J Oncol Pharm Pract. 2022 Dec 4:10781552221137302. doi: 10.1177/10781552221137302. Online ahead of print.

NO ABSTRACT

PMID:36464835 | DOI:10.1177/10781552221137302

Neurosci Biobehav Rev. 2022 Dec 1:104965. doi: 10.1016/j.neubiorev.2022.104965. Online ahead of print.

NO ABSTRACT

PMID:36463971 | DOI:10.1016/j.neubiorev.2022.104965

J Psychiatr Res. 2022 Nov 18;157:152-161. doi: 10.1016/j.jpsychires.2022.11.010. Online ahead of print.

NO ABSTRACT

PMID:36463630 | DOI:10.1016/j.jpsychires.2022.11.010

Expert Rev Clin Pharmacol. 2022 Dec 3. doi: 10.1080/17512433.2023.2154652. Online ahead of print.

NO ABSTRACT

PMID:36461813 | DOI:10.1080/17512433.2023.2154652

Chem Res Toxicol. 2022 Dec 2. doi: 10.1021/acs.chemrestox.2c00214. Online ahead of print.

NO ABSTRACT

PMID:36459538 | DOI:10.1021/acs.chemrestox.2c00214

Cancer Control. 2022 Jan-Dec;29:10732748221143879. doi: 10.1177/10732748221143879.

ABSTRACT

OBJECTIVE: Interleukin-17A (IL-17A) genetic polymorphisms are associated with multiple cancer types, including colorectal cancer (CRC). However, no previous study was performed in the Bangladeshi population to evaluate the association. Our study aimed to find the association between two IL-17A variants (rs10484879 C/A and rs3748067 G/A) and susceptibility of CRC.

METHODS AND MATERIALS: This retrospective case-control study comprised 292 CRC patients and 288 age, sex, and BMI matched healthy volunteers. Genotyping of both variants was done by the tetra-primer ARMS-PCR method, and the results were analyzed by the SPSS software package (version-25.0).

RESULTS: Logistic regression analysis indicated that in case of IL-17A rs10484879 polymorphism, AC and AA genotype carriers showed 2.44- and 3.27-times significantly increased risk for CRC development (OR = 2.44, P = .0008 and OR = 3.27, P = .0133, individually). A significant association was also observed for AC + AA genotype (OR = 2.58, P = .0001). Again, over-dominant and allelic model revealed statistically significant link to CRC risk (OR = 2.13, P = .0035 and OR = 2.22, P = .001). For rs3748067 polymorphism, AG and AA genotype carriers showed 2.30- and 2.45-times enhanced risk for CRC (OR = 2.30, P = .005 and OR = 2.45, P = .031). A statistically significant association was also observed for AG + AA genotype (OR = 2.35, P = .001), over-dominant model (OR = 2.05, P = .014), and allelic model (OR = 2.11, P = .0004).

CONCLUSION: This study highlights that IL-17A rs10484879 and rs3748067 polymorphisms may be associated with CRC development. However, further functional research with larger samples may reveal more statistically significant outcomes.

PMID:36458977 | DOI:10.1177/10732748221143879

Front Big Data. 2022 Nov 15;5:1059088. doi: 10.3389/fdata.2022.1059088. eCollection 2022.

ABSTRACT

INTRODUCTION: A growing number of healthcare providers make complex treatment decisions guided by electronic health record (EHR) software interfaces. Many interfaces integrate multiple sources of data (e.g., labs, pharmacy, diagnoses) successfully, though relatively few have incorporated genetic data.

METHOD: This study utilizes informatics methods with predictive modeling to create and validate algorithms to enable informed pharmacogenomic decision-making at the point of care in near real-time. The proposed framework integrates EHR and genetic data relevant to the patient's current medications including decision support mechanisms based on predictive modeling. We created a prototype with EHR and linked genetic data from the Department of Veterans Affairs (VA), the largest integrated healthcare system in the US. The EHR data included diagnoses, medication fills, and outpatient clinic visits for 2,600 people with HIV and matched uninfected controls linked to prototypic genetic data (variations in single or multiple positions in the DNA sequence). We then mapped the medications that patients were prescribed to medications defined in the drug-gene interaction mapping of the Clinical Pharmacogenomics Implementation Consortium's (CPIC) level A (i.e., sufficient evidence for at least one prescribing action) guidelines that predict adverse events. CPIC is a National Institute of Health funded group of experts who develop evidence based pharmacogenomic guidelines. Preventable adverse events (PAE) can be defined as a harmful outcome from an intervention that could have been prevented. For this study, we focused on potential PAEs resulting from a medication-gene interaction.

