Frequency of pharmacogenomic variants affecting safety and efficacy of immunomodulators and biologics in a South Asian population from Sri Lanka.

BACKGROUND: Immunomodulators are important for management of autoimmune diseases and hematological malignancies. Significant inter-individual variation in drug response/reactions exists due to genetic polymorphisms. We describe frequency of identified genetic polymorphisms among Sri Lankans. METHODS: Sri Lankan data were obtained from an anonymized database of 670 participants. Data on variants and global distribution of Minor Allele frequency (MAF) of other populations (South Asian, Ashkenazi-Jewish, East-Asian, European-Finnish, European-non-Finnish, Latino-American, African/African-American) were obtained from pharmGKB online database. RESULTS: SLC19A1 (rs1051266) variant had a MAF (95% CI) of 63.3% (60.7-65.9). Other common variants included FCGR3A (rs396991), MTHFR (rs1801133), ITPA (rs1127354), CYP2C9*3 (rs1057910) and NUD15*3 (rs116855232), with MAFs of 35.3% (32.7-37.9), 12.2% (10.4-13.9), 10.9% (9.2-12.6), 9.8% (8.2-11.4), 8.3% (6.8-9.8) respectively. Less commonly present variants included CYP2C9*2 (rs1799853) (2.5%[1.7-3.4]), TPMT*3C (rs1142345) (1.9%[1.1-2.6]), TPMT*3B (rs1800460) (0.2%[0-0.5]), CYP3A5*6 (rs10264272) (0.2%[0-0.4]) and CYP3A4*18 (rs28371759) (0.1%[0-0.2]). The SLC19A1 (rs1051266), NUD15*3 (rs116855232), CYP2C9*3 (rs1057910), FCGR3A (rs396991), and ITPA (rs1127354) showed significantly higher frequencies in Sri Lankans compared to many other populations, exceptions include FCGR3A in Ashkenazi-Jewish and ITPA in East-Asians. Conversely, MTHFR (rs1801133), TPMT*3B (rs1800460), and CYP2C9*2 (rs1799853) were significantly less prevalent among Sri Lankans than in  many other populations. Sri Lankans exhibited lower prevalence of TPMT*3C (rs1142345) compared to European-non-Finnish, Latino-Americans, and African/African-Americans; CYP3A4*18 (rs28371759) compared to East-Asians; and CYP3A5*6 (rs10264272) compared to African/African-Americans and Latino-Americans. CONCLUSION: Sri Lankans exhibit higher frequencies in variants reducing methotrexate efficacy (SLC19A1), increasing azathioprine myelotoxicity (NUDT15), and lower frequencies in variants linked to increased azathioprine toxicity (TPMT*3B, TPMT*3C), reduced tacrolimus efficacy (CYP3A4*18), and methotrexate toxicity risk (MTHFR). Beneficial variants enhancing rituximab efficacy (FCGR3A) are more prevalent, while those reducing tacrolimus dosage (CYP3A5*6) are less common. This highlights need for targeted medication strategies to improve treatment outcomes.

A Review of the Regulatory Challenges of Personalized Medicine.

Personalized medicine integrates genomics with clinical and familial histories, revolutionizing healthcare by tailoring treatments to individual patient characteristics. At its core, pharmacogenomics enables the customization of medication prescriptions based on genetic profiles, enhancing drug efficacy and safety. This precision medicine approach addresses disease diagnosis, prevention, and treatment, offering targeted therapies for conditions like autoimmune disorders, rheumatoid arthritis, and neoplastic conditions. Examples of pharmacogenomics and personalized medicine include treatment for certain conditions like blood clotting disorders (warfarin (blood thinner), genetic variability, acute lymphoblastic leukemia (ALL), and thiopurine methyltransferase (TPMT) testing) in leukemia treatment. Historically, personalized medicine has evolved from Hippocrates' humoral theories to modern molecular diagnostics. The shift from cellular to molecular-level investigations has led to the current post-genomic era, emphasizing the four chemical components of DNA in understanding and treating disorders. This evolution enhances our ability to predict disease susceptibility, treatment response, and potential adverse reactions, demanding advancements in privacy laws, payment systems, regulatory standards, and education. Personalized healthcare optimizes treatment by considering genetic, environmental, and lifestyle factors, reducing adverse reactions, and improving patient satisfaction. It drives genomic and biotechnological research, fostering the development of targeted therapies and diagnostic tools, and streamlining drug development. Applications in lung cancer, renal carcinoma, and rheumatoid arthritis (RA) illustrate the efficacy of personalized medicine. Targeted therapies, such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), show significant success in lung cancer. Biomarkers guide renal carcinoma treatments, while gene expression profiles predict rheumatoid arthritis outcomes with tumor necrosis factor-alpha (TNF-α) blockers. The US FDA's increasing approvals of personalized treatments underscore its commitment to precision medicine. However, regulatory challenges persist, necessitating clear processes and policies. Ethical considerations, including equitable access and privacy, are critical for responsible implementation. The FDA's increasing approvals of personalized treatments highlight its commitment to advancing precision medicine, yet regulatory challenges remain, requiring the development of clear processes and policies to manage innovation safely. While these hurdles are being addressed through evolving guidelines and collaborative efforts, ethical considerations, including equitable access and privacy, are critical for responsible implementation. Early examples, such as warfarin and imatinib, demonstrate the role of genetic information in guiding treatment, illustrating the potential of personalized medicine to optimize healthcare outcomes.

ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer.

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38-7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09-17.55] months versus negative expression 13.3 [95% CI 7.32-19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08-9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed.

Functional significance of CYP2B6 gene rare allelic variants identified in Japanese individuals.

Cytochrome P450 2B6 (CYP2B6) catalyzes the metabolism of many drugs, including efavirenz and propofol. Genetic polymorphisms in CYP2B6 alter its enzymatic activity and substantially affect its pharmacokinetics. High-frequency variants, such as CYP2B6*6, are associated with the risk of developing side effects due to reduced CYP2B6 activity. However, the impact of rare alterations on enzyme function remains unknown, and some of these variants may significantly decrease the CYP2B6 activity. Therefore, in this study, we evaluated in vitro the functional alterations in 29 missense variants of the CYP2B6 gene identified in 8,380 Japanese individuals. Wild-type CYP2B6 and 29 rare CYP2B6 variants were transiently expressed in mammalian cells. The expression levels of variant CYP2B6 proteins in the microsomal fractions extracted from 293FT cells were assessed using western blotting and reduced-carbon monoxide difference spectroscopy, and a specific peak at 450 nm was detected in the wild-type and 19 variants. Furthermore, kinetic parameters were determined by assaying the reactions with efavirenz and propofol and quantifying the metabolite concentrations. We found that 12 variants had significantly lower or abolished enzymatic activity with both the substrates. In silico three-dimensional docking and molecular-dynamics simulations suggested that these functional changes were due to conformational changes in essential regions, such as the heme-binding site and ligand channels involved in transporting substrates to the active site. These findings have implications for predicting the plasma concentrations of CYP2B6 substrates and controlling their side effects.

Influence of different factors (duration of disease, gender, education, patients' history, job and age) in metformin response in type 2 diabetes mellitus patient.

OBJECTIVE: Aim: This study aims to evaluate how various factors affect various aspects of glycemic control in individuals with type 2 diabetes who are undergoing metformin treatment. PATIENTS AND METHODS: Materials and Methods: A cross-sectional study involved 150 participants who met specific criteria, including being aged between 30 and 70, having a type 2 diabetes diagnosis, and using 1000 mg of metformin as the monotherapy for at least three months. Collected data encompassed various measures, such as levels of glycated hemoglobin (HbA1c), fasting blood glucose concentrations, fasting serum insulin levels, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and insulin sensitivity. RESULTS: Results: Our research reveals that when it comes to factors such as several socio-demographic variables, there is no statistically significant difference (p-value ≥ 0.05) between patients who exhibit a positive response to metformin and those who do not. Nevertheless, distinctions were noted in patients' previous history and the duration of their illness, which did influence their treatment response. CONCLUSION: Conclusions: Glycemic parameters in individuals with type 2 diabetes can be impacted by a range of factors, such as age, gender, and occupation also it's important to note that these outcomes influenced by additional variables like the adherence for medication, and the existence of diabetes-related complications.

Drug metabolizing enzymes pharmacogenetic variation-informed antidepressant therapy approach for common mental disorders: A systematic review and meta-analysis.

