Anticancer Res. 2021 May;41(5):2397-2402. doi: 10.21873/anticanres.15014.

ABSTRACT

BACKGROUND/AIM: Experimental oncology commonly uses cells as oncological models, providing a framework for the testing of drugs, and investigation of cytotoxicity, mutagenesis and carcinogenesis. Investigations into poly-ADP-ribose polymerase 1 (PARP1) inhibition have become ever more relevant due to its approval as a therapeutic option for tumors with BRCA1/2 DNA repair-associated mutation and the seemingly high PARP expression levels in some tumor subtypes. In this study, we aimed to determine PARP1 gene expression of different hematological cancer-derived cell lineages and compare them to that of normal cell lines.

MATERIALS AND METHODS: PARP1 gene expression in seven different neoplastic lineages, representing three different hematological disorders (chronic myeloid leukemia, Burkitt lymphoma and acute lymphoblastic leukemia), was quantified by quantitative real-time polymerase chain reaction.

RESULTS: All hematological malignant lineages in this study overexpressed PARP1 when compared to the normal cell line MRC-5, with Burkitt's lymphoma cells having the highest expression values (fold change: 93).

CONCLUSION: Overexpression of PARP1 in hematological malignant lineages is a finding of crucial importance to future studies exploring possible cellular oncogenic pathways and supports investigations into the effectiveness of PARP1 inhibitors against hematological disorders.

PMID:33952464 | DOI:10.21873/anticanres.15014

Medicine (Baltimore). 2021 May 7;100(18):e25781. doi: 10.1097/MD.0000000000025781.

ABSTRACT

INTRODUCTION: Azathioprine (AZA) has been widely used for the treatment of various immune-related diseases and has become a mainstay in the treatment of inflammatory bowel disease. However, patients with genetic mutations may experience severe adverse events when treated with azathioprine. Most of the previous literature focused on the TPMP gene-related adverse reactions, herein, we report a case of Crohn's disease patient with nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) variation and wild-type TPMP gene who developed toxoplasma gondii infection after azathioprine treatment.

PATIENT CONCERNS: A 56-year-old Crohn's disease patient developed toxoplasma gondii infection within 2 months after the administration of azathioprine; however, he had no relevant high-risk factors.

DIAGNOSIS: Subsequent genetic testing revealed that the patient was heterozygous for NUDT15. Therefore, it was reasonable to consider that the patient's genetic mutation resulted in reduced tolerance to azathioprine, leading to low immunity and eventually toxoplasma infection.

INTERVENTIONS: AZA was then discontinued; after anti-infection, antipyretic and other supportive treatments were administered, the patient's condition gradually improved.

OUTCOMES: The patient was followed up at 1, 3, and 6 months after discharge; fortunately, he was in good health.

CONCLUSION: We report a case of Crohn's disease in a patient who developed severe pneumonia caused by toxoplasma gondii infection due to the administration of AZA, with normal TPMP gene but NUDT15 gene mutation. This indicates that NUDT15 variation may contribute to severe adverse events in patients treated with azathioprine, and we suggest that NUDT15 genotype be detected before the use of azathioprine in order to provide personalized therapy and reduce side effects.

PMID:33950972 | PMC:PMC8104275 | DOI:10.1097/MD.0000000000025781

J Clin Immunol. 2021 May 5. doi: 10.1007/s10875-021-01045-z. Online ahead of print.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a public health emergency. The most common symptoms of COVID-19 are fever, cough, and fatigue. While most patients with COVID-19 present with mild illness, some patients develop pneumonia, an important risk factor for mortality, at early stage of viral infection, putting these patients at increased risk of death. So far, little has been known about differences in the T cell repertoires between COVID-19 patients with and without pneumonia during SARS-CoV-2 infection. Herein, we aimed to investigate T cell receptor (TCR) repertoire profiles and patient-specific SARS-CoV-2-associated TCR clusters between COVID-19 patients with mild disease (no sign of pneumonia) and pneumonia. The TCR sequencing was conducted to characterize the peripheral TCR repertoire profile and diversity. The TCR clustering and CDR3 annotation were exploited to further discover groups of patient-specific TCR clonotypes with potential SARS-CoV-2 antigen specificities. Our study indicated a slight decrease in the TCR repertoire diversity and a skewed CDR3 length usage in patients with pneumonia compared to those with mild disease. The SARS-CoV-2-associated TCR clusters enriched in patients with mild disease exhibited significantly higher TCR generation probabilities and most of which were highly shared among patients, compared with those from pneumonia patients. Importantly, using similarity network-based clustering followed by the sequence conservation analysis, we found different patterns of CDR3 sequence motifs between mild disease- and pneumonia-specific SARS-CoV-2-associated public TCR clusters. Our results showed that characteristics of overall TCR repertoire and SARS-CoV-2-associated TCR clusters/clonotypes were divergent between COVID-19 patients with mild disease and patients with pneumonia. These findings provide important insights into the correlation between the TCR repertoire and disease severity in COVID-19 patients.

