Pharmacogenomics. 2023 Sep 14. doi: 10.2217/pgs-2023-0095. Online ahead of print.

ABSTRACT

Background: HLA-B*58:01 is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of this testing to prevent SJS/TEN. Methods: A model was developed to compare three strategies: no screening, use allopurinol; HLA-B*58:01 screening; and no screening, use probenecid. A willingness-to-pay of three-times gross domestic product per capita was used. Results: Compared with 'no screening, use allopurinol', 'screening' increased quality-adjusted life-years by 0.0069 with the incremental cost of Vietnam dong (VND) 14,283,633 (US$617), yielding an incremental cost-effectiveness ratio of VND 2,070,459,122 (US$89,398) per quality-adjusted life-year. Therefore, 'screening' was unlikely to be cost-effective under the current willingness-to-pay. Testing's cost-effectiveness may change with targeted high-risk patients, reimbursed febuxostat or lower probenecid prices. Conclusion: The implementation of nationwide HLAB*58:01 testing before the use of allopurinol is not cost-effective, according to this analysis. This may be due to the lack of quality data on the effectiveness of testing and costing data in the Vietnamese population.

PMID:37706247 | DOI:10.2217/pgs-2023-0095

J Pharm Bioallied Sci. 2023 Jul-Sep;15(3):101-106. doi: 10.4103/jpbs.jpbs_313_23. Epub 2023 Aug 15.

ABSTRACT

BACKGROUND: Clinical pharmacogenetics is a rapidly growing field that focuses on the study of genetic variations and their impact on drug metabolism, efficacy, and safety. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension in Iraq but not all patients respond equally to these drugs.

AIM: This article aims to review the current evidence on the clinical pharmacogenetics of ARBs in Iraq and its implications for personalized medicine.

MATERIALS AND METHODS: We conducted a literature review of studies on the genetic variations that affect the response to ARBs in Iraq. We also reviewed the prevalence of these genetic variants in the Iraqi population and discussed the potential clinical implications for personalized medicine.

RESULTS: The most studied genetic variations associated with ARB response in Iraq are the angiotensin-converting enzyme gene insertion/deletion polymorphism and the angiotensin II type 1 receptor gene A1166C polymorphism. The angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with variability in response to ARBs, while the angiotensin II type 1 receptor A1166C polymorphism is associated with an increased risk of cardiovascular events in patients treated with ARBs. The prevalence of these genetic variants in the Iraqi population varies widely depending on the region and ethnic group.

CONCLUSION: The clinical pharmacogenetics of ARBs in Iraq suggests that pharmacogenetic testing could improve the selection and dosing of ARBs in Iraqi patients, leading to better patient outcomes and cost-effective healthcare.

PMID:37705854 | PMC:PMC10496849 | DOI:10.4103/jpbs.jpbs_313_23

Clin Transl Sci. 2023 Sep 13. doi: 10.1111/cts.13634. Online ahead of print.

ABSTRACT

Given the high prevalence of pain in older adults and current trends in opioid prescribing, inclusion of genetic information in risk prediction tools may improve opioid risk assessment. Our objectives were to (1) determine the feasibility of recruiting socioeconomically disadvantaged and racially diverse middle aged and older adult populations for a study seeking to identify risk factors for opioid-related falls and other serious adverse effects and (2) explore potential associations between the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (CIP-RIOSORD) risk class and other patient factors with falls and serious opioid adverse effects. This was an observational study of 44 participants discharged home from the emergency department with an opioid prescription for acute pain and followed for 30 days. We found pain interference may predict opioid-related falls or serious adverse effects within older, opioid-treated patients. If validated, pain interference may prove to be a beneficial marker for risk stratification of older adults initiated on opioids for acute pain.

PMID:37705211 | DOI:10.1111/cts.13634

Pediatr Blood Cancer. 2023 Sep 13:e30669. doi: 10.1002/pbc.30669. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Significantly discrepant survival rates have been documented in single disease childhood cancer cohorts in South Africa; those from higher socioeconomic groups were shown to have a significantly lower risk of death than those from less affluent households. This study aimed to determine the impact of socioeconomic status (SES) on childhood cancer survival using pooled South African data.

