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Annals of the Academy of Medicine,... Mar 2024
Topics: Warfarin; Humans; Singapore; Algorithms; Anticoagulants; Pharmacogenetics; Male; International Normalized Ratio; Female; Cytochrome P-450 CYP2C9; Middle Aged; Aged; Vitamin K Epoxide Reductases
PubMed: 38920246
DOI: 10.47102/annals-acadmedsg.2023186 -
Current Neuropharmacology Jun 2024Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing...
BACKGROUND
Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype.
METHODS
An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded sample, we compared MnSOD activity in 159 TD, 227 non-TD and 280 healthy controls, as well as the allele frequencies and genotypes for the MnSOD Ala-9Val polymorphism in 352 TD, 486 non-TD and 1150 healthy controls.
RESULTS
EGb761 significantly reduced TD symptoms and increased MnSOD activity in TD patients compared to placebo (both p < 0.01). Moreover, we found an interaction between genotype and treatment response (p < 0.001). Furthermore, in the EGb761 group, patients carrying the Ala allele displayed a significantly lower AIMS total score than patients with the Val/Val genotype. In addition, MnSOD activity was significantly lower at baseline in TD patients compared with healthy controls or non-TD patients.
CONCLUSION
EGb761 treatment enhanced low MnSOD activity in TD patients and produced greater improvement in TD symptoms in patients with the Ala allele of the MnSOD Ala-9Val polymorphism.
PubMed: 38919004
DOI: 10.2174/1570159X22666240530095721 -
Critical Reviews in Oncology/hematology Jun 2024The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an... (Review)
Review
The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an unfavorable prognosis in patients affected by Acute Myeloid Leukemia (AML). In this setting, in recent years, new FLT3-inhibitors have demonstrated efficacy in improving survival and treatment response. Nevertheless, the development of primary and secondary mechanisms of resistance poses a significant obstacle to their efficacy. Understanding these mechanisms is crucial for developing novel therapeutic approaches to overcome resistance and improve the outcomes of patients. In this context, the use of novel FLT3 inhibitors and the combination of different targeted therapies have been studied. This review provides an update on the molecular alterations involved in FLT3 AML mechanisms of resistance, exploring how the molecular monitoring may be used to guide treatment strategy in FLT3-mutated AML.
PubMed: 38917943
DOI: 10.1016/j.critrevonc.2024.104424 -
Pharmacogenetics and Genomics Jun 2024This study aims to understand patient and healthcare provider perspectives on the integration and application of pharmacogenetics (PGx) testing in routine clinical...
OBJECTIVE
This study aims to understand patient and healthcare provider perspectives on the integration and application of pharmacogenetics (PGx) testing in routine clinical practice.
METHODS
Two anonymous online surveys were distributed globally for healthcare providers and patients respectively on the Qualtrics platform (version 3.24). The surveys were distributed through social platforms, email, and posters with QR codes from 27 October 2023 to 7 March 2024. The surveys evaluated participant familiarity with PGx, previous experience with PGx testing, perceived implementation challenges, and opinions on point-of-care (PoC) PGx testing devices.
RESULTS
This study collected 78 responses from healthcare providers and 98 responses from patients. The results revealed that 64% of healthcare providers had some level of familiarity with PGx, however, PGx testing in clinical practice was low. The primary challenges identified by healthcare providers included limited access to testing and lack of knowledge on PGx test interpretation. In contrast, 52% of patient respondents were aware of PGx testing, with a significant association between awareness and positive opinions toward PGx. Both healthcare providers and patients recognized the value of PoC PGx testing devices, with 98% of healthcare providers and 71% of patients believing PoC devices would improve the accessibility and implementation of PGx testing. Comparative analysis revealed a statistically significant difference in PGx awareness between healthcare providers and patients, with providers being more informed.
CONCLUSION
Improved PGx awareness, training, clinical guidelines, and PoC PGx testing devices may help promote the implementation of PGx-guided treatments in routine clinical practice.
PubMed: 38917295
DOI: 10.1097/FPC.0000000000000541 -
International Journal of... Apr 2024Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing...