PMID:33950324 | DOI:10.1007/s10875-021-01045-z

Cell Death Dis. 2021 May 4;12(5):441. doi: 10.1038/s41419-021-03727-3.

ABSTRACT

There is a male preponderance in gastric cancer (GC), which suggests a role of androgen and androgen receptor (AR). However, the mechanism of AR signaling in GC especially in female patients remains obscure. We sought to identify the AR signaling pathway that might be related to prognosis and examine the potential clinical utility of the AR antagonist for treatment. Deep learning and gene set enrichment analysis was used to identify potential critical factors associated with gender bias in GC (n = 1390). Gene expression profile analysis was performed to screen differentially expressed genes associated with AR expression in the Tianjin discovery set (n = 90) and TCGA validation set (n = 341). Predictors of survival were identified via lasso regression analyses and validated in the expanded Tianjin cohort (n = 373). In vitro and in vivo experiments were established to determine the drug effect. The GC gender bias was attributable to sex chromosome abnormalities and AR signaling dysregulation. The candidates for AR-related gene sets were screened, and AR combined with miR-125b was associated with poor prognosis, particularly among female patients. AR was confirmed to directly regulate miR-125b expression. AR-miR-125b signaling pathway inhibited apoptosis and promoted proliferation. AR antagonist, bicalutamide, exerted anti-tumor activities and induced apoptosis both in vitro and in vivo, using GC cell lines and female patient-derived xenograft (PDX) model. We have shed light on gender differences by revealing a hormone-regulated oncogenic signaling pathway in GC. Our preclinical studies suggest that AR is a potential therapeutic target for this deadly cancer type, especially in female patients.

PMID:33947843 | DOI:10.1038/s41419-021-03727-3

Clin Cancer Res. 2021 May 4:clincanres.4050.2020. doi: 10.1158/1078-0432.CCR-20-4050. Online ahead of print.

ABSTRACT

PURPOSE: In BRAFV600MUT metastatic melanoma, cyclin-D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of CDK4 inhibitors. In this phase I-II study, we aimed to establish the maximum tolerated dose (MTD) of palbociclib when added to vemurafenib.

PATIENTS AND METHODS: BRAFV600E/KMUT metastatic melanoma patients harboring CDKN2A loss and RB1 expression were included and stratified into 2 groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics and tumor molecular profiling.

RESULTS: Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were AJCC stage IVM1c (N=16; 88.9%), high LDH (N=9; 50.0%), and median number of previous treatments of 2. One and five patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25mg and vemurafenib 960mg in strata 2. No significant evidence for drug-drug interactions was highlighted. The median PFS was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib.

CONCLUSIONS: Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25mg, a significant clinical benefit was achieved in pretreated melanoma patients. An association between the transcriptomic data and clinical response was highlighted.

PMID:33947696 | DOI:10.1158/1078-0432.CCR-20-4050

Cells. 2021 Apr 29;10(5):1051. doi: 10.3390/cells10051051.

ABSTRACT

The WW domain-containing oxidoreductase gene (WWOX) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of WWOX in a chromosomal region frequently altered in human cancers has initiated multiple current studies to establish its role in this disease. All of this work suggests that WWOX, due to its ability to interact with a large number of partners, exerts its tumor suppressive activity through a wide variety of molecular actions that are mostly cell specific.

PMID:33946771 | DOI:10.3390/cells10051051

Pharmacogenomics. 2021 May 4. doi: 10.2217/pgs-2021-0006. Online ahead of print.