METHODS: Five databases spanning January 2000 to December 2021 were interrogated. SES status was assigned based on a public sector annual household income classification. H0 households (formally unemployed) received free healthcare. H1, H2 and H3 (annual income > United States Dollar [USD] 19,000) households paid for healthcare relative to their income. The Spearman test assessed correlations between SES and disease stage in patients with solid tumours. Hazard ratios were determined using Cox regression modelling. The Kaplan-Meier procedure estimated overall survival (OS).

RESULTS: A total of 1598 children were eligible for analysis; 1269 had a solid tumour with a negative correlation between SES and stage (Spearman rho = -.178; p < .001). Patients with solid tumours and lower SES showed proportionately higher numbers of stage III and IV disease (p < .01). This proportion decreased with higher SES categories. In the multivariate analyses adjusted for sex, age, tumour type and stage, higher SES was associated with lower mortality risk (p < .001), indicating that the impact of SES on survival was in excess of any effect that could be explained by lower stage disease alone. There was a strong positive correlation between race and SES (Fisher's exact tests, p < .001) across all groups and all SES strata. Five-year OS was 85.3% in children from H3 households versus 46.3% in children from H0 households (p < .001).

CONCLUSION: SES significantly impacts childhood cancer survival for children with solid tumours in South Africa. SES is a robust surrogate for race in South Africa as a prognostic metric of disease outcome in childhood cancer. Advocacy to increase social support for impoverished patients is essential to achieve equitable improvements in outcomes treated with standardised national treatment guidelines.

PMID:37705154 | DOI:10.1002/pbc.30669

Pediatr Clin North Am. 2023 Oct;70(5):995-1011. doi: 10.1016/j.pcl.2023.05.010. Epub 2023 Jul 3.

ABSTRACT

Pharmacogenomics, where genomic information is used to tailor medication management, is a strategy to maximize drug efficacy and minimize toxicity. Although pediatric evidence is less robust than for adults, medications influenced by pharmacogenomics are prescribed to children and adolescents. Evidence-based guidelines and drug label annotations are available from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Pharmacogenomics Knowledgebase (PharmGKB). Some pediatric health care facilities use pharmacogenomics to provide dosing recommendations to pediatricians. Herein, we use a case-based approach to illustrate the use of pharmacogenomic data in pediatric clinical care and provide resources for finding and using pharmacogenomic guidelines.

PMID:37704356 | DOI:10.1016/j.pcl.2023.05.010

Pharmacogenomics. 2023 Sep 13. doi: 10.2217/pgs-2023-0099. Online ahead of print.

ABSTRACT

Background: Polymorphisms in the CYP2C9, VKORC1, MDR1 and APOE genes may impact warfarin dose. Aim: To investigate the influence of sociodemographic and clinical factors and polymorphisms *1, *2 and *3 for CYP2C9, -1639G>A for VKORC1, 3435C>T for MDR1, and ϵ2, ϵ3 and ϵ4 for APOE genes on the mean weekly warfarin maintenance dose in adults. Methods: This cross-sectional study recruited a calculated sample of 315 patients in three anticoagulation clinics in Brazil. A model containing the variables significantly associated with warfarin dose was estimated. Results: The mean age of patients was 64.1 ± 13.1 years, with 173 (54.9%) women. Age, use of amiodarone, genotype VKORC1 GA, genotype VKORC1 AA, genotypes CYP2C9*1/*2 or *1/*3 and genotypes CYP2C9*2/*2 or *2/*3 or *3/*3 were associated with a reduced warfarin dose. Conclusion: This study pointed out factors that could impact the management of oral anticoagulation.

PMID:37702085 | DOI:10.2217/pgs-2023-0099

Pharmacogenomics. 2023 Sep 13. doi: 10.2217/pgs-2023-0125. Online ahead of print.

ABSTRACT

Precision medicine has revolutionized clinical care for patients with cancer through the development of targeted therapy, identification of inherited cancer predisposition syndromes and the use of pharmacogenetics to optimize pharmacotherapy for anticancer drugs and supportive care medications. While germline (patient) and somatic (tumor) genomic testing have evolved separately, recent interest in paired germline/somatic testing has led to an increase in integrated genomic testing workflows. However, paired germline/somatic testing has generally lacked the incorporation of germline pharmacogenomics. Integrating pharmacogenomics into paired germline/somatic genomic testing would be an efficient method for increasing access to pharmacogenomic testing. In this perspective, the authors argue for the benefits of implementing a comprehensive approach integrating somatic and germline testing that is inclusive of pharmacogenomics in clinical practice.

PMID:37702060 | DOI:10.2217/pgs-2023-0125

Neurohospitalist. 2023 Oct;13(4):434-437. doi: 10.1177/19418744231189078. Epub 2023 Jul 10.

ABSTRACT

Clobazam is a 1,5-benzodiazepine frequently used as an adjunctive agent for refractory seizures and status epilepticus. Clobazam undergoes metabolism to an active metabolite norclobazam which is subsequently hydroxylated by CYP2C19, a cytochrome with several pharmacogenetic variants. Patients with poor metabolizer phenotypes may have elevated norclobazam levels and subsequent adverse effects. We present a case of an Asian American male receiving clobazam at a standard therapeutic dose for seizure disorder who became comatose secondary to significantly elevated norclobazam concentrations. Genetic testing revealed the patient was a poor CYP2C19 metabolizer, accounting for the impaired clearance. Clinicians should be aware of the patient populations at risk for these genetic polymorphisms and adjust initial doses based on package labeling or consider therapeutic drug monitoring to avoid adverse effects.

PMID:37701253 | PMC:PMC10494815 | DOI:10.1177/19418744231189078

J Community Genet. 2023 Sep 13. doi: 10.1007/s12687-023-00668-6. Online ahead of print.

ABSTRACT

Circassians and Chechens in Jordan, both with Caucasian ancestry, are genetically isolated due to high rate of endogamous marriages. Recent interest in these populations has led to studies on their genetic similarities, differences, and epidemiological differences in various diseases. Research has explored their predisposition to conditions like diabetes, hypertension, and cancer. Moreover, pharmacogenetic (PGx) studies have also investigated medication response variations within these populations, and forensic studies have further contributed to understanding these populations. In this review article, we first discuss the background of these minority groups. We then show the results of a principle component analysis (PCA) to investigate the genetic relationships between Circassian and Chechen populations living in Jordan. We here present a summary of the findings from the 10 years of research conducted on them. The review article provides a comprehensive summary of research findings that are truly valuable for understanding the unique genetic characteristics, diseases' prevalence, and medication responses among Circassians and Chechens living in Jordan. We believe that gaining deeper comprehension of the root causes of various diseases and developing effective treatment methods that benefit the society as a whole are imperative to engaging a wide range of ethnic groups in genetic research.

PMID:37700208 | DOI:10.1007/s12687-023-00668-6

Pharmacotherapy. 2023 Sep 12. doi: 10.1002/phar.2875. Online ahead of print.

ABSTRACT

INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and report pilot outcome data.

METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks were assessed.

RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6 genotype-guided recommendations to change therapy (n=11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n=48), there was no difference in change in mean composite pain score (-1.01±2.1 vs -0.41±2.5; p=0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs 3.47 ± 1.78; p=0.63) between the usual care arm (n=26) and genotype-guided arm (n=22), respectively.

CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.

PMID:37698371 | DOI:10.1002/phar.2875

Inflamm Bowel Dis. 2023 Sep 11:izad181. doi: 10.1093/ibd/izad181. Online ahead of print.

ABSTRACT

BACKGROUND: The identification of new biomarkers predictive of response to antitumor necrosis factor alpha (anti-TNF-α) monoclonal antibodies remains an unmet medical need in Crohn's disease (CD) because a high percentage of patients show no clinical improvement after treatment or can lose response over time. MicroRNAs (miRNAs) can regulate inflammatory and immunological responses and were found to play a role in CD.

METHODS: Baseline serum samples from 37 CD patients previously treated with infliximab or adalimumab, as per clinical practice, were obtained from the serum library at the Gastroenterology Unit of the University Hospital of Pisa, Italy. Patients were categorized as responders or nonresponders based on the following treatment outcomes: clinical remission at weeks 14 and 54 and endoscopic remission at week 54. The expression levels of a panel of selected miRNAs were analyzed by real-time polymerase chain reaction. Comparisons of miRNA expression between responders and nonresponders and statistical analyses were performed by MedCalc and GraphPad Prism software. Receiver operating characteristic curve analyses were calculated to evaluate the predictive performance of potential biomarkers.

RESULTS: Patients in clinical remission at week 14 had a lower let-7e expression, whereas those in clinical remission at week 54 had lower levels of circulating miR-126 than nonresponders. The receiver operating characteristic curve analysis identified optimal cutoff values with assay sensitivity and specificity of 92.9% and 61.1%, for let-7e, and 62.5% and 83.3%, for miR-126, respectively.

CONCLUSION: These results provide evidence that expression levels of circulating let-7e and miR-126 at baseline may predict clinical remission in CD patients treated with anti-TNF-α biologics.

PMID:37696681 | DOI:10.1093/ibd/izad181

Curr Gastroenterol Rep. 2023 Sep 11. doi: 10.1007/s11894-023-00895-4. Online ahead of print.

ABSTRACT

PURPOSE OF THE REVIEW: This review focuses on recent advancements in anti-TNF therapeutic drug monitoring (TDM), pharmacogenetics and personalized drug selection for children with inflammatory bowel disease (IBD).

RECENT FINDINGS: Several real-world studies and one clinical trial in children have demonstrated that proactive TDM, targeting higher exposure concentrations (> 5 µg/mL), can improve disease remission rates and enhance durability of the anti-TNF biologics. Recent data from both adult and pediatric IBD patients have revealed an association between a genetic polymorphism (HLA-DQA1*05) and the development of auto-drug antibodies. The impact of this association on clinical outcomes, considering more routine use proactive TDM and dose optimization in children, is still under investigation. Additionally, recent studies have identified potential inflammatory signatures and biomarkers that may serve as companion diagnostics for anti-TNF biologics. The effective management of anti-TNF therapies in children with IBD requires evidence-based precision dosing strategies, including routine TDM and proactive pharmacodynamic assessments.

PMID:37695555 | DOI:10.1007/s11894-023-00895-4

Pharmacogenet Genomics. 2023 Oct 1;33(8):181-208. doi: 10.1097/FPC.0000000000000507. Epub 2023 Sep 6.

NO ABSTRACT

PMID:37695025 | DOI:10.1097/FPC.0000000000000507

Front Pharmacol. 2023 Aug 11;14:1246765. doi: 10.3389/fphar.2023.1246765. eCollection 2023.

ABSTRACT

The CYP2C9 gene encodes the major drug metabolism enzyme CYP2C9. This gene is highly polymorphic, and no-function (CYP2C9*3) plus decreased function (CYP2C9*2, *5, *8 and *11) star alleles (haplotypes) are commonly used to predict CYP2C9 metabolic phenotypes. This study explores the pharmacogenomic implications of the differential distribution of genotype-predicted CYP2C9 phenotypes across Latin American populations. Data from 1,404 individuals from the South American countries Brazil, Colombia and Peru, from Puerto Rico in the Caribbean and from persons with Mexican ancestry living in North America were analysed. The results showed that the distribution of CYP2C9 alleles and diplotypes, and diplotype-predicted CYP2C9 phenotypes vary significantly across the distinct country cohorts, as well as among self-identified White, Brown and Black Brazilians. Differences in average proportions of biogeographical ancestry across the study groups, especially Native American and African ancestry, are the likely explanation for these results. The differential distribution of genotype-predicted CYP2C9 phenotypes has potentially clinically-relevant pharmacogenomic implications, through its influence on the proportion of individuals at high risk for adverse response to medications that are CYP2C9 substrates, the proportion on individuals with CPIC therapeutic recommendations for dosing and choice of nonsteroidal antinflammatory drugs (NSAIDs) and the number of individuals that need to be genotyped in order to prevent adverse effects of NSAIDs. Collectively, these findings are likely to impact the perceived benefits, cost-effectiveness and clinical adoption of pharmacogenomic screening for drugs that are predominantly metabolized by CYP2C9.

PMID:37693910 | PMC:PMC10488705 | DOI:10.3389/fphar.2023.1246765

medRxiv. 2023 Sep 1:2023.08.30.23294860. doi: 10.1101/2023.08.30.23294860. Preprint.

ABSTRACT

BACKGROUND: Genetic polymorphisms have been associated with risk of anti-tuberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.

METHODS: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015-2019, and who were evaluable for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24 month follow-up. Analyses included 43 polymorphisms in 20 genes related to anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.

RESULTS: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A , and the genes METTL17 and PRSS57 , but none achieved genome-wide significance.

CONCLUSIONS: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.

PMID:37693472 | PMC:PMC10491388 | DOI:10.1101/2023.08.30.23294860

Front Genet. 2023 Aug 25;14:1249164. doi: 10.3389/fgene.2023.1249164. eCollection 2023.

