Magnes Res. 2021 Aug 26. doi: 10.1684/mrh.2021.0484. Online ahead of print.

ABSTRACT

Chronic stress has been implicated in the development and progression of heart disease. In the past decade, a link between chronic stress and cardiac fibrosis has been described. Here, we focused on investigating the effects of one of the key molecular effectors of the stress response-adrenocorticotropic hormone (ACTH) on cardiac histopathology. More importantly, as the literature data support interplay between magnesium (Mg) and the hypothalamo-pituitary-adrenal (HPA) stress system, we explored potential cardioprotective effects of Mg supplementation in a rat model of ACTH-induced cardiac remodeling. Protracted ACTH exposure in rats resulted in a prominent increase in proliferation of fibroblasts and excessive collagen deposition in the heart, accompanied by enhanced proliferation of cardiomyocytes and vascular endothelial cells. Our results show, for the first time, that administration of Mg in rats was effective in ameliorating the development of ACTH-evoked cardiac fibrosis, while facilitating cardiomyocyte proliferation. Furthermore, we propose that Mg supplementation attenuates ACTH-induced HPA axis hyperactivity, as one of the underlying plausible mechanisms, which may contribute to its cardioprotective effects.

PMID:34463274 | DOI:10.1684/mrh.2021.0484

Biomed Pharmacother. 2021 Aug 24;142:112083. doi: 10.1016/j.biopha.2021.112083. Online ahead of print.

ABSTRACT

Eslicarbazepine acetate is a third-generation anti-epileptic prodrug quickly and extensively transformed to eslicarbazepine after oral administration. Reduction in seizure frequency in patients managed with eslicarbazepine is only partial in the majority of patients and many of them suffer considerable ADRs that require a change of treatment. The P-glycoprotein, encoded by the ABCB1 gene, is expressed throughout the body and can impact the pharmacokinetics of several drugs. In terms of epilepsy treatment, this transporter was linked to drug-resistant epilepsy, as it conditions drug access into the brain due to its expression at the blood-brain barrier. Therefore, we aimed to investigate the impact of three ABCB1 common polymorphisms (i.e., C3435T, or rs1045642, G2677A or rs2032582 and C1236T or rs1128503) in the pharmacokinetics and safety of eslicarbazepine. For this purpose, 22 healthy volunteers participating in a bioequivalence clinical trial were recruited. No significant relationship was observed between sex, race and ABCB1 polymorphism and eslicarbazepine pharmacokinetic variability. In contrast, ABCB1 C1236T C/C diplotype was significantly related to the occurrence of ADRs: one volunteer with this genotype suffered dizziness, somnolence and hand paresthesia, while no other volunteer suffered any of these ADRs (p < 0.045). To the best of our knowledge, this is the first study published to date evaluating eslicarbazepine pharmacogenetics. Further studies with large sample sizes are needed to compare the results obtained here.

PMID:34463270 | DOI:10.1016/j.biopha.2021.112083

Drug Test Anal. 2021 Aug 30. doi: 10.1002/dta.3156. Online ahead of print.

ABSTRACT

The use of specific medicine up to several months before a doping control is not be reported on the doping control form, while the drug could then still be detectable in urine in case of a very slow elimination. It may lead to a positive test result. For example, dorzolamide, a carbonic anhydrase inhibitor for topical ophthalmic application, has a very slow elimination rate via the renal route (half-life > 4 months). This substance can be a source of unintended anti-doping rule violations.

PMID:34463045 | DOI:10.1002/dta.3156

J Pain Symptom Manage. 2021 Aug 27:S0885-3924(21)00519-4. doi: 10.1016/j.jpainsymman.2021.08.007. Online ahead of print.

NO ABSTRACT

PMID:34461232 | DOI:10.1016/j.jpainsymman.2021.08.007

Clin Pharmacol Ther. 2021 Aug 30. doi: 10.1002/cpt.2407. Online ahead of print.

ABSTRACT

Anticoagulation response to warfarin during the initial stage of therapy varies among individuals. In this study, we aimed to combine pharmacometabolomic and pharmacogenetic data to predict inter-individual variation in warfarin response, and, on this basis, suggest an initial daily dose range. The baseline metabolic profiles, genotypes, and clinical information of 160 patients with heart valve disease served as the variables of the function international normalized ratio during the initial 7-day medication (INRday7 ) to screen for potential biomarkers. The partial least-squares model showed that two baseline metabolites (uridine and guanosine), one SNP (VKORC1), and four clinical parameters (weight, creatinine level, amiodarone usage, and initial daily dose) had good predictive power for INRday7 (R2 = 0.753 for the training set, 0.643 for the test set). With these biomarkers, a machine learning algorithm (two-dimensional linear discriminant analysis-multinomial logit model, 2D-LDA) was used to predict the subgroups with extremely warfarin-sensitive or less warfarin-sensitive patients with a prediction accuracy of 91% for the training set and 90% for the test set, indicating that individual responses to warfarin could be effectively predicted. Based on this model, we have successfully designed an algorithm,"IniWarD", for predicting an effective dose range in the initial 7-day warfarin therapy. The results indicate that the daily dose range suggested by the IniWarD system is more appropriate than that of the conventional genotype-based method, and the risk of bleeding or thrombus due to warfarin could thus be avoided.

PMID:34460938 | DOI:10.1002/cpt.2407

PLoS Genet. 2021 Aug 30;17(8):e1009713. doi: 10.1371/journal.pgen.1009713. Online ahead of print.

ABSTRACT

Genome-wide association studies (GWASs) have uncovered a wealth of associations between common variants and human phenotypes. Here, we present an integrative analysis of GWAS summary statistics from 36 phenotypes to decipher multitrait genetic architecture and its link with biological mechanisms. Our framework incorporates multitrait association mapping along with an investigation of the breakdown of genetic associations into clusters of variants harboring similar multitrait association profiles. Focusing on two subsets of immunity and metabolism phenotypes, we then demonstrate how genetic variants within clusters can be mapped to biological pathways and disease mechanisms. Finally, for the metabolism set, we investigate the link between gene cluster assignment and the success of drug targets in randomized controlled trials.

PMID:34460823 | DOI:10.1371/journal.pgen.1009713

JAMA Neurol. 2021 Aug 30. doi: 10.1001/jamaneurol.2021.2598. Online ahead of print.

ABSTRACT

IMPORTANCE: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

OBJECTIVE: To identify the genetic variants associated with juvenile ALS.

DESIGN, SETTING, AND PARTICIPANTS: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

MAIN OUTCOMES AND MEASURES: De novo variants present only in the index case and not in unaffected family members.

RESULTS: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

CONCLUSIONS AND RELEVANCE: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.

PMID:34459874 | DOI:10.1001/jamaneurol.2021.2598

Br J Dermatol. 2021 Aug 30. doi: 10.1111/bjd.20693. Online ahead of print.

NO ABSTRACT

PMID:34459498 | DOI:10.1111/bjd.20693

JAMIA Open. 2021 Aug 27;4(3):ooab067. doi: 10.1093/jamiaopen/ooab067. eCollection 2021 Jul.

ABSTRACT

BACKGROUND: Applied pharmacogenomics presents opportunities for improving patient care through precision medicine, particularly when paired with appropriate clinical decision support (CDS). However, a lack of patient resources for understanding pharmacogenomic test results may hinder shared decision-making and patient confidence in treatment. We sought to create a patient pharmacogenomics education and results delivery platform complementary to a CDS system to facilitate further research on the relevance of patient education to pharmacogenomics.

METHODS: We conceptualized a model that extended the data access layer of an existing institutional CDS tool to allow for the pairing of decision supports offered to providers with patient-oriented summaries at the same level of phenotypic specificity. We built a two-part system consisting of a secure portal for patient use and an administrative dashboard for patient summary creation. The system was built in an ASP.NET and AngularJS architecture, and all data was housed in a HIPAA-compliant data center, with PHI secure in transit and at rest.

RESULTS: The YourPGx Patient Portal was deployed on the institutional network in June 2019. Fifty-eight unique patient portal summaries have been written so far, which can provide over 4500 results modules to the pilot population of 544 patients. Patient behavior on the portal is being logged for further research.

CONCLUSIONS: To our knowledge, this is the first automated system designed and deployed to provide detailed, personalized patient pharmacogenomics education complementary to a clinical decision support system. Future work will expand upon this system to allow for telemedicine and patient notification of new or updated results.

PMID:34458686 | PMC:PMC8390782 | DOI:10.1093/jamiaopen/ooab067

Biol Psychiatry. 2021 Jul 7:S0006-3223(21)01429-3. doi: 10.1016/j.biopsych.2021.06.021. Online ahead of print.

ABSTRACT

BACKGROUND: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology.

METHODS: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [18F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS).

RESULTS: Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO.

CONCLUSIONS: This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.

PMID:34456009 | DOI:10.1016/j.biopsych.2021.06.021

Eur J Pharmacol. 2021 Aug 25:174444. doi: 10.1016/j.ejphar.2021.174444. Online ahead of print.

ABSTRACT

Pyroptosis is mainly considered a gasdermin-regulated cell death mechanism characterized by cellular lysis and the release of several pro-inflammatory factors. Nowadays, pyroptosis has notably been gained extensive attention from clinicians and researchers. However, current studies report that downregulation of pyroptosis-mediated cell death plays a significant role in developing multiple cancers. Increasing studies also suggest that pyroptosis can impact all stages of carcinogenesis. Inducing pyroptotic cellular death could be a promising therapeutic option for managing and regulating multiple cancers in the near future. Our current review highlights the molecular and morphological features of pyroptosis and its potential roles in various cancers. In addition, we have also highlighted the biological characteristics and significances of GSDMD and GSDME and their critical functions in cancer progression, management, and regulation.

PMID:34453928 | DOI:10.1016/j.ejphar.2021.174444

Eur J Clin Pharmacol. 2021 Aug 28. doi: 10.1007/s00228-021-03146-5. Online ahead of print.

ABSTRACT

PURPOSE: The purpose of this paper is to study the correlation between demographic and clinical factors and warfarin dose of patients in Chinese Han population taking warfarin and study gene polymorphisms impact of related gene loci (CYP2C9*3, VKORC1-1639G > A) on warfarin doses, to establish a model to predict initial standard dose and maintenance dose based on CYP2C9*3, VKORC1-1639G > A genotype.

METHODS: The study collects the data of patients in our hospital and other subcenters which incorporates 2160 patients to establish the initial dose model and 1698 patients for the stable dose model, and sequences 26 multigene sites in 451 patients. Based on the patient's dosage, clinical data, and demographic characteristics, the genetic and non-genetic effects on the initial dose and stable dose of warfarin are calculated by using statistical methods, and the prediction model of initial standard dose and maintenance dose can be established via multiple linear regression.

RESULTS: The initial dose of warfarin (mg/day) was calculated as (1.346 + 0.350 × (VKORC1-1639G > A) - 0.273 × (CYP2C9*3) + 0.245 × (body surface area) - 0.003 × (age) - 0.036 × (amine-iodine) + 0.021 × (sex))2. This model incorporated seven factors and explained 55.3% of the individualization differences of the warfarin drug dose. The maintenance dose of warfarin (mg/day) was calculated as (1.336 + 0.299 × (VKORC1-1639G > A) + 0.480 × (body surface area) - 0.214 × (CYP2C9*3) - 0.074 × (amine-iodine) - 0.003 × (age) - 0.077 × (statins) - 0.002 × (height))2. This model incorporated six factors and explained 42.4% of the individualization differences in the warfarin drug dose.