BACKGROUND
Pharmacogenetic research has led to significant progress in understanding how genetic factors influence drug response in tuberculosis (TB) treatment. One ongoing challenge is the variable occurrence of adverse drug reactions in some TB patients. Previous studies have indicated that genetic variations in the N-acetyltransferase 2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes can impact the blood concentrations of the first-line anti-TB drugs isoniazid (INH) and rifampicin (RIF), respectively. This study aimed to investigate the influence of pharmacogenetic markers in the NAT2 and SLCO1B1 genes on TB treatment outcomes using whole-exome sequencing (WES) analysis.
METHODS
DNA samples were collected from 30 healthy Iranian adults aged 18-40 years. The allelic frequencies of single-nucleotide polymorphisms (SNPs) in the NAT2 and SLCO1B1 genes were determined through WES.
RESULTS
Seven frequent SNPs were identified in the NAT2 gene (rs1041983, rs1801280, rs1799929, rs1799930, rs1208, rs1799931, rs2552), along with 16 frequent SNPs in the SLCO1B1 gene (rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs2291075, rs201722521, rs11045852, rs11045854, rs756393362, rs11045859, rs74064211, rs201556175, rs34671512, rs71581985, rs4149085).
CONCLUSION
Genetic variations in NAT2 and SLCO1B1 can affect the metabolism of INH and RIF, respectively. A better understanding of the pharmacogenetic profile in the study population may facilitate the design of more personalized and effective TB treatment strategies. Further research is needed to directly correlate these genetic markers with clinical outcomes in TB patients.
Topics: Humans; Arylamine N-Acetyltransferase; Liver-Specific Organic Anion Transporter 1; Adult; Antitubercular Agents; Male; Young Adult; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Adolescent; Female; Isoniazid; Iran; Tuberculosis; Gene Frequency; Exome Sequencing; Pharmacogenomic Testing; Pharmacogenetics
PubMed: 38916393
DOI: 10.4103/ijmy.ijmy_106_24 -
Reumatismo Jun 2024To evaluate the association of the rs11125908 polymorphism in the COMMD1 gene in the Cuban population with rheumatoid arthritis (RA).
OBJECTIVE
To evaluate the association of the rs11125908 polymorphism in the COMMD1 gene in the Cuban population with rheumatoid arthritis (RA).
METHODS
In this case-control study, 161 RA patients and 150 control subjects were genotyped for rs11125908 by the allele-specific polymerase chain reaction method. DNA sequencing was used to verify the assignation of the polymorphism. The odds ratios (OR) and their 95% confidence interval were calculated by logistic regression to determine the associations between genotypes and RA using the SNPStats software.
RESULTS
An association of the single nucleotide polymorphism with the disease was found in the overdominant model (p=0.025; OR=1.91) for the AG genotype. Our analyses revealed an association between rs11125908 and the subgroup of patients with swollen joints < median under the codominant model for AG (p=0.034; OR=2.30) and GG genotype (p=0.034; OR=0.82) and with the overdominant model (p=0.01; OR=2.38). The subgroup of patients with an age of onset lower than the mean and AG genotype showed an association in the overdominant model (p=0.027; OR=2.27). Disease activity score 28 with erythrocyte sedimentation rate and disease duration variables were not associated with the rs11125908 polymorphism.
CONCLUSIONS
rs11125908 was associated with RA and with the number of swollen joints and age of onset subgroup analyses. We provide concepts for treatments for RA, based on pharmacological management of COMMD1 expression.
Topics: Humans; Arthritis, Rheumatoid; Polymorphism, Single Nucleotide; Male; Female; Case-Control Studies; Middle Aged; Cuba; Adult; Adaptor Proteins, Signal Transducing; Genotype; Genetic Predisposition to Disease; Aged
PubMed: 38916163
DOI: 10.4081/reumatismo.2024.1691 -
The World Journal of Biological... Jun 2024For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and... (Review)
Review
BACKGROUND
For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging.
METHODS
In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)).
RESULTS
Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings.
CONCLUSION
All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.
PubMed: 38913780
DOI: 10.1080/15622975.2024.2366235 -
Clinical Toxicology (Philadelphia, Pa.) Jun 2024Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying...