ABSTRACT

Introduction: Preventing side effects is important to ensure optimal psychopharmacotherapy and therapeutic adherence among psychiatric patients. Obtaining the pharmacogenetic profile of CYP2C19 and CYP2D6 can play an important role in this. When the genotype-predicted phenotype shifts because of the use of co-medication, this is called phenoconversion. The aim was to study the influence of the pharmacogenetic (PGx) profile and phenoconversion on side effects experienced by psychiatric patients. Methods: A retrospective cohort study was performed using data from 117 patients from a psychiatric outpatient clinic. Patients were genotyped with a psychiatric PGx panel and side effects were evaluated using the Udvalg for Kliniske Undersølgelser side effects rating scale (UKU). Results: Of all patients, 10.3% and 9.4% underwent phenoconversion (any shift in predicted phenotype) for CYP2C19 and CYP2D6 respectively. No significant associations were found between the phenotype and UKU-score. 75% of the patients with an Intermediate metabolizer (IM) or Poor metabolizer (PM) phenoconverted phenotype of CYP2C19 experienced nausea and vomiting compared to 9.1% of the Normal metabolizer (NM) and Ultrarapid metabolizer (UM) patients (p = 0.033). 64% of the patients with an IM or PM phenoconverted phenotype of CYP2D6 experienced the side effect depression compared to 30.4% NMs and UMs (p = 0.020). CYP2D6 IM and PM patients had a higher concentration-dose ratio than NM patients (p < 0.05). Discussion: This study underlines the importance to consider phenoconversion when looking at a patient's genotype. This is important for a better prediction of the phenotype and preventing possible side effects under a specific psychopharmacotherapy.

PMID:37693320 | PMC:PMC10486269 | DOI:10.3389/fgene.2023.1249164

Front Genet. 2023 Aug 24;14:1187415. doi: 10.3389/fgene.2023.1187415. eCollection 2023.

ABSTRACT

Introduction: Dexmedetomidine (DXM) is widely used as an adjuvant to anesthesia or a sedative medicine, and differences in individual sensitivity to the drug exist. This study aimed to investigate the effect of genetic polymorphisms on these differences. Methods: A total of 112 patients undergoing hand surgery were recruited. DXM 0.5 μg/kg was administered within 10 min and then continuously injected (0.4 μg/kg/h). Narcotrend index, effective dose and onset time of sedation, MAP, and HR were measured. Forty-five single nucleotide polymorphisms (SNPs) were selected for genotype. Results: We observed individual differences in the sedation and hemodynamics induced by DXM. ABCG2 rs2231142, CYP2D6 rs16947, WBP2NL rs5758550, KATP rs141294036, KCNMB1 rs11739136, KCNMA1 rs16934182, ABCC9 rs11046209, ADRA2A rs1800544, and ADRB2 rs1042713 were shown to cause statistically significant (p < 0.05) influence on the individual variation of DXM on sedation and hemodynamics. Moreover, the multiple linear regression analysis indicated sex, BMI, and ADRA2A rs1800544 are statistically related to the effective dose of DXM sedation. Discussion: The evidence suggests that the nine SNPs involved in transport proteins, metabolic enzymes, and target proteins of DXM could explain the individual variability in the sedative and hemodynamic effects of DXM. Therefore, with SNP genotyping, these results could guide personalized medication and promote clinical and surgical management.

PMID:37693312 | PMC:PMC10483403 | DOI:10.3389/fgene.2023.1187415

Front Genet. 2023 Aug 24;14:1242711. doi: 10.3389/fgene.2023.1242711. eCollection 2023.

ABSTRACT

Voriconazole (VRZ) is a broad-spectrum antifungal medication widely used to treat invasive fungal infections (IFI). The administration dosage and blood concentration of VRZ are influenced by various factors, posing challenges for standardization and individualization of dose adjustments. On the one hand, VRZ is primarily metabolized by the liver, predominantly mediated by the cytochrome P450 (CYP) 2C19 enzyme. The genetic polymorphism of CYP2C19 significantly impacts the blood concentration of VRZ, particularly the trough concentration (Ctrough), thereby influencing the drug's efficacy and potentially causing adverse drug reactions (ADRs). Recent research has demonstrated that pharmacogenomics-based VRZ dose adjustments offer more accurate and individualized treatment strategies for individuals with hepatic insufficiency, with the possibility to enhance therapeutic outcomes and reduce ADRs. On the other hand, the security, pharmacokinetics, and dosing of VRZ in individuals with hepatic insufficiency remain unclear, making it challenging to attain optimal Ctrough in individuals with both hepatic insufficiency and IFI, resulting in suboptimal drug efficacy and severe ADRs. Therefore, when using VRZ to treat IFI, drug dosage adjustment based on individuals' genotypes and hepatic function is necessary. This review summarizes the research progress on the impact of genetic polymorphisms and hepatic insufficiency on VRZ dosage in IFI individuals, compares current international guidelines, elucidates the current application status of VRZ in individuals with hepatic insufficiency, and discusses the influence of CYP2C19, CYP3A4, CYP2C9, and ABCB1 genetic polymorphisms on VRZ dose adjustments and Ctrough at the pharmacogenomic level. Additionally, a comprehensive summary and analysis of existing studies' recommendations on VRZ dose adjustments based on CYP2C19 genetic polymorphisms and hepatic insufficiency are provided, offering a more comprehensive reference for dose selection and adjustments of VRZ in this patient population.

PMID:37693307 | PMC:PMC10484623 | DOI:10.3389/fgene.2023.1242711

Anesth Pain Med (Seoul). 2023 Jul;18(3):220-232. doi: 10.17085/apm.22260. Epub 2023 Jul 26.

ABSTRACT

Dantrolene sodium (DS) was first introduced as an oral antispasmodic drug. However, in 1975, DS was demonstrated to be effective for managing malignant hyperthermia (MH) and was adopted as the primary therapeutic drug after intravenous administration. However, it is difficult to administer DS intravenously to manage MH. MH is life-threatening, pharmacogenomically related, and induced by depolarizing neuromuscular blocking agents or inhalational anesthetics. All anesthesiologists should know the pharmacology of DS. DS suppresses Ca2+ release from ryanodine receptors (RyRs). RyRs are expressed in various tissues, although their distribution differs among subtypes. The anatomical and physiological functions of RyRs have also been demonstrated as effective therapeutic drugs for cardiac arrhythmias, Alzheimer's disease, and other RyR-related diseases. Recently, a new formulation was introduced that enhanced the hydrophilicity of the lipophilic DS. The authors summarize the pharmacological properties of DS and comment on its indications, contraindications, adverse effects, and interactions with other drugs by reviewing reference articles.

PMID:37691593 | DOI:10.17085/apm.22260

Curr Drug Metab. 2023 Sep 7. doi: 10.2174/1389200224666230907093349. Online ahead of print.

ABSTRACT

Drug therapy is the primary modality for depression; however, its outcome is often unpredictable, ranging from beneficial effects to serious adverse effects. Genetic variations in drug metabolizing enzymes and pharmacodynamic molecules are responsible for a considerable proportion of interindividual differences in the effectiveness and toxicity of antidepressants. For the improvement in the use of antidepressants, the focus is mainly on personalized treatment emphasizing interindividual differences in genes. This study provides a comprehensive review of the literature on the clinical applications of pharmacogenomics for antidepressant therapy. The polymorphisms of metabolizing enzymes (CYP2D6, CYP2C19, and others) governing the pharmacokinetic behavior of drugs are potential predictors of side effects or treatment failure with medications and there are good pharmacogenetic clinical recommendations for a wide selection of psychopharmacological agents based on functional diplotypes of CYP2C19 and CYP2D6. The relationship between pharmacodynamic genes, including FKBP5, SLC6A4, BDNF, ABCB1, HTR1A, and HTR2A, and clinical outcomes varies in different races. Receptors that are currently used as drug targets for antidepressant drugs are evolutionarily conserved to a higher extent than genes encoding drug metabolism, and the actionability of pharmacodynamic-related genotyping is currently still questionable. The limited availability of large-scale, long-term clinical studies on different races and medications currently impedes the implementation of pharmacogenomics in antidepressant treatment. The use of pharmacokinetic and pharmacodynamic modeling, and therapeutic drug monitoring combined with genetic, somatic, dietary, and environmental factors represents a promising avenue for improving the precision and effectiveness of antidepressant therapy.

PMID:37691197 | DOI:10.2174/1389200224666230907093349