Pharmacogenomics. 2023 Aug 24. doi: 10.2217/pgs-2023-0097. Online ahead of print.

ABSTRACT

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes and SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e., CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.

PMID:37615099 | DOI:10.2217/pgs-2023-0097

Front Pharmacol. 2023 Aug 8;14:1267344. doi: 10.3389/fphar.2023.1267344. eCollection 2023.

NO ABSTRACT

PMID:37614312 | PMC:PMC10442934 | DOI:10.3389/fphar.2023.1267344

Nat Commun. 2023 Aug 23;14(1):4863. doi: 10.1038/s41467-023-39858-8.

ABSTRACT

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

PMID:37612283 | DOI:10.1038/s41467-023-39858-8

Comput Biol Med. 2023 Aug 10;165:107329. doi: 10.1016/j.compbiomed.2023.107329. Online ahead of print.

ABSTRACT

Screening potential drug-drug interactions, drug-gene interactions, contraindications, and other factors is crucial in clinical practice. However, implementing these screening concepts in real-world settings poses challenges. This work proposes an approach towards precision medicine that combines genetic and nongenetic factors to facilitate clinical decision-making. The approach focuses on raising the performance of four potential interaction screenings in the prescribing process, including drug-drug interactions, drug-gene interactions, drug-herb interactions, drug-social lifestyle interactions, and two potential considerations for patients with liver or renal impairment. The work describes the design of a curated knowledge-based model called the knowledge model for potential interaction and consideration screening, the screening logic for both the detection module and inference module, and the personalized prescribing report. Three case studies have demonstrated the proof-of-concept and effectiveness of this approach. The proposed approach aims to reduce decision-making processes for healthcare professionals, reduce medication-related harm, and enhance treatment effectiveness. Additionally, the recommendation with a semantic network is suggested to assist in risk-benefit analysis when health professionals plan therapeutic interventions with new medicines that have insufficient evidence to establish explicit recommendations. This approach offers a promising solution to implementing precision medicine in clinical practice.

PMID:37611418 | DOI:10.1016/j.compbiomed.2023.107329

Pharmacogenomics. 2023 Aug 23. doi: 10.2217/pgs-2023-0103. Online ahead of print.

ABSTRACT

Background: This study investigated the use of COMT G1947A and OPRM1 A118G polymorphisms as predictive markers for sufentanil epidural analgesia. Methods: The visual analogue scale (VAS) score, and sufentanil consumption of 136 pairs of parturients using sufentanil with lidocaine and ropivacaine for epidural analgesia were used for analysis. Results: OPRM1 AG/GG had lower VAS score difference between fifth and 0 min (1.55 vs 1.87; p = 0.012) and higher consumption (19.65 μg vs 17.11 μg; p = 0.049) than AA carriers. COMT GA/AA had higher VAS score difference than GG carriers (1.86 vs 1.55; p = 0.021). Conclusion: Sufentanil may provide better epidural labor analgesia in OPRM1 AA and COMT GA/AA carriers compared with OPRM1 AG/GG and COMT GG carriers. Clinical Trial Registration: ChiCTR1900026897 (Chinese Clinical Trial Center Registry).

PMID:37610885 | DOI:10.2217/pgs-2023-0103

Pharmacogenomics. 2023 Aug 23. doi: 10.2217/pgs-2023-0109. Online ahead of print.

ABSTRACT

Metformin, a hypoglycemic drug for Type 2 diabetes mellitus, shows variability in pharmacokinetics and response due to membrane transporters. This study followed 34 Type 2 diabetes mellitus patients on metformin treatment. Genetic variants in 11 metformin transport-related genes were analyzed, revealing associations. Specifically, SLC47A1 rs2289669 A/A and SLC22A4 rs1050152 T/T genotypes correlated with glycated hemoglobin values at 6 months. SLC47A1 rs2289669 G/A genotype influenced glucose levels at 6 months, while SLC29A4 rs3889348 A/A, SLC47A1 rs2289669 A/A, SLC22A4 rs1050152 C/T and SLC47A2 rs12943590 A/A genotypes were linked to glucose levels at 12 months. Additionally, ABCB1 rs2032582 C/A and ABCG2 rs2231137 C/T genotypes impacted cholesterol levels at 12 months. These findings shed light on metformin response determinants, offering insights for further research.

PMID:37610884 | DOI:10.2217/pgs-2023-0109

Pharmacogenomics. 2023 Aug 23. doi: 10.2217/pgs-2023-0105. Online ahead of print.