ABSTRACT

Aim: We examined the relationships between visfatin/NAMPT and nitrite concentrations (a marker of nitric oxide [NO] formation) or sFlt-1 levels in 205 patients with preeclampsia (PE) responsive or nonresponsive to antihypertensive therapy, and whether NAMPT SNPs rs1319501 and rs3801266 affect nitrite concentrations in PE and 206 healthy pregnant women. Patients & methods: Circulating visfatin/NAMPT and sFlt-1 levels were measured by ELISA, and nitrite concentrations by using an ozone-based chemiluminescence assay. Results: In nonresponsive PE patients, visfatin/NAMPT levels were inversely related to nitrite concentrations and positively related to sFlt-1 levels. NAMPT SNP rs1319501 affected nitrite concentrations in nonresponsive PE patients and was tightly linked with NAMPT functional SNPs in Europeans. Conclusion: NAMPT SNP rs1319501 and visfatin/NAMPT affect NO formation, sFlt-1 levels and antihypertensive therapy response in PE.

PMID:33944612 | DOI:10.2217/pgs-2021-0006

Pharmacotherapy. 2021 May 4. doi: 10.1002/phar.2532. Online ahead of print.

ABSTRACT

INTRODUCTION: Levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) influence recombinant tissue plasminogen activator (rtPA) therapy response in patients with acute ischemic stroke (AIS). Serum levels of MMPs and TIMPs along with the expression of genes coding these proteins are related to the recovery and appearance of adverse effects (AE) after AIS. Consequently, it is important to explore whether polymorphisms in regulatory sequences of MMPs and TIMPs are associated with rtPA response in AIS patients.

OBJECTIVES: To determine whether selected polymorphic variants within MMP-2, MMP-9, and TIMP-2 genes may influence rtPA therapy response with regards to outcomes in patients with AIS and the occurrence of AE.

METHODS: Our study included 166 patients suffering AIS, treated with rtPA. Patients' recovery was estimated using the Modified Rankin Scale (mRS) 3 months after the AIS occurred. Favorable outcome was defined with scores 0-1, and poor outcome with scores 2-6. Genotyping was performed using Real-Time PCR (rs243866, rs243865, rs243864, rs2277698, and rs8179090) and PCR-RFLP (rs2285053, rs3918242) methods. Additionally, rtPA AE were followed during the hospitalization.

RESULTS: There was no significant association between genotypes and alleles of selected polymorphisms and rtPA therapy response measured through the decrease of the mRS score in patients with AIS. Intracranial hemorrhage, as well as parenchymal hematoma type 2, were significantly more frequent in patients with TT genotype of the MMP-9-1562C/T polymorphism (p=0.047, p=0.011, respectively). Patients with intracranial hemorrhages after rtPA were significantly more likely to have the TT genotype of TIMP-2-303C/T polymorphism and the TT genotype of MMP-9-1562C/T polymorphism (p<0.001).

CONCLUSION: TT genotype of the MMP-9-1562C/T polymorphism may be a risk factor for rtPA-induced hemorrhagic complications after AIS.

PMID:33942334 | DOI:10.1002/phar.2532

J Clin Endocrinol Metab. 2021 May 4:dgab290. doi: 10.1210/clinem/dgab290. Online ahead of print.

ABSTRACT

PURPOSE: We aimed to evaluate the effect of mineralocorticoid receptor antagonists on aldosterone-to-renin ratio in patients with primary aldosteronism.

METHODS: We prospectively enrolled 121 patients with confirmed primary aldosteronism who started a mineralocorticoid receptor antagonist (canrenone) treatment. Eighteen patients (11 with unilateral and 7 with bilateral primary aldosteronism) composed the short-term study cohort and underwent aldosterone, renin and potassium measurement after 2 and 8 weeks of canrenone therapy. The long-term cohort comprised 102 patients (16 with unilateral and 67 with bilateral primary aldosteronism, and 19 with undetermined subtype) who underwent hormonal and biochemical re-assessment after 2 to 12 months of canrenone therapy.

RESULTS: Renin and potassium levels showed a significant increase, and aldosterone-to-renin ratio displayed a significant reduction compared with baseline after both a short and long-term treatment. These effects were progressively more evident with higher doses of canrenone and after longer periods of treatment. We demonstrated that canrenone exerted a deep impact on the diagnostic accuracy of the screening test for primary aldosteronism: the rate of false negative tests raised to 16.7%, 38.9%, 54.5% and 72.5% after 2 weeks, 8 weeks, 2-6 months and 7-12 months of mineralocorticoid receptor antagonist treatment, respectively.

CONCLUSIONS: Mineralocorticoid receptor antagonists should be avoided in patients with hypertension before measurement of renin and aldosterone for screening of primary aldosteronism.