RESULTS: The final model showed AUC scores of 0.972 with an F1 score of 0.97 with genetic data as compared to 0.766 and 0.73 respectively, without genetic data integration.

DISCUSSION: Over 98% of people in the cohort were on at least one medication with CPIC level a guideline in their lifetime. We compared predictive power of machine learning models to detect a PAE between five modeling methods: Random Forest, Support Vector Machine (SVM), Extreme Gradient Boosting (XGBoost), K Nearest neighbors (KNN), and Decision Tree. We found that XGBoost performed best for the prototype when genetic data was added to the framework and improved prediction of PAE. We compared area under the curve (AUC) between the models in the testing dataset.

PMID:36458283 | PMC:PMC9705957 | DOI:10.3389/fdata.2022.1059088

Front Pharmacol. 2022 Nov 15;13:752314. doi: 10.3389/fphar.2022.752314. eCollection 2022.

ABSTRACT

Clinical trial and individual patient treatment outcomes have produced accumulating evidence that effective primaquine (PQ) treatment of Plasmodium vivax and P. ovale liver stage hypnozoites is associated with genetic variation in the human cytochrome P450 gene, CYP2D6. Successful PQ treatment of individual and population-wide infections by the Plasmodium species that generate these dormant liver stage forms is likely to be necessary to reach elimination of malaria caused by these parasites globally. Optimizing safe and effective PQ treatment will require coordination of efforts between the malaria and pharmacogenomics research communities.

PMID:36457706 | PMC:PMC9705595 | DOI:10.3389/fphar.2022.752314

J Acoust Soc Am. 2022 Nov;152(5):2828. doi: 10.1121/10.0015092.

ABSTRACT

In 2019, the U.S. Food and Drug Administration issued guidance to increase the efficiency of drug development and support precision medicine, including tailoring treatments to those patients who will benefit based on genetic variation even in the absence of a documented mechanism of action. Although multiple advancements have been made in the field of pharmacogenetics (PGx) for other disease conditions, there are no approved PGx guidelines in the treatment of hearing disorders. In studies of noise-induced hearing loss (NIHL), some progress has been made in the last several years associating genomic loci with susceptibility to noise damage. However, the power of such studies is limited as the underlying physiological responses may vary considerably among the patient populations. Here, we have summarized previous animal studies to argue that NIHL subtyping is a promising strategy to increase the granularity of audiological assessments. By coupling this enhanced phenotyping capability with genetic association studies, we suggest that drug efficacy will be better predicted, increasing the likelihood of success in clinical trials when populations are stratified based on genetic variation or designed with multidrug combinations to reach a broader segment of individuals suffering or at risk from NIHL.

PMID:36456290 | DOI:10.1121/10.0015092

Chin Med J (Engl). 2022 Nov 30. doi: 10.1097/CM9.0000000000002419. Online ahead of print.

NO ABSTRACT

PMID:36455204 | DOI:10.1097/CM9.0000000000002419

Pharmacogenomics. 2022 Dec 1. doi: 10.2217/pgs-2022-0148. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) testing is commonly utilized to predict a patient's response to medications based on the presence of genetic variants. However, certain conditions have been associated with potentially inaccurate PGx results. The majority of medications are predominantly metabolized in the liver; therefore, in the case of liver transplantation, PGx results may be misinterpreted in the context of drug-metabolizing enzymes. Other instances of ambiguous PGx results have been reported in the literature in conditions such as allogeneic stem cell or bone marrow transplant, chronic lymphocytic leukemia, acute or chronic myeloid leukemia and blood transfusion. In order to prevent potential inaccuracies in PGx testing, Sanford Imagenetics developed an active, interruptive alert to inform providers of the potential for inaccurate PGx results.

PMID:36454237 | DOI:10.2217/pgs-2022-0148

J Int Med Res. 2022 Nov;50(11):3000605221138492. doi: 10.1177/03000605221138492.

ABSTRACT

OBJECTIVE: Although the prevalence of autism spectrum disorder (ASD) is increasing, appropriate diagnosis and prevention strategies are still lacking. This case-control study was designed to explore the association between ASD and the rs1867503 and rs9951150 polymorphisms of the TF and TCF4 genes, respectively.

METHODS: Ninety-six children with ASD and 118 healthy children were recruited and polymerase chain reaction-restriction fragment length polymorphism technique was applied for genotyping.

RESULTS: The frequencies of the mutant allele G were 48% and 44% for the rs1867503 and rs9951150 polymorphisms, respectively. In our analysis, both TF and TCF4 polymorphisms were associated with an increased risk of developing ASD. AG heterozygotes (OR = 3.18), GG mutant homozygotes (OR = 2.62), AG + GG combined genotypes (OR = 2.98), and G mutant alleles of TF rs1867503 (OR = 1.94) were associated with a significantly elevated risk of ASD. Likewise, AG heterozygotes (OR = 2.92), GG mutant homozygotes (OR = 2.36), AG + GG combined genotypes (OR = 2.72), and G minor alleles of TCF4 rs9951150 (OR = 1.92) were associated with a significantly elevated risk of ASD.

CONCLUSIONS: Our results indicate that TF rs1867503 and TCF4 rs9951150 polymorphisms may be strongly associated with the development of ASD in Bangladeshi children.

PMID:36448207 | DOI:10.1177/03000605221138492

Pain Rep. 2022 Nov 24;7(6):e1046. doi: 10.1097/PR9.0000000000001046. eCollection 2022 Nov-Dec.

ABSTRACT

INTRODUCTION: Many patients with chronic pain use prescription opioids. Epigenetic modification of the μ-opioid receptor 1 (OPRM1) gene, which codes for the target protein of opioids, may influence vulnerability to opioid abuse and response to opioid pharmacotherapy, potentially affecting pain outcomes.

OBJECTIVE: Our objective was to investigate associations of clinical and sociodemographic factors with OPRM1 DNA methylation in patients with chronic musculoskeletal pain on long-term prescription opioids.

METHODS: Sociodemographic variables, survey data (Rapid Estimate of Adult Health Literacy in Medicine-Short Form, Functional Comorbidity Index [FCI], PROMIS 43v2.1 Profile, Opioid Risk Tool, and PROMIS Prescription Pain Medication Misuse), and saliva samples were collected. The genomic DNA extracted from saliva samples were bisulfite converted, amplified by polymerase chain reaction, and processed for OPRM1-targeted DNA methylation analysis on a Pyrosequencing instrument (Qiagen Inc, Valencia, CA). General linear models were used to examine the relationships between the predictors and OPRM1 DNA methylation.

RESULTS: Data from 112 patients were analyzed. The best-fitted multivariable model indicated, compared with their counterparts, patients with > eighth grade reading level, degenerative disk disease, substance abuse comorbidity, and opioid use < 1 year (compared with >5 years), had average methylation levels that were 7.7% (95% confidence interval [CI] 0.95%, 14.4%), 11.7% (95% CI 2.7%, 21.1%), 21.7% (95% CI 10.7%, 32.5%), and 16.1% (95% CI 3.3%, 28.8%) higher than the reference groups, respectively. Methylation levels were 2.2% (95% CI 0.64%, 3.7%) lower for every 1 unit increase in FCI and greater by 0.45% (95% CI 0.08%, 0.82%) for every fatigue T score unit increase.

CONCLUSIONS: OPRM1 methylation levels varied by several patient factors. Further studies are warranted to replicate these findings and determine potential clinical utility.

PMID:36447952 | PMC:PMC9699511 | DOI:10.1097/PR9.0000000000001046

Pharmgenomics Pers Med. 2022 Nov 23;15:967-976. doi: 10.2147/PGPM.S382214. eCollection 2022.

ABSTRACT

PURPOSE: In Switzerland 167 drugs on the market contain information about pharmacogenetics in their drug label (PGx drug). Preemptive pharmacogenetic testing is reimbursed by health care insurance for only seven drugs (abacavir, carbamazepine, 6-mercaptopurine, azathioprine, 5-fluorouracil, capecitabine, and irinotecan) although, it is proposed to be a cost-effective approach to personalized medicine. The aim of this study was to describe the use of PGx drugs and their corresponding genes in Switzerland.

METHODS: We identified 90 drugs with dosing recommendations from the Pharmacogenetic Knowledgebase involving 24 genes. We assessed the utilization of those drugs between 2016 and 2020, using claims data from a large Swiss insurance company (Helsana).

RESULTS: Of 841 491 persons with drug claims during the whole study period, 78.7% were exposed to PGx drugs. Ibuprofen, pantoprazole, and tramadol had the highest number of users. Seven genes (CYP2C19, CYP2C9, CYP2D6, SLCO1B1, HLA-B, MT-RNR1, and VKORC1) were responsible for over 95% of all potential drug-gene interactions.

CONCLUSION: The prevalence of PGx drug prescriptions is high in the Swiss population. Therefore, intensified preemptive testing may be a useful option as a substantial amount of the Swiss population might benefit.

PMID:36447837 | PMC:PMC9701506 | DOI:10.2147/PGPM.S382214

BMC Pregnancy Childbirth. 2022 Nov 29;22(1):884. doi: 10.1186/s12884-022-05205-w.

ABSTRACT

BACKGROUND: Postpartum hemorrhage remains a key contributor to overall maternal morbidity in the United States. Current clinical assessment methods used to predict postpartum hemorrhage are unable to prospectively identify about 40% of hemorrhage cases. Oxytocin is a first-line pharmaceutical for preventing and treating postpartum hemorrhage, which acts through oxytocin receptors on uterine myocytes. Existing research indicates that oxytocin function is subject to variation, influenced in part by differences in the DNA sequence within the oxytocin receptor gene. One variant, rs53576, has been shown to be associated with variable responses to exogenous oxytocin when administered during psychological research studies. How this variant may influence myometrial oxytocin response in the setting of third stage labor has not been studied. We tested for differences in the frequency of the oxytocin receptor genotype at rs53576 in relationship to the severity of blood loss among a sample of individuals who experienced vaginal birth.

METHODS: A case-control prospective design was used to enroll 119 postpartum participants who underwent vaginal birth who were at least 37 weeks of gestation. Cases were defined by either a 1000 mL or greater blood loss or instances of heavier bleeding where parturients were given additional uterotonic treatment due to uterine atony. Controls were matched to cases on primiparity and labor induction status. Genotype was measured from a maternal blood sample obtained during the 2nd postpartum month from 95 participants. Statistical analysis included bivariate tests and generalized linear and Poisson regression modeling.

RESULTS: The distribution of the genotype across the sample of 95 participants was 40% GG (n = 38), 50.5% AG (n = 48) and 9.5% AA (n = 9). Blood loss of 1000 mL or greater occurred at a rate of 7.9% for GG, 12.5% for AG and 55.6% for AA participants (p = 0.005). Multivariable models demonstrated A-carriers (versus GG) had 275.2 mL higher blood loss (95% CI 96.9-453.4, p < 0.01) controlling for parity, intrapartum oxytocin, self-reported ancestry, active management of third stage or genital tract lacerations. Furthermore, A-carrier individuals had a 79% higher risk for needing at least one second-line treatment (RR = 1.79, 95% CI = 1.08-2.95) controlling for covariates. Interaction models revealed that A-carriers who required no oxytocin for labor stimulation experienced 371.4 mL greater blood loss (95% CI 196.6-546.2 mL).

CONCLUSIONS: We provide evidence of a risk allele in the oxytocin receptor gene that may be involved in the development of postpartum hemorrhage among participants undergoing vaginal birth, particularly among those with fewer risk factors. The findings, if reproducible, could be useful in studying pharmacogenomic strategies for predicting, preventing or treating postpartum hemorrhage.

PMID:36447139 | DOI:10.1186/s12884-022-05205-w

Drug Metab Dispos. 2022 Nov 29:DMD-MR-2022-000856. doi: 10.1124/dmd.122.000856. Online ahead of print.

ABSTRACT

Many clinically used antiviral drugs are nucleoside or nucleotide analogue drugs, which have a unique mechanism of action that requires intracellular phosphorylation. This dependence on intracellular activation presents novel challenges for the discovery and development of nucleoside/nucleotide analogue drugs. Contrary to many small molecule drug development programs that rely on plasma pharmacokinetics and systemic exposures, the precise mechanisms that result in efficacious intracellular nucleoside triphosphate concentrations must be understood in the process of nucleoside/nucleotide drug development. The importance is highlighted here, using the following as case studies: the herpes treatment acyclovir, the cytomegalovirus therapy ganciclovir, and human immunodeficiency virus (HIV) treatments based on tenofovir, which are also in use for HIV prophylaxis. For each drug, the specificity of metabolism that results in its activation in different cells or tissues is discussed, and the implications explored. Acyclovir's dependence on a viral enzyme for activation provides selective pressure for resistance mutations. Ganciclovir is also dependent on a viral enzyme for activation, and suicide gene therapy capitalizes on that for a novel oncology treatment. The tissue of most relevance for tenofovir activation depends on its use as treatment or as prophylaxis, and the pharmacogenomics and drug-drug interactions in those tissues must be considered. Finally, differential metabolism of different tenofovir prodrugs and its effects on toxicity risk are explored. Taken together, these examples highlight the importance of understanding tissue specific metabolism for optimal use of nucleoside/nucleotide drugs in the clinic. Significance Statement Nucleoside and nucleotide analogue drugs are cornerstones in current antiviral therapy and prevention efforts that require intracellular phosphorylation for activity. Understanding their cell and tissue specific metabolism enables their rational, precision use for maximum efficacy.

PMID:36446610 | DOI:10.1124/dmd.122.000856

Int J Pharm Compd. 2022 Nov-Dec;26(6):480-488.

ABSTRACT

Skin injuries, whether acute or chronic, can present therapeutic challenges engendered by wound type and etiology as well as the pharmacogenomic profile and treatment preferences of the patient. As a result, standardized manufactured medications may fail to promote healing or their use may prove intolerable (complications that impose a burden on patients and ultimately on the society in which they live and the healthcare system that supports them). For cases in which commercially available wound-healing products fail or cannot be used, a uniquely formulated pharmaceutical compound may be effective. In this article, the differences between acute and chronic dermal injuries are presented, wound infection is discussed, specific compounds designed to treatment some of the most challenging dermal-wound types are listed, and two complete formulations that have also proven safe and effective in promoting the healing of external skin damage are provided.

PMID:36445767

Int J Pharm Compd. 2022 Nov-Dec;26(6):474-479.

ABSTRACT

Patients' responses to medical treatment vary greatly; while many may benefit from pharmacological therapy, others may suffer from harmful drug reactions or show no response at all. To provide an effective individualized care, one must understand the elements that lead to varying patient outcomes and how these factors may interplay in an individual's treatment outcome. Pharmacogenomics is the future of pharmacy, and there is a growing demand for this service. Compounding pharmacies are already at the forefront of meeting patients' unique drug requirements. This gives them the opportunity to provide their patients with more valuable services than only selling drugs dictated by the formula! This article discusses pharmacogenomics as a competitive strategy for compounding pharmacies.

PMID:36445766

Cardiovasc Drugs Ther. 2022 Nov 29. doi: 10.1007/s10557-022-07392-2. Online ahead of print.

ABSTRACT

PURPOSE: Chronic kidney disease (CKD) is a risk factor for ischemic and bleeding events with dual antiplatelet therapy after percutaneous coronary intervention (PCI). Whether the presence of CYP2C19 loss of function (LOF) alleles modifies this risk, and whether a genotype-guided (GG) escalation of P2Y12 inhibitor therapy post PCI is safe in this population is unclear.

METHODS: This was a post hoc analysis of randomized patients in TAILOR PCI. Patients were divided into two groups based on estimated glomerular filtration rate (eGFR) threshold of < 60 ml/min/1.73 m2 for CKD (n = 539) and non-CKD (n = 4276). The aggregate of cardiovascular death, stroke, myocardial infarction, stent thrombosis, and severe recurrent coronary ischemia at 12-months post-PCI was assessed as the primary endpoint. Secondary endpoint was major or minor bleeding.

RESULTS: Mean (standard deviation) eGFR among patients with CKD was 49.5 (8.4) ml/min/1.72 m2. Among all patients, there was no significant interaction between randomized strategy and CKD status for any endpoint. Among LOF carriers, the interaction between randomized strategy and CKD status on composite ischemic outcome was not significant (p = 0.2). GG strategy was not associated with an increased risk of bleeding in either CKD group.

CONCLUSIONS: In this exploratory analysis, escalation of P2Y12 inhibitor therapy following a GG strategy did not reduce the primary outcome in CKD. However, P2Y12 inhibitor escalation following a GG strategy was not associated with increased bleeding risk in CKD. Larger studies in CKD are needed.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01742117?term=TAILOR-PCI&draw=2&rank=1 . NCT01742117.

PMID:36445624 | DOI:10.1007/s10557-022-07392-2

Brief Bioinform. 2022 Nov 29:bbac490. doi: 10.1093/bib/bbac490. Online ahead of print.

ABSTRACT

Transcriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types. TSR relies on the assumption that a drug that can revert gene expression changes induced by a disease back to original, i.e. healthy, levels is likely to be therapeutically active in treating the disease. Here, we aimed to validate the concept of TSR using the PRISM repurposing data set, which is-as of writing-the largest pharmacogenomic data set. The predictive utility of the TSR approach as it has currently been used appears to be much lower than previously reported and is completely nullified after the drug gene expression signatures are adjusted for the general anti-proliferative downstream effects of drug-induced decreased cell viability. Therefore, TSR mainly relies on generic anti-proliferative drug effects rather than on targeting cancer pathways specifically upregulated in tumor types.

PMID:36445193 | DOI:10.1093/bib/bbac490