ABSTRACT

Ethnicity is known to have an impact on drug responses. This is particularly important for drugs that have a narrow therapeutic window, nonlinearity in pharmacokinetics and are metabolized by enzymes that demonstrate genetic polymorphisms. However, most clinical trials are conducted among Caucasians, which might limit the usefulness of the findings of such studies for other ethnicities. The representation of participants from Saudi Arabia in global clinical trials is low. Therefore, there is a paucity of evidence to assess the impact of ethnic variability in the Saudi population on drug response. In this article, the authors assess the projected impact of genetic polymorphisms in drug-metabolizing enzymes and drug targets on drug response in the Saudi population.

PMID:37610881 | DOI:10.2217/pgs-2023-0105

Psychiatr Ann. 2021 Apr;51(4):175-184. doi: 10.3928/00485713-20210309-01.

ABSTRACT

Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyper-activity disorder (ADHD), represent a group of conditions that manifest early in child development and produce impairments across multiple domains of functioning. Although a number of pharmacological and psychosocial treatments exist to improve the symptoms associated with these syndromes, treatment advances have lagged. The Precision Medicine Initiative was launched with the goal of revolutionizing medicine by progressing beyond the historical one-size-fits-all approach. In this review, we evaluate current research efforts to personalize treatments for ASD and ADHD. Most pharmacogenetic testing has focused on the cytochrome P450 enzyme family with a particular focus on CYP2D6 and CYP2C19, which are genes that produce an enzyme that acts as a key metabolizer of many prescribed medications. This article provides an update on the state of the field of pharmacogenetics and "therapy-genetics" in the context of ASD and ADHD, and it also encourages clinicians to follow US Food and Drug Administration recommendations regarding pharmacogenetic testing.

PMID:37609560 | PMC:PMC10443929 | DOI:10.3928/00485713-20210309-01

Front Oncol. 2023 Aug 7;13:1232476. doi: 10.3389/fonc.2023.1232476. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fonc.2022.979519.].

PMID:37609387 | PMC:PMC10441771 | DOI:10.3389/fonc.2023.1232476

Front Psychiatry. 2023 Aug 7;14:1250253. doi: 10.3389/fpsyt.2023.1250253. eCollection 2023.

ABSTRACT

BACKGROUND: Pharmacogenetic analyses can predict interpersonal differences in response to psychopharmacotherapy, which greatly facilitates the selection of the most effective medication at optimal doses. By personalizing therapy in this way, we can minimize adverse drug reactions (ADR) and prevent polypharmacy. Most psychotropic medications are metabolized by the cytochrome P450 enzymes CYP2D6, CYP2C19, and CYPA3A4, which influence drug metabolism and concentration, affecting both efficacy and the occurrence of ADR. The relationships between genetic variations and enzymatic activity allow pharmacogenetic analysis to provide important data for optimal drug selection. The following case report illustrates the impact of pharmacogenetic analysis on the course of pharmacologic treatment in an elderly patient with a major depressive episode.

METHODS: We present a case of a 79-year-old patient treated for severe depression with psychotic symptoms. We collected data on treatment selection and response to treatment before and after pharmacogenetic analysis. For pharmacogenetic analysis, common functional variants in CYP1A2, CYP3A4, CYP2B6, CYP2C19, and CYP2D6 were genotyped, and corresponding evidence-based treatment recommendations were prepared.

RESULTS: The patient suffered from lack of efficacy and serious ADR of several medications, resulting in worsening depression and treatment resistance over the course of several months of treatment. Pharmacogenetic analysis provided important insights into the patient's pharmacokinetic phenotype and allowed us to personalize treatment and achieve remission of the depressive episode.

CONCLUSION: In the case presented, we have shown how consideration of pharmacogenetic characteristics in an individual patient can improve treatment outcome and patient well-being. Knowledge of the patient's pharmacogenetic characteristics helped us to personalize treatment, resulting in complete remission of psychopathology. Due to the complexity of psychiatric disorders, the efficacy of combinations of different medications, which are often required in individual patients, cannot be clearly explained. Therefore, it is of great importance to conduct further pharmacokinetic and pharmacogenetic studies to better assess gene-drug interactions in psychopharmacotherapy.

PMID:37608991 | PMC:PMC10440381 | DOI:10.3389/fpsyt.2023.1250253

Diabetes Obes Metab. 2023 Aug 22. doi: 10.1111/dom.15246. Online ahead of print.

ABSTRACT

AIM: To validate pharmacodynamic responses to sodium-glucose co-transporter-2 (SGLT2) inhibitors and test for association with genetic variants in SLC5A4, SLC5A9, and SLC2A9.

METHODS: Canagliflozin (300 mg), a SGLT2 inhibitor, was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses, including drug-induced increases in urinary excretion of glucose, sodium and uric acid.

RESULTS: This pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; P = 6 × 10-5 ), serum creatinine (+0.05 mg/dL; P = 8 × 10-4 ) and serum uric acid (-0.90 mg/dL; P = 5 × 10-10 ). The effects of sex on glucosuria depended upon how data were normalized. Whereas males' responses were ~60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated glomerular filtration rate or age in those healthy individuals without diabetes with an estimated glomerular filtration rate of more than 60 mL/min/1.73m2 .

CONCLUSIONS: Normalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as HbA1c and renal function.

PMID:37608471 | DOI:10.1111/dom.15246

Methods Mol Biol. 2023;2967:181-192. doi: 10.1007/978-1-0716-3358-8_15.

ABSTRACT

Polymerase chain reaction (PCR) is a laboratory technique used to amplify a targeted region of DNA, demarcated by a set of oligonucleotide primers. Long-range PCR is a form of PCR optimized to facilitate the amplification of large fragments. Using the adapted long-range PCR protocol described in this chapter, we were able to generate PCR products of 6.6, 7.2, 13, and 20 kb from human genomic DNA samples. For some of the long PCRs, successful amplification was not possible without the use of PCR enhancers. Thus, we also evaluated the impact of some enhancers on long-range PCR and included the findings as part of this updated chapter.

PMID:37608112 | DOI:10.1007/978-1-0716-3358-8_15

Small. 2023 Aug 22:e2206688. doi: 10.1002/smll.202206688. Online ahead of print.

ABSTRACT

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer , accounting for approximately 85% of lung cancers. For more than 40 years, platinum (Pt)-based drugs are still one of the most widely used anticancer drugs even in the era of precision medicine and immunotherapy. However, the clinical limitations of Pt-based drugs, such as serious side effects and drug resistance, have not been well solved. This study constructs a new albumin-encapsulated Pt(IV) nanodrug (HSA@Pt(IV)) based on the Pt(IV) drug and nanodelivery system. The characterization of nanodrug and biological experiments demonstrate its excellent drug delivery and antitumor effects. The multi-omics analysis of the transcriptome and the ionome reveals that nanodrug can activate ferroptosis by affecting intracellular iron homeostasis in NSCLC. This study provides experimental evidence to suggest the potential of HSA@Pt(IV) as a nanodrug with clinical application.

PMID:37606911 | DOI:10.1002/smll.202206688

Acta Neuropsychiatr. 2023 Aug 22:1-35. doi: 10.1017/neu.2023.38. Online ahead of print.

ABSTRACT

OBJECTIVE: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-β by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-β-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering APOE-ε4 carrier status and blood pressure response to angiotensin modulators.

METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for one year, taking APOE-ε4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs.

RESULTS: For 193 patients (67.4% women, 53.4% APOE-ε4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=0.281), while arterial hypertension was prevalent in 80.3% (n=124 used an ACEi, n=21 used an ARB). ARBs benefitted mostly APOE-ε4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ε4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations.

CONCLUSION: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

PMID:37605989 | DOI:10.1017/neu.2023.38

Front Mol Biosci. 2023 Aug 4;10:1215204. doi: 10.3389/fmolb.2023.1215204. eCollection 2023.

ABSTRACT

Breast cancer is the second leading cause of cancer death in women among all cancer types. It is highly heterogeneous in nature, which means that the tumors have different morphologies and there is heterogeneity even among people who have the same type of tumor. Several staging and classifying systems have been developed due to the variability of different types of breast cancer. Due to high heterogeneity, personalized treatment has become a new strategy. Out of all breast cancer subtypes, triple-negative breast cancer (TNBC) comprises ∼10%-15%. TNBC refers to the subtype of breast cancer where cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptors (ERs, PRs, and HERs). Tumors in TNBC have a diverse set of genetic markers and prognostic indicators. We scanned the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases for potential drugs using human breast cancer cell lines and drug sensitivity data. Three different machine-learning approaches were used to evaluate the prediction of six effective drugs against the TNBC cell lines. The top biomarkers were then shortlisted on the basis of their involvement in breast cancer and further subjected to testing for radion resistance using data from the Cleveland database. It was observed that Panobinostat, PLX4720, Lapatinib, Nilotinib, Selumetinib, and Tanespimycin were six effective drugs against the TNBC cell lines. We could identify potential derivates that may be used against approved drugs. Only one biomarker (SETD7) was sensitive to all six drugs on the shortlist, while two others (SRARP and YIPF5) were sensitive to both radiation and drugs. Furthermore, we did not find any radioresistance markers for the TNBC. The proposed biomarkers and drug sensitivity analysis will provide potential candidates for future clinical investigation.

PMID:37602329 | PMC:PMC10436744 | DOI:10.3389/fmolb.2023.1215204

Cureus. 2023 Jul 19;15(7):e42169. doi: 10.7759/cureus.42169. eCollection 2023 Jul.

