Enzymes and Pathways of Kavain Bioactivation and Biotransformation.

Chem Res Toxicol. 2019 Jul 02;:

Authors: Wang P, Zhu J, Shehu AI, Lu J, Chen J, Zhong XB, Ma X

Abstract
Kavain is an active and major component in Piper methysticum Forst. (kava), which is a widely used dietary supplement for the treatment of anxiety, insomnia, and stress. However, kava-containing products can cause liver toxicity, and its underlying mechanisms are understudied. Cytochrome P450s (CYPs)-mediated bioactivation and biotransformation are highly associated with drug toxicity. In the current study, we profiled the metabolic pathways of kavain in mouse liver, urine, and feces. Overall, 28 kavain metabolites were identified including 17 new ones. The metabolic pathways of kavain include glutathione (GSH) conjugation, oxidation, dehydrogenation, O-demethylation, sulfation, and glucuronidation. The identification of kavain-GSH adducts suggests the formation of reactive metabolites of kavain in the liver. We further illustrated that CYP2C19, a highly polymorphic and inducible enzyme, was the major enzyme contributing to kavain biotransformation and bioactivation. Our data can be used to guide the safe use of kava products by preventing potential herb-drug interactions and hepatotoxicity.

PMID: 31265262 [PubMed - as supplied by publisher]

Precision Medicine in Oncology Pharmacy Practice.

Acta Med Acad. 2019 Apr;48(1):90-104

Authors: Saadeh C, Bright D, Rustem D

Abstract
The objective of this review is to provide an overview of the components, process and resources available to apply precision medicine strategies to drug therapy in cancer medicine, with an emphasis on oncology pharmacy practice. Precision medicine initiatives in oncology take into account individual variability in genes, environment and lifestyle factors. Genomic assays of patient tumors is now the standard of care in oncology and recommendations for targeted drug therapies are often formulated by interprofessional teams. Pharmacogenomics (PGx) is a component of precision medicine based on polymorphisms that impact medication selection and/or dosing. Several oncolytic agents used in the treatment of cancer and supportive care have pharmacogenomic- based dosing recommendations to minimize potential toxicities. Several resources are reviewed here to guide treatment options in oncology as they relate to somatic mutations and PGx. Examples include: OncoKB is a precision oncology knowledge base that offers evidence-based information for somatic mutations. The Clinical Pharmacogenetics Implementation Consortium provides PGx-based guidelines for several oncolytic therapies used to treat cancer and for supportive care. Pharmacists can be integral members of the interprofessional team in many practice settings in precision medicine. Involvement can include membership in molecular tumor boards, PGx dosing services and provide patient education. CONCLUSION: Precision medicine is a rapidly evolving field in oncology that requires an interprofessional approach of drug therapy experts.

PMID: 31264437 [PubMed - in process]

c-Kit-positive ILC2s exhibit an ILC3-like signature that may contribute to IL-17-mediated pathologies.

Nat Immunol. 2019 Jul 01;:

Authors: Bernink JH, Ohne Y, Teunissen MBM, Wang J, Wu J, Krabbendam L, Guntermann C, Volckmann R, Koster J, van Tol S, Ramirez I, Shrestha Y, de Rie MA, Spits H, Romero Ros X, Humbles AA

Abstract
Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1β and IL-23. We also report a role for transforming growth factor-β in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.

PMID: 31263279 [PubMed - as supplied by publisher]

Broad-spectrum Cross-resistance to Anticancer Drugs Mediated by Epidermal Growth Factor Receptor.

Anticancer Res. 2019 Jul;39(7):3585-3593

Authors: Yan GE, Efferth T

Abstract
BACKGROUND: The oncogenic role of epidermal growth factor receptor (EGFR) has been intensively studied. However, its emerging role in drug resistance has not been fully addressed.
MATERIALS AND METHODS: This study systematically investigated the correlation of mRNA and protein expression of EGFR, as well as gene amplification and mutations with the log-transformed half-maximal inhibitory concentration (log10IC50) values obtained from the NCI panel of 60 human tumor cell lines against 83 standard anticancer agents and the top 10 natural cytotoxic products previously screened by us.
RESULTS: EGFR protein expression, rather than other measurements, was most frequently associated with drug response. Log10IC50 and EGFR protein level were significantly positively correlated under all investigated DNA topoisomerase (TOPO) II inhibitors, followed by 81% of alkylating agents and platinum-based compounds, 71% of anti-hormones, 66% of TOPO I inhibitors and 50% of antibiotics. Furthermore, 60% of cytotoxic natural products did not reveal significant correlations.
CONCLUSION: Collectively, we showed a broad-spectrum of cross-resistance towards clinical drugs mediated by EGFR. Natural cytotoxic products may be further developed as novel drugs to overcome EGFR-associated resistance to clinically established anticancer drugs.

