basel, Switzerland) Apr 2024Physical activity could increase the production of oxidative stress biomarkers, affecting the metabolism and excretion of antiretroviral drugs and, consequently, the...
BACKGROUND
Physical activity could increase the production of oxidative stress biomarkers, affecting the metabolism and excretion of antiretroviral drugs and, consequently, the clinical outcome. Nowadays, people living with HIV (PLWH) are mostly switching from triple to dual therapy, but no data are available in terms of physical functioning and oxidative stress. The aim of this study was to evaluate if some antioxidant biomarkers and physical functioning tests could be different according to triple or dual antiretroviral therapy.
METHODS
PLWH were evaluated at baseline (BL), while treated with three drugs, and six months after the switch to dual therapy. Physical functioning was quantified using validated tools. Mitochondrial and cytosol antioxidant molecules were evaluated through liquid chromatography.
RESULTS
Twenty-five patients were analyzed. A statistically significant difference between triple and dual therapy was found for mitochondrial glutathione, but not for physical tests. Evaluating differences between physically active and inactive individuals, the following statistically significant differences were suggested, considering triple therapy (mitochondrial n-formyl-methionine = 0.022, triglycerides = 0.023) and double therapy (mitochondrial glycine = 0.035, cytosol glutamic acid = 0.007, cytosol s-adenosylmethionine = 0.021).
CONCLUSIONS
For the first time, this study suggests possible differences in terms of antioxidant molecules and physical functioning in PLWH switching from triple to dual therapy.
PubMed: 38790623
DOI: 10.3390/antiox13050518