PMID:33942084 | DOI:10.1210/clinem/dgab290

Farm Hosp. 2021 Apr 15;45(3):155-159. doi: 10.7399/fh.11607.

ABSTRACT

OBJECTIVE: The main purpose of this study is to evaluate the potential clinical impact of pharmacogenetic testing on the reduction of the toxicity in patients treated with fluoropyrimidines. This will be achieved by comparing the frequency of adverse events and the incidence of toxicity of two groups of patients that will differ from each other only in that one will receive pharmacogenetic counseling. The hypothesis is that availability of a pharmacogenetic report prior to treatment initiation has a positive effect. One of the main secondary goals is to analyze allele frequencies and the association of polymorphisms rs895819 (miR27A) and rs1801160 (DPYD*6) with toxicity by conducting an observational study to determine their clinical relevance and standardize a dose adjustment recommendation.

METHOD: The study has an single-center ambispective, quasi-experimental design and is based on a multidisciplinary protocol involving implementation and standardization of DPYD*2A; DPYD*13; c.2846A&gt;T; and HapB3 measurements. Following these measurements, pharmacogenetic counseling will be carried out and its clinical impact will be evaluated. The primary endpoint of the study is severe toxicity and/or mortality. The toxicity observed in two groups with similar epidemiological characteristics will be compared: the intervention group (candidates for treatment with fluoropyrimidines who will be subjected to the protocol) and the control group (retrospective cohort). Additionally, rs895819 (MIR27A) and rs1801160 (DPYD*6) will be determined. Testing for these variants is not part of the hospital's daily practice, nor are they included in clinical guidelines. However, according to recently published studies, the activity of dihydropyrimidine dehydrogenase might be affected by these variants, as they may be associated with toxicity. The results of the measurements of these two variants will not be incorporated to pharmacogenetics counseling until their association with toxicity is determined by means of the observational study to be conducted. The project, as well as the patient information sheet and the informed consent form, were approved by the Ethics Committee of the participating center (code 20/006).

PMID:33941060 | DOI:10.7399/fh.11607

Biomed Pharmacother. 2021 Apr 30;139:111631. doi: 10.1016/j.biopha.2021.111631. Online ahead of print.

ABSTRACT

The exposure to linezolid is characterized by a large inter-individual variability; age, renal dysfunction and body weight explain this variability only to a limited extent and a considerable portion of it remains unexplained; therefore, we decided to investigate the role of individual genetic background focusing in particular on the risk of linezolid underexposure. 191 patients in therapy with linezolid at the standard dose of 600 mg twice daily were considered. Linezolid plasma concentration was determined at the steady state and classified as "below", "within" or "above" reference range. Genetic polymorphisms for ATP Binding Cassette Subfamily B Member 1 (ABCB1), Cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5, and Cytochrome P450 Oxidoreductase (POR) were investigated. Age significantly correlated with drug exposure, and patients CYP3A5 expressers (GA and AA) were found at high risk to be underexposed to the drug when treated at standard dose. This association was confirmed even after correction with age. No association was found with ABCB1 polymorphism. Our data suggest that CYP3A5 polymorphisms might significantly affect linezolid disposition, putting patients at higher risk to be underexposed, while P-glycoprotein polymorphism seem not to play any role.

PMID:33940510 | DOI:10.1016/j.biopha.2021.111631

Pharmacol Res. 2021 Apr 30:105643. doi: 10.1016/j.phrs.2021.105643. Online ahead of print.

ABSTRACT

Lung cancer has become a paradigm for the future of precision medicine in oncology, and liquid biopsy (LB) and radiomics may have great potential in this scenario. They are both minimally invasive, easy to perform, and can be repeated during patient's follow-up. Also, increasing evidence suggests that LB and radiomics may provide an efficient way to screen and diagnose tumors at an early stage, including the monitoring of any change in the tumor molecular profile. This could allow treatment optimization, patient's quality of life improvement, and healthcare-related costs reduction. Latest reports on lung cancer patients suggest a combination of these two strategies, along with cutting-edge data analysis, to decode valuable information regarding tumor type, aggressiveness, progression, and response to treatment. The approach seems more compatible with clinical practice than the current standard, and provides new diagnostic companions being able to suggest the best treatment strategy compared to conventional methods. To implement radiomics and liquid biopsy research findings directly into clinical practice, an artificial intelligence (AI)-based system could help to coherently link patient clinical data together with respective of tumor molecular profile and imaging characteristics. AI could also solve problems and limitations related to LB and radiomics methodologies. Further work is needed, including new health policies and the access to large amounts of high-quality and well-organized data, allowing the complementary and synergistic combination of LB and imaging to provide an attractive choice to the traditional molecular profile in the personalized treatment of lung cancer.