PMID: 31262883 [PubMed - in process]

Vitamin D and Psychosis in Alzheimer Disease: New Insights From Pharmacogenomics Research.

Am J Geriatr Psychiatry. 2019 Jun 04;:

Authors: Vyas CM, Okereke OI

PMID: 31262684 [PubMed - as supplied by publisher]

Recent Topics on The Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities.

Int J Mol Sci. 2019 Jun 29;20(13):

Authors: Zhang W, Egashira N, Masuda S

Abstract
Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity commonly occurs in clinical practice, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms through which CNIs cause neurotoxicity include increasing the permeability or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in the electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures, mycophenolate mofetil induces depression and headaches, methotrexate affects the central nervous system, the mouse monoclonal immunoglobulin G2 antibody (used against the cluster of differentiation 3) also induces headaches, and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms help reduce neurotoxic events considerably. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, combination therapy with drugs used to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize recent topics on the mechanisms of immunosuppressive drug-related neurotoxicity. In addition, information about the neuroprotective effects of several immunosuppressants is also discussed.

PMID: 31261959 [PubMed - in process]

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/07/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenomics in general practice: The time has come.

Aust J Gen Pract. 2019 Mar;48(3):100-105

Authors: Polasek TM, Mina K, Suthers G

Abstract
BACKGROUND: Patients respond to medications differently because of variations in the genes that determine medication exposure and medication response.
OBJECTIVE: The aim of this review is to introduce pharmacogenomic testing and explain how to start using pharmacogenomic tests in general practice.
DISCUSSION: Knowledge of the variants in pharmacogenomics is useful when prescribing a variety of medications. International guidelines have identified at least 15 genes for which testing can inform the prescribing of 30 different medications with good evidence of clinical benefit. Nonetheless, pharmacogenomic tests should not be used as the sole basis for prescribing decisions, and should be considered in the context of other relevant clinical and laboratory features. General practitioners can incorporate pharmacogenomic tests into their clinical practice for patients with medication-related problems or those who are likely to require medications for which pharmacogenomics can provide guidance.

PMID: 31256470 [PubMed - in process]

The lysosomal aminopeptidase tripeptidyl peptidase 1 displays increased activity in malignant pancreatic cysts.

Biol Chem. 2019 Jul 01;:

Authors: Ivry SL, Knudsen GM, Caiazza F, Sharib JM, Jaradeh K, Ravalin M, O'Donoghue AJ, Kirkwood KS, Craik CS

Abstract
Incidental detection of pancreatic cysts has increased dramatically over the last decade, but risk stratification and clinical management remain a challenge. Mucinous cysts are precursor lesions to pancreatic cancer, however, the majority are indolent. Current diagnostics cannot identify mucinous cysts that harbor cancer or reliably differentiate these lesions from nonmucinous cysts, which present minimal risk of malignant progression. We previously determined that activity of two aspartyl proteases was increased in mucinous cysts. Using a global protease activity profiling technology, termed multiplex substrate profiling by mass spectrometry (MSP-MS), we now show that aminopeptidase activity is also elevated in mucinous cysts. The serine aminopeptidase, tripeptidyl peptidase 1 (TPP1), was detected by proteomic analysis of cyst fluid samples and quantitation using targeted mass spectrometry demonstrated that this protease was significantly more abundant in mucinous cysts. In a cohort of 110 cyst fluid samples, TPP1 activity was increased more than 3-fold in mucinous cysts relative to nonmucinous cysts. Moreover, TPP1 activity is primarily associated with mucinous cysts that harbor high-grade dysplasia or invasive carcinoma. Although only 59% accurate for differentiating these lesions, measurement of TPP1 activity may improve early detection and treatment of high-risk pancreatic cysts when used in conjunction with other promising biomarkers.

PMID: 31256057 [PubMed - as supplied by publisher]

Lithium pharmacogenetics.