IMPORTANCE: Currently, 30-50 % of individuals with depression and 40 % with anxiety-collectively referred to as common mental disorders (CMDs), exhibit inadequate responses to antidepressant treatments. OBJECTIVE: To assess the effectiveness and safety of drug-metabolizing enzyme pharmacogenetic variation informed treatment (PGxIT) versus usual antidepressant treatment (UT) in patients with CMDs. DATA SOURCES: A literature search was conducted in the MEDLINE, Scopus, and Cochrane Library databases from inception until January 30, 2024. STUDY SELECTION: Studies were selected based on CMD diagnoses, reporting on the genetic variations of drug-metabolizing enzyme (DME) genes in relation to antidepressants, involving PGxIT and UT groups with human subjects, and published in English. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality assessment were performed independently by two authors. A pooled risk ratio (RR) with 95 % CI was estimated using both random and fixed-effect models, and heterogeneity was assessed using Cochran's Q test and the I2 statistic. The publication bias of eligible studies was assessed using post hoc Doi plots and the LFK index. RESULTS: This systematic review included 18 studies (n = 7021). The PGxIT demonstrated greater efficacy in the remission of symptoms of depressive disorder at 8 weeks (RR 1.523 [95 % CI: 1.255-1.843]; I2 = 48 %) and 12 weeks (RR 1.631 [95 % CI: 1.001-2.657]; I2 = 86 %; p < 0.01), and symptoms of anxiety disorder compared to UT. Additionally, the risk of adverse drug events (ADEs) was significantly lower in the PGxIT group (RR = 0.65 [95 % CI: 0.52-0.82]; I2 = 0 %) than in the UT group. The certainty of evidence for both outcomes was moderate. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis suggest that pharmacogenetically guided antidepressant treatment, based on genetic variation in drug-metabolizing enzymes, is associated with superior efficacy in the remission of symptoms for patients with depressive disorders and a reduction in ADEs compared to usual treatment and the findings of the systematic review for remission in anxiety disorders indicate that, PGx guided treatment is also associated with increased remission of symptoms in anxiety disorders compared to usual treatment.

Receptor Pharmacogenomics: Deciphering Genetic Influence on Drug Response.

The paradigm "one drug fits all" or "one dose fits all" will soon be challenged by pharmacogenetics research and application. Drug response-efficacy or safety-depends on interindividual variability. The current clinical practice does not include genetic screening as a routine procedure and does not account for genetic variation. Patients with the same illness receive the same treatment, yielding different responses. Integrating pharmacogenomics in therapy would provide critical information about how a patient will respond to a certain drug. Worldwide, great efforts are being made to achieve a personalized therapy-based approach. Nevertheless, a global harmonized guideline is still needed. Plasma membrane proteins, like receptor tyrosine kinase (RTK) and G protein-coupled receptors (GPCRs), are ubiquitously expressed, being involved in a diverse array of physiopathological processes. Over 30% of drugs approved by the FDA target GPCRs, reflecting the importance of assessing the genetic variability among individuals who are treated with these drugs. Pharmacogenomics of transmembrane protein receptors is a dynamic field with profound implications for precision medicine. Understanding genetic variations in these receptors provides a framework for optimizing drug therapies, minimizing adverse reactions, and advancing the paradigm of personalized healthcare.

Herb-drug interaction study of Yiqi Fumai lyophilized injection (YQFM) on pharmacokinetics of aspirin, nifedipine, and clopidogrel in rats.

Yiqi Fumai lyophilized injection (YQFM), a compound traditional Chinese medicine prescription derived from "Sheng Mai Powder," is approved for the treatment of cardiovascular diseases. YQFM is usually prescribed in combination with some Western medicines to treat patients, such as aspirin, nifedipine, and clopidogrel. However, the herb-drug interactions (HDIs) of YQFM are still unclear. We determined the effect of YQFM on drug metabolism-related CYP450 enzymes by in vitro assays. And the effects of YQFM on the pharmacokinetics of aspirin, nifedipine, or clopidogrel were analyzed in rats, as well as the effect of YQFM on the prothrombin time of aspirin or clopidogrel, to evaluate the safety and efficacy of co-administration. Our study indicated that the clinical dose of YQFM did not significantly influence the relevant CYP450 isoenzymes. Besides, YQFM had no effect on the pharmacokinetics of aspirin, nifedipine, or clopidogrel single and multiple administrations in rats. In pharmacodynamics study, YQFM also had no impact on prothrombin time of aspirin or clopidogrel. Based on the results of pharmacogenomics, pharmacokinetics, and pharmacodynamics, the HDIs of YQFM have a good safety profile, and the combination with the above three drugs might have synergistic effects due to the different efficacy of YQFM-quality markers.