PMID:33940185 | DOI:10.1016/j.phrs.2021.105643

Front Pharmacol. 2021 Apr 15;12:657985. doi: 10.3389/fphar.2021.657985. eCollection 2021.

ABSTRACT

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene-drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19-11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10-0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians' knowledge on PGx and on test availability, and health systems' issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.

PMID:33935777 | PMC:PMC8082421 | DOI:10.3389/fphar.2021.657985

Front Pharmacol. 2021 Apr 14;12:639854. doi: 10.3389/fphar.2021.639854. eCollection 2021.

ABSTRACT

Background and Objectives: Genetic data on the pharmacokinetics of rivaroxaban and identification of factors that affect its biotransformation, distribution, and excretion will allow for generation of algorithms for personalized use of this drug in patients with atrial fibrillation (AF). Here we tested the effects of ABCB1 (ATP-binding cassette subfamily B member 1) polymorphisms on the valley rivaroxaban blood concentration and on the frequency of hemorrhagic events in patients with AF and propose a personal anticoagulation therapy management protocol. Patients and Methods: This is a retrospective study. We enrolled Mongolian descent patients who met the criteria from May 2018 to August 2019 in Beijing and Fujian. Clinical data on gender, height, weight, liver and kidney functions, drug trough concentration, and drug dosage were collected; we recorded the bleeding events until 6 months after initiating the medication. ABCB1 single nucleotide polymorphisms including rs1128503, rs1045642, and rs4148738 were identified. After reaching the steady state of plasma concentration, the peripheral blood was collected to detect the trough rivaroxaban plasma concentrations before the next medication. Results: We included 155 patients in this study including 81 men and 74 women, with an average age of 71.98 ± 10.72 years. The distribution of ABCB1 genotypes conformed to the Hardy-Weinberg equilibrium. Multiple comparisons between wild (TT) and mutant (CT and CC) genotypes at the rs1045642 locus showed no significant differences of rivaroxaban trough concentrations (TT vs. CT, p = 0.586; TT vs. CC, p = 0.802; and CT vs. CC, p = 0.702). Multiple comparison between wild (TT) and mutant (CC) genotypes at the rs1128503 locus revealed a significant difference of rivaroxaban trough concentrations (TT vs. CC, p = 0.0421). But wild (TT) vs mutant (CT) genotypes and mutant CT vs mutant CC genotypes at the rs1128503 locus showed no significant differences of rivaroxaban trough concentrations (TT vs. CT, p = 0.0651; TT vs. CT, p = 0.6127). Multiple comparisons between wild (GG) and mutant (AG and AA) genotypes at the rs4148738 locus showed no significant differences of rivaroxaban trough concentrations (GG vs. AG, p = 0.341; GG vs. AA, p = 0.612; AG vs. AA, p = 0.649). There was no significant correlation between ABCB1 gene variation loci rs1045642, rs1128503, rs4148738 and bleeding events. Conclusion: rs1128503 locus variations are correlated with the serum concentration of rivaroxaban in patients of Mongolian descent. But no significant correlation between rs1128503 locus variations and bleeding events were obtained.

PMID:33935730 | PMC:PMC8079976 | DOI:10.3389/fphar.2021.639854

Pharmgenomics Pers Med. 2021 Apr 23;14:477-485. doi: 10.2147/PGPM.S291723. eCollection 2021.

ABSTRACT

Dabigatran is a novel direct oral anticoagulant agent, whose plasma concentration is closely related to bleeding risk. Genetic polymorphisms can affect the level of plasma dabigatran. The purpose of this study was to understand the relationship between dabigatran-related genes and the plasma level of dabigatran in healthy Chinese subjects after taking a single oral dose. This study was performed with a single-center, single-dose, randomized, open-label, and four-period crossover trial design under both fasting and fed conditions. A total of 106 eligible healthy subjects were enrolled in the study and 104 were genotyped. One-way analysis of variance (ANOVA) was used to compare pharmacokinetic parameters among different genotypes and linear regression was applied to explore the multiplicative interaction between variables. In this study, we found that the genotype frequencies of CES1 rs2244613 and CES1 rs8192935 were significantly different between Chinese and Caucasians, but the genotype frequencies of ABCB1 rs1045642 and ABCB1 rs4148738 were similar in both populations. CES1 rs8192935 were associated with the peak concentration of dabigatran. There was no significant gender difference in the exposure level of dabigatran. Furthermore, food significantly delayed the absorption of dabigatran but had little effect on Cmax and AUC0-∞.