CONCLUSION: The genetic and non-genetic factors affecting warfarin dose in Chinese Han population were studied systematically in this study. The pharmacogenomic dose prediction model constructed in this study can predict anticoagulant efficacy of warfarin and has potential application value in clinical practice.

PMID:34453556 | DOI:10.1007/s00228-021-03146-5

Clin Pharmacol Ther. 2021 Aug 28. doi: 10.1002/cpt.2404. Online ahead of print.

ABSTRACT

Atovaquone-proguanil (ATV-PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine-pyrimethamine plus AQ for seasonal malaria chemoprevention (SMC) in African children. This randomized, double-blind, placebo-controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PK) of ATV-PG plus AQ in healthy adult males and females of Black sub-Saharan African origin. Participants were randomized to four treatment groups: ATV-PG/AQ (n=8), ATV-PG/placebo (n=12), AQ/placebo (n=12), and placebo/placebo (n=12). Treatments were administered orally once daily for three days (Days 1-3) at daily doses of ATV-PQ 1000/400 mg and AQ 612 mg. Co-administration of ATV-PG/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ or the AQ metabolite N-desethyl-amodiaquine. Adverse events occurred in 8/8 (100%) of participants receiving ATV-PG/AQ, 11/12 (91.7%) receiving ATV-PG, 11/12 (91.7%) receiving AQ, and 3/12 (25%) receiving placebo. The safety and tolerability profiles of ATV-PG and AQ were consistent with previous reports. In the ATV-PG/AQ group, 2/8 participants experienced extrapyramidal adverse effects (EPAE) on Day 3, both psychiatric and physical, which appeared unrelated to drug plasma PK or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV-PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children.

PMID:34453327 | DOI:10.1002/cpt.2404

Mol Psychiatry. 2021 Aug 27. doi: 10.1038/s41380-021-01256-1. Online ahead of print.

ABSTRACT

Drug addiction, one of the major health problems worldwide, is characterized by the loss of control in drug intake, craving, and withdrawal. At the individual level, drugs of abuse produce serious consequences on health and have a negative impact on the family environment and on interpersonal and work relationships. At a wider scale, they have significant socio-economic and public health consequences and they cause delinquency and citizen insecurity. Cocaine, a psychostimulant substance, is one of the most used illicit drugs, especially in America, Western Europe, and Australia. Cocaine use disorders (CUD) are complex multifactorial conditions driven by both genetic and environmental influences. Importantly, not all people who use cocaine develop CUD, and this is due, at least in part, to biological factors that are encoded in the genome of individuals. Acute and repeated use of cocaine induces epigenetic and gene expression changes responsible for the neuronal adaptations and the remodeling of brain circuits that lead to the transition from use to abuse or dependence. The purpose of this review is to delineate such factors, which should eventually help to understand the inter-individual variability in the susceptibility to cocaine addiction. Heritability estimates for CUD are high and genetic risk factors for cocaine addiction have been investigated by candidate gene association studies (CGAS) and genome-wide association studies (GWAS), reviewed here. Also, the high comorbidity that exists between CUD and several other psychiatric disorders is well known and includes phenotypes like schizophrenia, aggression, antisocial or risk-taking behaviors. Such comorbidities are associated with a worse lifetime trajectory, and here we report shared genetic factors that may contribute to them. Gene expression changes and epigenetic modifications induced by cocaine use and chronic abuse in humans are addressed by reviewing transcriptomic studies performed on neuronal cells and on postmortem brains. We report some genes which expression is altered by cocaine that also bear genetic risk variants for the disorder. Finally, we have a glance to the pharmacogenetics of CUD treatments, still in early stages. A better understanding of the genetic underpinnings of CUD will foster the search of effective treatments and help to move forward to personalized medicine.

PMID:34453125 | DOI:10.1038/s41380-021-01256-1

Cell Death Dis. 2021 Aug 27;12(9):812. doi: 10.1038/s41419-021-04097-6.

NO ABSTRACT

PMID:34453036 | DOI:10.1038/s41419-021-04097-6

Expert Opin Drug Metab Toxicol. 2021 Aug 27. doi: 10.1080/17425255.2021.1974398. Online ahead of print.

ABSTRACT

INTRODUCTION: Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, such as mercaptopurine and tioguanine (TG), fundamental chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, thus enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response.

AREAS COVERED: This review gives an overview on TPMT gene and function, and discusses the well-established pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published between 1990 and June 2021, and on PharmGKB for thiopurine drugs.

EXPERT OPINION: In order to titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a pre-emptive TPMT genotyping to establish a safe initial dose to a close phenotypic monitoring of the TPMT activity and/or of the active metabolites during the long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes as well as novel individualized TG regimens in maintenance for TPMT wild type subjects could be investigated to further improve outcomes while avoiding the risk of severe hepatotoxicity.

PMID:34452592 | DOI:10.1080/17425255.2021.1974398

Pharmaceuticals (Basel). 2021 Aug 21;14(8):822. doi: 10.3390/ph14080822.

ABSTRACT

Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism of its activity in ameliorating obesity-promoted colitis is still unclear. This study explored the possibility that melatonin has beneficial functions in HFD-induced dextran sodium sulfate (DSS)-induced colitis in mice. Here, we revealed that HFD-promoted obesity accelerated DSS-induced colitis, while melatonin intervention improved colitis. Melatonin significantly alleviated inflammation by increasing anti-inflammatory cytokine release and reducing the levels of proinflammatory cytokines in HFD- and DSS-treated mice. Furthermore, melatonin expressed antioxidant activities and reversed intestinal barrier integrity, resulting in improved colitis in DSS-treated obese mice. We also found that melatonin could reduce the ability of inflammatory cells to utilize fatty acids and decrease the growth-promoting effect of lipids by inhibiting autophagy. Taken together, our study indicates that the inhibitory effect of melatonin on autophagy weakens the lipid-mediated prosurvival advantage, which suggests that melatonin-targeted autophagy may provide an opportunity to prevent colitis in obese individuals.

PMID:34451919 | DOI:10.3390/ph14080822

Pharmaceuticals (Basel). 2021 Aug 16;14(8):804. doi: 10.3390/ph14080804.

ABSTRACT

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from "real life" data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

PMID:34451901 | DOI:10.3390/ph14080804

J Antimicrob Chemother. 2021 Aug 27:dkab319. doi: 10.1093/jac/dkab319. Online ahead of print.

NO ABSTRACT

PMID:34450632 | DOI:10.1093/jac/dkab319

S D Med. 2021 Jul;74(7):294-301.

ABSTRACT

INTRODUCTION: A major goal of the current personalized medicine era is to utilize pharmacogenetics (PGx) in order to influence how medications and therapies are prescribed by providers. However, disparities for prescribing medications between adults and children exist. Research has shown that children are not just small adults and there are different challenges for pediatric providers in regards to ordering and interpreting PGx tests. The goal of this study was to obtain an initial understanding of current pharmacogenetic testing by pediatric providers, as well as determine perceived barriers.

METHODS: We distributed an online survey to pediatric providers at six different institutions across the U.S.

RESULTS: Of the 252 respondents who completed the survey, 24 percent reported previously ordering PGx tests, however, over 90 percent of respondents reported they would feel more comfortable ordering and interpreting results with the assistance of a pharmacist, geneticist, genetic counselor or PGx expert. Additionally, participants identified specific barriers towards the utilization of PGx testing, as well as suggested solutions to overcome these barriers, including increasing provider education regarding testing, collaboration through a multidisciplinary team approach and established PGx programs.

CONCLUSION: As the pharmacogenetic field continues to demonstrate clinical utility in the pediatric population, it will be important to continuously identify and address barriers that exist for providers to allow for more successful implementation of PGx in the pediatric setting, as well as enhance patient care.

PMID:34449988