ABSTRACT

Background Clopidogrel hyporesponsiveness with decreased antiplatelet activity is prevalent in percutaneous coronary intervention (PCI) patients due to reduced function polymorphism in the CYP2C19 enzyme gene which results in poor conversion of this prodrug to an active metabolite. However, pharmacogenetic testing is not part of routine clinical practice in India. Methodology In this retrospective observational study, we observed the prevalence of loss of function (LOF) gene variants of CYP2C19 (*2, *3) in 60 patients undergoing PCI with complex anatomies in a tertiary healthcare hospital in North India. We do not have follow-up data for a few patients. However, the treatment regimen was recorded, and the occurrence of any clinical event was monitored for the remaining 52 patients for six months. Results The mean age of the patients was 61.76 ± 10.14 years. We found that 52% of patients carried these LOF mutations, of which 37% were intermediate metabolizers, while 15% were poor metabolizers of clopidogrel. However, out of 52 patients for whom follow-up data were available, 22 (42.3%) were intermediate metabolizers, while six (11.54%) showed genotypes associated with poor metabolism of clopidogrel. Clopidogrel (75 mg BD) was the primary replacement drug in place of ticagrelor (90 mg BD) during follow-up after four weeks (based on the clinician's discretion). Conclusions No major ischemic event was reported during the follow-up of these 52 patients. The intermediate metabolizers' LOF in one copy of the CYP2C19 gene seems to overcome genetic deficiency with the clopidogrel 75 mg BD regime, which is comparable to maintenance with ticagrelor 90 mg BD. This study can be extrapolated to a larger cohort to observe statistically significant differences among various groups.

PMID:37602077 | PMC:PMC10439363 | DOI:10.7759/cureus.42169

Front Genet. 2023 Aug 2;14:1261876. doi: 10.3389/fgene.2023.1261876. eCollection 2023.

NO ABSTRACT

PMID:37600661 | PMC:PMC10436194 | DOI:10.3389/fgene.2023.1261876

JPGN Rep. 2023 Jul 17;4(3):e338. doi: 10.1097/PG9.0000000000000338. eCollection 2023 Aug.

NO ABSTRACT

PMID:37600608 | PMC:PMC10435021 | DOI:10.1097/PG9.0000000000000338

J Chemother. 2023 Aug 20:1-11. doi: 10.1080/1120009X.2023.2247208. Online ahead of print.

ABSTRACT

Voriconazole (VRC) displays highly variable pharmacokinetics impacting treatment efficacy and safety. To provide evidence for optimizing VRC therapy regimens, the authors set out to determine the factors impacting VRC steady-state trough concentration (Cmin) in patients with various albumin (Alb) level. A total of 275 blood samples of 120 patients and their clinical characteristics and genotypes of CYP2C19, CYP3A4, CYP3A5, CYP2C9, FMO3, ABCB1, POR, NR1I2 and NR1I3 were included in this study. Results of multivariate linear regression analysis demonstrated that C-reactive protein (CRP) and total bilirubin (T-Bil) were predictors of the VRC Cmin adjusted for dose in patients with hypoalbuminemia (Alb < 35 g/L) (R2 = 0.16, P < 0.001). Additionally, in patients with normal albumin level (Alb ≥ 35 g/L), it resulted in a significant model containing factors of the poor metabolizer (PM) CYP2C19 genotype and CRP level (R2 = 0.26, P < 0.001). Therefore, CRP and T-Bil levels ought to receive greater consideration than genetic factors in patients with hypoalbuminemia.

PMID:37599449 | DOI:10.1080/1120009X.2023.2247208

Expert Opin Drug Metab Toxicol. 2023 Aug 20. doi: 10.1080/17425255.2023.2249404. Online ahead of print.

ABSTRACT

INTRODUCTION: Parkinson's disease is a chronic neurodegenerative multisystemic disorder that affects approximately 2% of the population over 65 years old. This disorder is characterized by motor symptoms which are frequently accompanied by non-motor symptoms such as cognitive disorders. Current drug therapies aim to reduce the symptoms and increase the patient's life expectancy. Nevertheless, there is heterogeneity in therapy response in terms of efficacy and adverse effects. This wide range in response may be linked to genetic variability in the human genome. Thus, pharmacogenomics may help to tailor and personalize drug therapy for Parkinson's disease.

AREAS COVERED: This review describes and updates the clinical impact of genetic factors associated with the efficacy and adverse drug reactions related to common medications used to treat Parkinson's disease. Additionally, we highlight current informative recommendations for the drug treatment of Parkinson's disease.

EXPERT OPINION: The pharmacokinetic, pharmacodynamic, and safety profiles of Parkinson's disease drugs do not favor the development of pharmacogenetic tests with a high probability of success. The chances of obtaining ground-breaking pharmacogenetics biomarkers for Parkinson's disease therapy are limited. Nevertheless, additional information on the metabolism of certain drugs, and an analysis of the potential of pharmacogenetics in novel drugs could be of interest.

PMID:37599424 | DOI:10.1080/17425255.2023.2249404