INTRODUCTION
Although valproic acid is generally well tolerated, hepatotoxicity is a common side effect in patients receiving long-term treatment. However, the mechanisms underlying valproic acid-associated hepatotoxicity remain elusive.
METHODS
To investigate the mechanisms and explore the potential risk factors for valproic acid-associated hepatotoxicity, 165 age-matched pediatric patients were recruited for laboratory tests and glutamate-glutamine cycle analysis.
RESULTS
The concentration of glutamate in patients with hepatotoxicity was significantly greater than that in control patients, while the concentration of glutamine in patients with hepatotoxicity was significantly lower than that in control patients ( ˂ 0.05). In addition, the frequencies of the heterozygous with one mutant allele and homozygous with two mutant alleles genotypes in were significantly higher in the hepatotoxicity group than those in the control group (47.1 percent versus 32.5 percent, = 0.010; 17.6 percent versus 5.2 percent, = 0.001, respectively). Moreover, heterozygous carriers with one mutant allele and homozygous carriers with two mutant alleles genotypes of exhibited significant differences in the concentrations of glutamine and glutamate concentrations ( ˂ 0.001 and = 0.001, respectively) and liver function indicators (activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase, ˂ 0.001, respectively). Furthermore, logistic regression analysis indicated that ( = 0.002, odds ratio: 3.027, 95 percent confidence interval, 1.521 - 6.023) and glutamate ( = 0.001, odds ratio: 2.235, 95 percent confidence interval, 1.369 - 3.146) were associated with a greater risk for hepatotoxicity, while glutamine concentrations were negatively associated with hepatotoxicity ( = 0.001, odds ratio: 0.711, 95 percent confidence interval, 0.629 - 0.804).
DISCUSSION
Understanding pharmacogenomic risks for valproic acid induced hepatotoxicity might help direct patient specific care. Limitations of our study include the exclusive use of children from one location and concomitant medication use in many patients.
CONCLUSION
Perturbation of the glutamate-glutamine cycle is associated with valproic acid-associated hepatotoxicity. Moreover, , glutamate and glutamine concentrations are potential risk factors for valproic acid-associated hepatotoxicity.
PubMed: 38913595
DOI: 10.1080/15563650.2024.2366920 -
American Journal of Health-system... Jun 2024In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been...
In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
PubMed: 38912618
DOI: 10.1093/ajhp/zxae171 -
Journal of Cancer 2024In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach....
In this study, we aimed to elucidate the role of mitochondrial calcium uptake 1/2 (MiCU1/2) in breast cancer (BRCA) by employing a comprehensive multi-omics approach. Unlike previous research, we utilized a novel web application tailored for whole tumor tissue, single-cell, and spatial transcriptomics analysis to investigate the association between MiCU1/2 and the tumor immune microenvironment (TIME). Our gene set enrichment analysis (GSEA) provided insights into the primary biological effects of MiCU1/2, while our CRISPR-based drug screening repository identified potential effective drugs. Our study revealed that high MiCU1/2 expression serves as an independent diagnostic biomarker, correlating with advanced clinical status and indicating poorer recurrence-free survival (RFS) rates in BRCA patients. Additionally, spatial transcriptome analysis highlighted the heightened expression of MiCU1/2 in tumors and its relevance in surrounding immune cells. Furthermore, using the CIBERSORT algorithm, we discovered a positive correlation between MiCU1/2 levels and macrophage infiltration, underscoring their potential impact on immune infiltration. We also identified expression patterns of immune-related genes associated with responses against various immune cell types, including CXCL, MIF, GDF, SPP1, and IL16. Finally, our pharmacogenomic screening identified potential small molecule drugs capable of effectively targeting breast cancer cells with elevated MiCU1/2 expression. Overall, our study establishes MiCU1/2 as a promising novel biomarker for BRCA diagnosis and prognostic prediction, as well as a potential therapeutic target, highlighting the importance of exploring these pathways to advance patient care and outcomes in BRCA treatment.
PubMed: 38911376
DOI: 10.7150/jca.95979