Genetics Affecting the Prognosis of Dental Treatments.

Genetics plays a significant role in determining an individual's susceptibility to dental diseases, the response to dental treatments, and the overall prognosis of dental interventions. Here, the authors explore the various genetic factors affecting the prognosis of dental treatments focusing on dental caries, orthodontic treatment, oral cancer, prosthodontic treatment, periodontal disease, developmental disorders, pharmacogenetics, and genetic predisposition to faster wound healing. Understanding the genetic underpinnings of dental health can help personalize treatment plans, predict outcomes, and improve the overall quality of dental care.

Genotype-Guided Antiplatelet Therapy: JACC Review Topic of the Week.

The clinical efficacy and safety of antiplatelet agents vary among patients. Consequently, some patients are at increased risk of recurrent ischemic events during treatment. This interindividual variability can be a result of genetic variants in enzymes that play a role in drug metabolism. The field of pharmacogenomics explores the influence of these genetic variants on an individual's drug response. Tailoring antiplatelet treatment based on genetic variants can potentially result in optimized dosing or a change in drug selection. Most evidence supports guiding therapy based on the CYP2C19 allelic variants in patients with an indication for dual antiplatelet therapy. In ticagrelor-treated or prasugrel-treated patients, a genotype-guided de-escalation strategy can reduce bleeding risk, whereas in patients treated with clopidogrel, an escalation strategy may prevent ischemic events. Although the clinical results are promising, few hospitals have implemented these strategies. New results, technological advancements, and growing experience may potentially overcome current barriers for implementation in the future.

Navigating the Intersection of Technology and Depression Precision Medicine.

This chapter primarily focuses on the progress in depression precision medicine with specific emphasis on the integrative approaches that include artificial intelligence and other data, tools, and technologies. After the description of the concept of precision medicine and a comparative introduction to depression precision medicine with cancer and epilepsy, new avenues of depression precision medicine derived from integrated artificial intelligence and other sources will be presented. Additionally, less advanced areas, such as comorbidity between depression and cancer, will be examined.

Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis: a genome-wide multi-centric association study.

BACKGROUND: Inter-individual differences in treatment response are marked in multiple sclerosis (MS). This is true for Natalizumab (NTZ), to which a subset of patients displays sub-optimal treatment response. We conducted a multi-centric genome-wide association study (GWAS), with additional pathway and network analysis to identify genetic predictors of response to NTZ. METHODS: MS patients from three different centers were included. Response to NTZ was dichotomized, nominating responders (R) relapse-free patients and non-responders (NR) all the others, over a follow-up of 4 years. Association analysis on ~ 4.7 M imputed autosomal common single-nucleotide polymorphisms (SNPs) was performed fitting logistic regression models, adjusted for baseline covariates, followed by meta-analysis at SNP and gene level. Finally, these signals were projected onto STRING interactome, to elicit modules and hub genes linked to response. RESULTS: Overall, 1834 patients were included: 119 from Italy (R = 94, NR = 25), 81 from Germany (R = 61, NR = 20), and 1634 from Sweden (R = 1349, NR = 285). The top-associated variant was rs11132400T (p = 1.33 × 10-6, OR = 0.58), affecting expression of several genes in the locus, like KLKB1. The interactome analysis implicated a module of 135 genes, with over-representation of terms like canonical WNT signaling pathway (padjust = 7.08 × 10-6). Response-associated genes like GRB2 and LRP6, already implicated in MS pathogenesis, were topologically prioritized within the module. CONCLUSION: This GWAS, the largest pharmacogenomic study of response to NTZ, suggested MS-implicated genes and Wnt/ß-catenin signaling pathway, an essential component for blood-brain barrier formation and maintenance, to be related to treatment response.

Genetic Determinants of Response to P2Y12 Inhibitors and Clinical Implications.