Psychiatry Res. 2019 Jun 24;:

Authors: Manchia M, Pisanu C, Squassina A

PMID: 31255321 [PubMed - as supplied by publisher]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/06/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/06/30

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Star Allele-Based Haplotyping versus Gene-Wise Variant Burden Scoring for Predicting 6-Mercaptopurine Intolerance in Pediatric Acute Lymphoblastic Leukemia Patients.

Front Pharmacol. 2019;10:654

Authors: Park Y, Kim H, Choi JY, Yun S, Min BJ, Seo ME, Im HJ, Kang HJ, Kim JH

Abstract
Nudix Hydrolase 15 (NUDT15) and Thiopurine S-Methyltransferase (TPMT) are strong genetic determinants of thiopurine toxicity in pediatric acute lymphoblastic leukemia (ALL) patients. Since patients with NUDT15 or TPMT deficiency suffer severe adverse drug reactions, star (*) allele-based haplotypes have been used to predict an optimal 6-mercaptopurine (6-MP) dosing. However, star allele haplotyping suffers from insufficient, inconsistent, and even conflicting designations with uncertain and/or unknown functional alleles. Gene-wise variant burden (GVB) scoring enables us to utilize next-generation sequencing (NGS) data to predict 6-MP intolerance in children with ALL. Whole exome sequencing was performed for 244 pediatric ALL patients under 6-MP treatments. We assigned star alleles with PharmGKB haplotype set translational table. GVB for NUDT15 and TPMT was computed by aggregating in silico deleteriousness scores of multiple coding variants for each gene. Poor last-cycle dose intensity percent (DIP < 25%) was considered as 6-MP intolerance, resulting therapeutic failure of ALL. DIPs showed significant differences ( p < 0.05) among NUDT15 poor (PM, n = 1), intermediate (IM, n = 48), and normal (NM, n = 195) metabolizers. TPMT exhibited no PM and only seven IMs. GVB showed significant differences among the different haplotype groups of both NUDT15 and TPMT ( p < 0.05). Kruskal-Wallis test for DIP values showed statistical significances for the seven different GVB score bins of NUDT15. GVB NUDT15 outperformed the star allele-based haplotypes in predicting patients with reduced last-cycle DIPs at all DIP threshold levels (i.e., 5%, 10%, 15%, and 25%). In NUDT15-and-TPMT combined interaction analyses, GVB NUDT15 , TPMT outperformed star alleles [area under the receiver operating curve (AUROC) = 0.677 vs. 0.645] in specificity (0.813 vs. 0.796), sensitivity (0.526 vs. 0.474), and positive (0.192 vs. 0.164) and negative (0.953 vs. 0.947) predictive values. Overall, GVB correctly classified five more patients (i.e., one into below and four into above 25% DIP groups) than did star allele haplotypes. GVB analysis demonstrated that 6-MP intolerance in pediatric ALL can be reliably predicted by aggregating NGS-based common, rare, and novel variants together without hampering the predictive power of the conventional haplotype analysis.

PMID: 31244663 [PubMed]

A Clinical DDI Study Assessing a Novel Drug Transporter Phenotyping Cocktail with Adefovir, Sitagliptin, Metformin, Pitavastatin and Digoxin.

Clin Pharmacol Ther. 2019 Jun 27;:

Authors: Trueck C, Hsin CH, Scherf-Clavel O, Schaeffeler E, Lenssen R, Gazzaz M, Gersie M, Taubert M, Quasdorff M, Schwab M, Kinzig M, Sörgel F, Stoffel MS, Fuhr U

Abstract
A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance [CLR ]), 100 mg sitagliptin (OAT3; CLR ), 500 mg metformin (several renal transporters; CLR ), 2 mg pitavastatin (OATP1B1; clearance/F) and 0.5 mg digoxin (intestinal P-gp, renal P-gp and OATP4C1; Cmax and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, while secondary metrics suggested that mainly adefovir was a victim of minor DDIs. All drugs were well tolerated. This cocktail may be another useful tool to assess transporter based DDIs in vivo. This article is protected by copyright. All rights reserved.

PMID: 31247117 [PubMed - as supplied by publisher]

Herbal Remedies: Throwing Off Phenotype Prediction-A Culprit for Pharmacogenomic-Guided Drug Therapy and Drug Safety.

Clin Pharmacol Ther. 2019 Jun 27;:

Authors: Dandara C, Thomford NE, Bapiro TE

PMID: 31245840 [PubMed - as supplied by publisher]

Association of genetic variants in CYP3A4, CYP3A5, CYP2C8, and CYP2C19 with tacrolimus pharmacokinetics in renal transplant recipients.

Curr Drug Metab. 2019 Jun 26;:

Authors: Wang Z, Zheng M, Yang H, Han Z, Tao J, Chen H, Sun L, Guo M, Wang L, Tan R, Wei JF, Gu M

Abstract
BACKGROUND: Our study aimed to investigate the pharmacogenetics of cytochrome P3A4 (CYP3A4), CYP3A5, CYP2C8, and CYP2C19 and their influence on TAC pharmacokinetics (PKs) in short-term renal transplant recipients.
METHOD: A total of 105 renal transplant recipients were enrolled. Target sequencing (TS) based on next-generation sequencing technology was used to detect all exons, exon/intron boundaries, and flanking regions of CYP3A4, CYP3A5, CYP2C8, and CYP2C19. After adjustment of minor allele frequencies (MAF) and Hardy-Weinberg equilibrium (HWE) analysis, tagger single-nucleotide polymorphisms (SNPs) and haplotypes were identified. Influence of tagger SNPs on TAC concentrations was analyzed.
RESULTS: A total of 94 SNPs were identified in TS analysis. Nine tagger SNPs were selected, and two SNPs (rs15524 and rs4646453) were noted to be significantly associated with TAC PKs in short-term post-transplant follow-up. Measurement time points of TAC, body mass index (BMI), usage of sirolimus, and incidence of delayed graft function (DGF) were observed to be significantly associated with TAC PKs. Three haplotypes were identified, and rs15524-rs4646453 was found to remarkably contribute to TAC PKs. Recipients carrying H2/H2 (GG-AA) haplotype also showed significantly high weight- and dose-adjusted TAC concentrations in posttransplant periods of 7, 14, and 30 days and 3 and 6 months.
CONCLUSIONS: Two tagger SNPs, namely, rs15524 and rs4646453, are significantly related to the variability of TAC disposition, and TAC measurement time points, BMI, usage of sirolimus, and incidence of DGF contribute to this influence. Recipients carrying H2/H2 (GG-AA) haplotype in rs15524-rs4646453 may require a low dosage of TAC during 1-year follow-up posttransplant.

PMID: 31244435 [PubMed - as supplied by publisher]

Absence of EGFR C797S Mutation in Tyrosine Kinase Inhibitor-Naïve Non-Small Cell Lung Cancer Tissues.

Pathol Oncol Res. 2019 Jun 26;:

Authors: Oscorbin IP, Shadrina AS, Kozlov VV, Voitsitsky VE, Filipenko ML

Abstract
EGFR tyrosine-kinase inhibitors (TKIs) are used as targeted therapeutics for the treatment of advanced non-small cell lung cancer (NSCLC) with EGFR-activating mutations. EGFR C797S is common causes of acquired resistance to third-generation TKIs. There is wide-spread opinion that resistance-conferring mutation present even in a small proportion of cancer cells before the start of therapy could potentially predict poor response to a targeted drug. In our study, we tested whether C797S can be found in previously untreated NSCLCs. We analyzed DNA samples extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue sections of 470 lung adenocarcinoma patients, including 235 samples with activating EGFR mutations. Screening was performed using highly sensitive droplet digital PCR assay. No tumor samples with baseline C797S were identified. C797S does not occur in TKI-naïve NSCLCs and provide evidence that screening for this mutation before TKIs administration may not be necessary.

PMID: 31243697 [PubMed - as supplied by publisher]

Roles of circular RNAs in immune regulation and autoimmune diseases.

Cell Death Dis. 2019 Jun 26;10(7):503

Authors: Zhou Z, Sun B, Huang S, Zhao L

Abstract
Circular RNAs (circRNAs), as a novel class of endogenously expressed non-coding RNAs (ncRNAs), have a high stability and often present tissue-specific expression and evolutionary conservation. Emerging evidence has suggested that circRNAs play an essential role in complex human pathologies. Notably, circRNAs, important gene modulators in the immune system, are strongly associated with the occurrence and development of autoimmune diseases. Here, we focus on the roles of circRNAs in immune cells and immune regulation, highlighting their potential as biomarkers and biological functions in autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), primary biliary cholangitis (PBC), and psoriasis, aiming at providing new insights into the diagnosis and therapy of these diseases.

PMID: 31243263 [PubMed - in process]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/06/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/06/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.