PMID:33935512 | PMC:PMC8081719 | DOI:10.2147/PGPM.S291723

CPT Pharmacometrics Syst Pharmacol. 2021 May 1. doi: 10.1002/psp4.12635. Online ahead of print.

ABSTRACT

The CYP2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their CYP2D6 genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype-based dose recommendations. The aim of this study was to quantify and compare the impact of different CYP2D6 genotypes and alleles on CYP2D6 metabolism using a large clinical dataset. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6-dependent metabolite was developed based on pharmacokinetic data from 578 subjects. The CYP2D6-mediated metabolism was quantified for each subject based on estimates from the final popPK model and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (CYP2D6*9), 0.34 (CYP2D6*10), 0.01 (CYP2D6*17), 0.65 (CYP2D6*29) and 0.21 (CYP2D6*41). The CYP2D6*17 and CYP2D6*41 alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the CYP2D6*9 allele was shown to be statistically significant (P = 0.02 and P = 0.05, respectively). The study provides new in vivo evidence of the enzyme function of different CYP2D6 genotypes and alleles. Our findings suggest that the activity score assigned to the CYP2D6*41 should be revisited, while CYP2D6*17 appears to exhibit substrate-specific behaviour. Further studies are needed to confirm the findings and to improve the understanding of CYP2D6 genotype-phenotype relationships across substrates.

PMID:33932135 | DOI:10.1002/psp4.12635

Clin Transl Med. 2021 Apr;11(4):e354. doi: 10.1002/ctm2.354.

NO ABSTRACT

PMID:33931979 | DOI:10.1002/ctm2.354

Expert Opin Drug Metab Toxicol. 2021 Apr 30. doi: 10.1080/17425255.2021.1925249. Online ahead of print.

ABSTRACT

Introduction: Clopidogrel is an antiplatelet medication described as a prodrug, which cannot exert the antiplatelet effect until being biotransformed to the active metabolite. It is commonly used to reduce the risk of blood coagulation in patients diagnosed with acute coronary syndrome, or ischemic stroke.Area covered: We reviewed published articles in PubMed and Google Scholar that focused on the mutations of CYP2C19, CYP3A4, CYP2C9, CYP2B6, and CYP1A2 genes related to clopidogrel clinical efficacy and safety.Expert opinion: Based on current pharmacogenetic studies, patients carrying CYP2C19*2, CYP2C19*3, CYP2C9*3, and CYP2B6*5 alleles may not respond to clopidogrel due to poor platelet inhibition efficacy revealed among them. In contrast, carriers of CYP2C19*17, CYP3A4*1G, and CYP1A2*1F alleles showed a more significant antiplatelet effect in clopidogrel users and expected to have a protective role as a genetic factor against cardiovascular events. Genotyping for either CYP2C19, CYP3A4, CYP2C9, CYP2B6, or CYP1A2 variants is not recommended when considering clopidogrel treatment for patients, as some trials showed specific non-genetic factors (e.g., age and diabetes) that could affect clopidogrel responsiveness. Instead, platelets inhibition tests could be used as predictors of the clinical efficacy and safety of clopidogrel treatment. Other P2Y12 receptor inhibitors should be considered as alternative medications.

PMID:33931001 | DOI:10.1080/17425255.2021.1925249

Psychoneuroendocrinology. 2021 Apr 18;129:105234. doi: 10.1016/j.psyneuen.2021.105234. Online ahead of print.

ABSTRACT

Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin β3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.

PMID:33930757 | DOI:10.1016/j.psyneuen.2021.105234

Clin Pharmacol Ther. 2021 Apr 30. doi: 10.1002/cpt.2279. Online ahead of print.

ABSTRACT

Genomic-guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of SNPs and structural variation. Here we introduce the Helix PGx database, an open-source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short-read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project. The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low-frequency star alleles as well as a disproportionate fraction (36%) of all novel predicted loss-of-function variants identified. Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10x higher frequency in one or more subgroups with non-European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard-of-care screening of these four pharmacogenes could impact nearly half of the general population.

PMID:33930192 | DOI:10.1002/cpt.2279