The CYP2C19 enzyme metabolizes clopidogrel, a prodrug, to its active form. Approximately 30% of individuals inherit a loss-of-function (LoF) polymorphism in the CYP2C19 gene, leading to reduced formation of the active clopidogrel metabolite. Reduced clopidogrel effectiveness has been well documented in patients with an LoF allele following an acute coronary syndrome or percutaneous coronary intervention. Prasugrel or ticagrelor is recommended in those with an LoF allele as neither is affected by CYP2C19 genotype. Although data demonstrate improved outcomes with a CYP2C19-guided approach to P2Y12 inhibitor selection, genotyping has not yet been widely adopted in clinical practice.

An inherited genetic variant of the CEP72 gene is associated with the development of vincristine-induced peripheral neuropathy in female patients with aggressive B-cell lymphoma.

Vincristine-induced peripheral neuropathy (VIPN) is an adverse effect of regimens used for the treatment of aggressive B-cell non-Hodgkin lymphoma (B-NHL). A single-nucleotide polymorphism (SNP) in the promotor region of the CEP72 gene has been identified as risk factor for the development of VIPN in children. To validate these results in adults we aimed to determine the association of the high-risk CEP72 (rs924607 TT genotype) with the occurrence and severity of VIPN. Analysis of SNP rs924607 (TT, CC or CT) was performed in all enrolled patients with available blood samples with a TaqMan genotyping assay. Rates and grades of VIPN were assessed prospectively as part of the RICOVER-60 trial. CEP72 genotype could be assessed in 519 patients. VIPN data was available for 499/519 patients who were included in the final analysis. 286 (57%) patients developed VIPN of any grade during treatment. Grade 2-4 VIPN occurred in 33% (166/499) of patients. The high-risk CEP72 TT genotype at rs924607 was identified in 97/499 (19%) patients. The TT genotype was not correlated with VIPN in the overall study population compared to patients with either CC or CT genotypes (p = 0.748). However, in the subgroup of female patients, the TT genotype was associated with increased occurrence of any-grade VIPN as well as grade 2-4 VIPN as compared to patients with either CC or CT genotypes (p = 0.016 and p = 0.020, respectively). Thus, the SNP rs924607 in the CEP72 gene is associated with increased VIPN incidence in female patients with aggressive B-NHL treated with CHOP chemotherapy. Trial registration ClinicalTrials.gov identifier: NCT00052936, submission date: 2005-06-23, EudraCT Number: 2010-019587-36.

Implementation of a pharmacist-guided pharmacogenomics dosing service at a rural NCI-designated comprehensive cancer center.

INTRODUCTION: The goal of pharmacogenetic testing is to identify genetic variants with significant implications on drug safety and efficacy. Several professional organizations and institutions have demonstrated the value of pharmacist involvement in the implementation of pharmacogenomic services. Therefore, we aimed to establish a pharmacist-guided model for interpretation of pharmacogenetic results for all oncology patients seen at the Dartmouth Cancer Center (DCC) in Lebanon, NH. METHODS: A pilot of a pharmacist-guided pharmacogenomics dosing service was implemented at the DCC. Pharmacy services included review of results from a next generation sequencing panel for DPYD, TPMT, NUDT15, and UGT1A1 variants. The pharmacist wrote a note in the electronic health record (EHR) detailing actionable drug-gene interactions and drug-dosing guidance, which was then routed to the treating oncologist. Outcomes collected included highlighting actionable mutations and defining pharmacist interventions. In addition, time spent formulating and documenting patient-specific drug-dosing recommendations was collected. RESULTS: From February 2024 through May 2024, a total of 71 patients with pharmacogenetic results, provided by the clinical molecular laboratory at Dartmouth Health, were reviewed by the pharmacist. The majority of patients tested were diagnosed with a malignancy of gastrointestinal origin. Twenty-one patients were found to have actionable variants in at least one of the four genes evaluated, and five of the 21 identified patients had active treatment plans for which dose changes were then implemented. CONCLUSIONS: Implementation of a pharmacist-guided pharmacogenomics based dosing service aided in optimizing drug therapy and has positioned Dartmouth Health for further expansion of pharmacogenomics and personalized patient care.

Genetic polymorphisms and platinum-induced hematological toxicity: a systematic review.

Background: Platinum-based chemotherapy bring severe hematological toxicity that can lead to dose reduction or discontinuation of therapy. Genetic variations have been reported to influence the risk and extent of hematological toxicity; however, the results are controversial and a comprehensive overview is lacking. This systematic review aimed to identify genetic biomarkers of platinum-induced hematological toxicity. Method: Pubmed, Embase and Web of science database were systematically reviewed for studies that evaluated the association of genetic variants and platinum-related hematological toxicity in tumor patients with no prior history of chemotherapy or radiation, published from inception to the 28th of January 2022. The studies should have specific toxicity scoring system as well as defined toxicity end-point. The quality of reporting was assessed using the Strengthening the Reporting of Genetic Association Studies (STREGA) checklist. Results were summarized using narrative synthesis. Results: 83 studies were eligible with over 682 single-nucleotide polymorphisms across 110 genes. The results are inconsistent and diverse with methodological issues including insufficient sample size, population stratification, various treatment schedule and toxicity end-point, and inappropriate statistics. 11 SNPs from 10 genes (ABCB1 rs1128503, GSTP1 rs1695, GSTM1 gene deletion, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, XPC rs2228001, XPCC1 rs25487, MTHFR rs1801133, MDM2 rs2279744, TP53 rs1042522) had consistent results in more than two independent populations. Among them, GSTP1 rs1695, ERCC1 rs11615, ERCC1 rs3212986, and XRCC1 rs25487 present the most promising results. Conclusion: Even though the results are inconsistent and several methodological concerns exist, this systematic review identified several genetic variations that deserve validation in well-defined studies with larger sample size and robust methodology. Systematic Review Registration: https://www.crd.york.ac.uk/, identifier CRD42021234164.

Pharmacogenomics and pediatric drug development: science and political power. A narrative review.

INTRODUCTION: Pharmacogenomics (PGx) investigates how genomes control enzyme expression. Developmental pharmacology (DP) describes the temporal sequence of enzymes impacting absorption, distribution, metabolism, and excretion (ADME) of food and drugs. AREAS COVERED: US and European Union (EU) legislation facilitate and/or enforce pediatric studies for all new drugs, called overall 'pediatric drug development' (PDD). DP and PDD look at patients' chronological age, but oscillate between legal and physiological meanings of the term 'child.' Children's bodies become mature with puberty. EXPERT OPINION: Decades after first DP observations in babies, PGx offers a better understanding of the variability of safety and efficacy of drugs, of the process of aging, and of shifting enzyme patterns across aging. We should rethink and revise outdated interpretations of ADME changes in minors. The Declaration of Helsinki forbids pointless studies that some pediatric researchers and regulatory agencies, more so the EMA than the FDA, demand pointless pediatric studies is regrettable. Medicine needs to differentiate between legal and physiological meanings of the term 'child' and should use objective measures of maturity.

Genetic analysis: Therapeutic drug monitoring of metformin and glimepiride on diabetic patients' plasma including genetic polymorphism.

Diabetes is a widespread disease that needs to be controlled. Therapeutic monitoring of drugs is very helpful in maintaining desirable doses. To study a correlation between the blood level of metformin (to a lesser extent, glimepiride) and genotyping (mainly the SULT1A1 genotype). Determine drug levels using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) tool. A validated LC-MS/MS method was developed to determine metformin and glimepiride levels in human plasma. DNA extraction was performed using Jena Bioscience's Blood DNA preparation, in which a column kit was used to extract DNA for genetic polymorphism. The investigation was carried out using both medications in type 2 diabetes patients alongside the genetic polymorphism. One hundred and six patients were assessed. The prevalence of homozygosity for SULT1A1 and wild-type CYP2D6 * 4 were 72.6% and 73.6%, respectively. After adjustment for daily intake of metformin, three patients out of five with the highest levels of metformin had no homozygosity (SULT1A1 genotype). Statistically, variables that demonstrated an insignificant correlation with the level of metformin were body mass index (rs (87) = 0.32, P = 0.011) and age (rs (87) =0.26, P = 0.017). The homozygous (SULT1A1 genotype) correlation was moderate (rs (87) =0.21, P = 0.052). According to the findings, patients with the wt/wt CYP2D6 genotype had considerably greater levels of endoxifen than those with the v/v CYP2D6 genotype. The study's results reported a probable correlation between the blood level of metformin (to a lesser extent, glimepiride) and genotyping (mainly the SULT1A1 genotype). Genotype-guided drug therapy may provide a novel contribution to maximize drug efficacy and/or minimize toxicity.

γ-Aminobutyric acid type A receptor ß1 subunit gene polymorphisms are associated with the sedative and amnesic effects of midazolam.

Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: ß = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: ß = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam.