Pharmacogenomics of osteonecrosis of the jaw.

Bone. 2019 Apr 22;:

Authors: Yang G, Singh S, Chen Y, Hamadeh IS, Langaee T, McDonough CW, Holliday LS, Lamba J, Moreb JS, Katz J, Gong Y

Abstract
Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.

PMID: 31022475 [PubMed - as supplied by publisher]

Effects of the ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of afatinib in healthy Chinese volunteers.

Xenobiotica. 2019 Apr 25;:1-21

Authors: Tan YN, Cao KN, Ren GH, Qin ZY, Zhao D, Li N, Chen XJ, Xia YF, Lu Y

Abstract
1. Afatinib is an oral, selective tyrosine kinase inhibitor (TKI) primarily transported by P-glycoprotein (MDR1, gene code ABCB1) and breast cancer resistance protein (BCRP, gene code ABCG2). In the present study, the effects of ABCB1 and ABCG2 genetic polymorphisms on the pharmacokinetics of afatinib in healthy Chinese was investigated. 2. Blood samples from 24 healthy participants who received afatinib were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (34G > A, 421C > A) polymorphisms. Subsequently, the association between afatinib plasma concentrations and target single-nucleotide polymorphisms (SNPs) was analyzed. 3. Among the five polymorphisms, plasma concentrations of afatinib in healthy subjects with ABCB1 1236CC-3435CC were remarkably higher than in other genotype subjects. No significant differences of afatinib exposure were found between the ABCG2 wild type and heterozygous groups. 4. The ABCB1 genetic polymorphism influenced the plasma exposure of afatinib, and gene testing before drug administration may be useful for clinically individualized use of afatinib. Our data suggest the usefulness of afatinib pharmacogenetics in treatment optimization.

PMID: 31021303 [PubMed - as supplied by publisher]

Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Platelet Reactivity and Early Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention and Treated With Aspirin and Clopidogrel.

Circ Cardiovasc Interv. 2019 May;12(5):e007019

Authors: Xu K, Ye S, Zhang S, Yang M, Zhu T, Kong D, Chen J, Xu L, Li J, Zhu H, Wang F, Yang L, Zhang J, Fan Y, Ying L, Hu X, Zhang X, Chan NC, Li C

Abstract
BACKGROUND: The genetic determinants of response to clopidogrel and aspirin are incompletely characterized. Recently, PEAR1 (platelet endothelial aggregation receptor-1) rs12041331 polymorphism has been shown to influence the platelet reactivity, but its impact on cardiovascular outcomes remains unclear in patients treated with antiplatelet agents.
METHODS AND RESULTS: In this prospective cohort study, 2439 Chinese patients with acute coronary syndrome or stable coronary artery disease undergoing coronary stent implantation and receiving clopidogrel and aspirin were consecutively recruited. Their platelet reactivity was determined by light transmission aggregometry at 5 and 30 days after coronary intervention. Genotyping was performed using an improved multiplex ligation detection reaction technique. All patients completed a 30-day follow-up for clinical outcomes. Genotyping for PEAR1 showed 768 (38.3%) GG homozygotes, 941 (46.9%) GA heterozygotes, and 298 (14.8%) AA homozygotes. The 30-day incidence of major adverse cardiovascular events, the composite of cardiovascular death, nonfatal myocardial infarction, and ischemic stroke were significantly higher in AA homozygotes than in non-AA homozygotes (adjusted hazard ratio, 2.78; 95% CI, 1.13-6.82; P=0.026), irrespective of CYP2C19*2 loss-of-function polymorphism and known outcome predictors including age, sex, smoking, and diabetes mellitus. The ADP-induced platelet aggregation was significantly lower in AA homozygotes than that in GG homozygotes at both time points, although no significant difference was found for the arachidonic acid-induced platelet aggregation among the 3 groups.
CONCLUSIONS: About 15% of Chinese patients undergoing coronary stent implantation were AA homozygotes for PEAR1 rs12041331. These patients had ≈3-fold increase in short-term major adverse cardiovascular events risk compared with non-AA homozygotes, and the adverse clinical outcome is unlikely to be mediated by suboptimal pharmacological response to aspirin or clopidogrel.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01968499.

PMID: 31018667 [PubMed - in process]

Safety, Pharmacokinetics, and Pharmacogenetics of Single-Dose Teriflunomide Sodium and Leflunomide in Healthy Chinese Subjects.

Clin Drug Investig. 2019 Apr 23;:

Authors: Yao X, Wu Y, Jiang J, Hu P, Liu D, Chen X

Abstract
BACKGROUND: Teriflunomide sodium, a novel derivative of leflunomide, was developed to treat systemic lupus erythematosus.
OBJECTIVE: The objectives of this trial were to study the safety, pharmacokinetics, and pharmacogenetics of teriflunomide sodium in healthy Chinese subjects in order to support its accelerated development.
METHODS: A clinical study was designed as a single-dose, randomized, parallel, open-label study. Healthy volunteers were randomly assigned to take teriflunomide sodium 10 mg or leflunomide 10 mg. Eligible healthy volunteers were monitored over a 98-day observation period. Blood and urine samples were collected and analyzed for teriflunomide and its metabolite concentrations, and ABCG2 and CYP2C9 genotypes were detected. The safety profile was also collected.
RESULTS: All adverse events were mild in intensity, and all subjects completed this trial without any other treatment. After a single administration of teriflunomide sodium and leflunomide, teriflunomide maximal concentrations were 1.32 ± 0.341 mg/L and 0.718 ± 0.169 mg/L, and area under the concentration-time curve from time zero to infinity (AUC∞) was 423 ± 229 mg·h/L and 303 ± 159 mg·h/L, respectively. Overall, teriflunomide AUC∞ in ABCG2 34A/A mutants was 70.4% lower than in wild-type ABCG2 34G/G after administration of teriflunomide sodium. In addition, after administration of leflunomide, teriflunomide AUC∞ in ABCG2 34A/A mutants was 30.0% lower than in subjects carrying ABCG2 34G/G.
CONCLUSIONS: Teriflunomide sodium was generally safe and well tolerated in healthy Chinese subjects. The relative bioavailability of teriflunomide between teriflunomide sodium and leflunomide after a single dose administration was approximately 150%. Additionally, ABCG2 34G>A was found to significantly affect teriflunomide pharmacokinetics, which suggested ABCG2 34G>A may be a significant influencing factor.
CLINICAL TRIAL REGISTRATION: This study was registered at the China National Medical Products Administration ( http://www.nmpa.gov.cn ; registration number 2014L01935), and also at the China platform for registry and publicity of drug clinical trials ( http://www.chinadrugtrials.org.cn ; registration number CTR20150314).

PMID: 31016613 [PubMed - as supplied by publisher]

Role of epigenetic mechanisms in cisplatin-induced toxicity.

Crit Rev Oncol Hematol. 2019 May;137:131-142

Authors: Quintanilha JCF, Saavedra KF, Visacri MB, Moriel P, Salazar LA

Abstract
Cisplatin (CDDP) is a highly effective antineoplastic agent, widely used in the treatment of various malignant tumors. However, its major problems are side effects associated to toxicity. Considerable inter-individual differences have been reported for CDDP-induced toxicity due to genetic and epigenetic factors. Genetic causes are well described; however, epigenetic modifications are not fully addressed. In the last few years, many evidences were found linking microRNA to the development of CDDP-mediated toxicity, particularly nephrotoxicity. In this review, we described how genetic and epigenetic modifications can be important determinants for the development of toxicity in patients treated with CDDP, and how these alterations may be interesting biomarkers for monitoring toxicity induced by CDDP. Considering the validation in different studies, we suggest that miR-34a, -146b, -378a, -192, and -193 represent an attractive study group to evaluate potential biomarkers to detect CDDP-related nephrotoxicity.

PMID: 31014509 [PubMed - in process]

The dysregulation of tRNAs and tRNA derivatives in cancer.

J Exp Clin Cancer Res. 2018 May 09;37(1):101

Authors: Huang SQ, Sun B, Xiong ZP, Shu Y, Zhou HH, Zhang W, Xiong J, Li Q

Abstract
Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

PMID: 29743091 [PubMed - indexed for MEDLINE]

Pharmacogenomics of Cisplatin-Induced Ototoxicity: Successes, Shortcomings and Future Avenues of Research.

Clin Pharmacol Ther. 2019 Apr 23;:

Authors: Drögemöller BI, Wright GEB, Lo C, Le T, Brooks B, Bhavsar AP, Rassekh SR, Ross CJD, Carleton BC

Abstract
Cisplatin is a highly effective chemotherapeutic. Unfortunately, its use is limited by cisplatin-induced ototoxicity (CIO). Substantial research has been performed to uncover the genetic variants associated with CIO, however, there has been a lack of consistency in the results that have been reported. This article aims to provide an overview of the current state of CIO genomics research, delving into the shortcomings of past research and providing recommendations for future avenues of study. This article is protected by copyright. All rights reserved.

PMID: 31012503 [PubMed - as supplied by publisher]

Pharmacogenomics-Driven Prediction of Antidepressant Treatment Outcomes: A Machine Learning Approach with Multi-Trial Replication.

Clin Pharmacol Ther. 2019 Apr 23;:

Authors: Athreya AP, Neavin D, Carrillo-Roa T, Skime M, Biernacka J, Frye MA, Rush AJ, Wang L, Binder EB, Iyer RK, Weinshilboum RM, Bobo WV

Abstract
We set out to determine whether machine learning-based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 Caucasian MDD outpatients treated with citalopram/escitalopram in the PGRN-AMPS (n = 398), STAR*D (n = 467), and ISPC (n = 165) trials. GWAS for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified SNPs in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with AUC > 0.7 (p<0.04) in PGRN-AMPS patients, with comparable prediction accuracies >69% (p<0.05) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers. This article is protected by copyright. All rights reserved.

PMID: 31012492 [PubMed - as supplied by publisher]

Diabetes: Is there a future for Pharmacogenomics guided treatment?

Clin Pharmacol Ther. 2019 Apr 23;:

Authors: Pearson ER

Abstract
Diabetes is a disease defined on the basis of hyperglycaemia. There are monogenic forms of diabetes where defining the genetic cause has a dramatic impact on treatment - with patients being able to transition from insulin to sulphonylureas. However, the majority of diabetes is type 2 diabetes. This review outlines the robust evidence accrued to date for pharmacogenetics of metformin, sulphonylureas, thiazolidinediones and DPP4 inhibitors, but highlights that these variants will only be of clinical utility when the genotype is already known at the point of prescribing. The future of pharmacogenetics in diabetes and other common complex disease relies on a paradigm shift - that of pre-emptive panel genotyping and use of clinical decision support tools to assimilate this genetic information with other clinical phenotypic data and to present this information simply to the prescriber. Given the recent dramatic fall in genotyping costs, this future is not far off. This article is protected by copyright. All rights reserved.

PMID: 31012484 [PubMed - as supplied by publisher]

Community pharmacists' educational needs for implementing clinical pharmacogenomic services.

J Am Pharm Assoc (2003). 2019 Apr 19;:

Authors: Berenbrok LA, Hart KM, McGrath SH, Coley KC, Somma McGivney MA, Empey PE

Abstract
OBJECTIVES: Pharmacist leadership and knowledge of pharmacogenomics is critical to the acceleration and enhancement of clinical pharmacogenomic services. This study aims for a qualitative description of community pharmacists' pharmacogenomic educational needs when implementing clinical pharmacogenomic services at community pharmacies.
METHODS: Pharmacists practicing at Rite Aid Pharmacy locations in the Greater Pittsburgh Area were recruited to participate in this qualitative analysis. Pharmacists from pharmacy locations offering pharmacogenomic testing and robust patient care services were eligible to participate in a semistructured, audio-recorded interview. The semistructured interview covered 4 domains crafted by the investigative team: (1) previous knowledge of pharmacogenomics; (2) implementation resources; (3) workflow adaptation; and (4) learning preferences. Interviews were transcribed verbatim and independently coded by 2 researchers. A thematic analysis by the investigative team followed. Supporting quotes were selected to illustrate each theme.
RESULTS: Eleven pharmacists from 9 unique pharmacy locations participated in this study. The average length of practice as a community pharmacist was 12 years (range, 1.5-31 years). Pharmacist's pharmacogenomic educational needs were categorized into 5 key themes: (1) enriched pharmacogenomic education and training; (2) active learning to build confidence in using pharmacogenomic data in practice; (3) robust and reputable clinical resources to effectively implement pharmacogenomic services; (4) team-based approach throughout implementation; (5) readily accessible network of pharmacogenomic experts.
CONCLUSION: This study describes the educational needs and preferences of community pharmacists for the successful provision of clinical pharmacogenomic services in community pharmacies. Pharmacists recognized their needs for enriched knowledge and instruction, practice applying pharmacogenomic principles with team-based approaches, robust clinical resources, and access to pharmacogenomic experts. This deeper understanding of pharmacist needs for pharmacogenomic education could help to accelerate and enhance the clinical implementation of pharmacogenomic services led by community pharmacists.

PMID: 31010787 [PubMed - as supplied by publisher]

Knowledge and Opinions Among Canadian Academic Physicians Regarding Genetic Screening to Prevent Severe Cutaneous Adverse Drug Reactions.

J Am Acad Dermatol. 2019 Apr 19;:

Authors: Chan FL, Shear NH, Maharaj A, Olteanu C, Hashimoto R, Ziv M, Dodiuk-Gad RP

PMID: 31009670 [PubMed - as supplied by publisher]

Pharmacogenomics guidelines: current status and future development.

Clin Exp Pharmacol Physiol. 2019 Apr 22;:

Authors: Guo C, Xie X, Li J, Huang L, Chen S, Li X, Yi X, Wu Q, Yang G, Zhou H, Liu J, Chen X

Abstract
Genetic polymorphisms impact biological responses to drugs. Current pharmacogenomics guidelines formulated by different countries, such as CPIC, DPWG, CPNDS, and RNPGx, play important roles in clinical practices. However, the drafting standards for these guidelines vary, resulting in differences in recommendations. The present review discusses these differences by head-to-head comparison of the existing pharmacogenomics guidelines and proposes new strategies for their future development. This article is protected by copyright. All rights reserved.

PMID: 31009088 [PubMed - as supplied by publisher]

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen.

Expert Rev Clin Pharmacol. 2019 Apr 22;:

Authors: Sanchez-Spitman AB, Swen JJ, Dezentje VO, Moes DJAR, Gelderblom H, Guchelaar HJ

Abstract
INTRODUCTION: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30-100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride, has been successfully evaluated. Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, gender, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes is considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed. Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.

PMID: 31008668 [PubMed - as supplied by publisher]

Glutathione S-transferase theta genotypes and environmental exposures in the risk of canine transitional cell carcinoma.

J Vet Intern Med. 2019 Apr 22;:

Authors: Luethcke KR, Ekena J, Chun R, Trepanier LA

Abstract
INTRODUCTION: Transitional cell carcinoma (TCC) in humans is associated with environmental exposures and variants in glutathione S-transferase (GST) genes. Scottish Terriers have a high breed risk for TCC, but the relationship between genetic and environmental risk in dogs is not fully understood.
HYPOTHESES: Scottish Terriers have a higher frequency of GST-theta variants compared to lower risk breeds. Dogs with TCC of any breed have a higher frequency of GST-theta variants along with higher environmental exposures, compared to controls.
ANIMALS: One hundred and five Scottish Terriers and 68 controls from lower risk breeds; 69 dogs of various breeds with TCC, and 72 breed- and sex-matched unaffected geriatric dogs.
METHODS: In this prospective case-control study, dogs were genotyped for 3 canine GST-theta variants: GSTT1 I2+28 G>A, a GSTT1 3'UTR haplotype, and GSTT5 Asp129_Gln130del. Owners of dogs with TCC and unaffected geriatric controls completed a household environmental questionnaire.
RESULTS: The GSTT1 3'UTR haplotype and GSTT5 Asp129_Gln130del variants were significantly underrepresented in Scottish Terriers (minor allele frequency [MAF] = 0.000 for both), compared to dogs from lower risk breeds (MAF = 0.108 and 0.100; P ≤ .0002). Dogs with TCC did not differ from unaffected geriatric controls across the 3 investigated loci. Transitional cell carcinoma was associated with household insecticide use (odds ratio [OR] = 4.28, 95% confidence interval [CI] = 1.44-12.33, P = .02), and was negatively associated with proximity to a farm (OR = 0.49, 95% CI = 0.25-0.99, P = .04).
CONCLUSIONS AND CLINICAL IMPORTANCE: Low-activity GST-theta loci are unlikely contributors to TCC risk in dogs. Increased risk is associated with household insecticide use, and possibly with less rural households.

PMID: 31008543 [PubMed - as supplied by publisher]

Association of CYP2C19 Polymorphisms With Clopidogrel Reactivity and Clinical Outcomes in Chronic Ischemic Stroke.

Circ J. 2019 Apr 19;:

Authors: Tanaka T, Yamagami H, Ihara M, Miyata T, Miyata S, Hamasaki T, Amano S, Fukuma K, Yamamoto H, Nakagawara J, Furui E, Uchiyama S, Hyun B, Yamamoto Y, Manabe Y, Ito Y, Fukunaga R, Abumiya T, Yasaka M, Kitagawa K, Toyoda K, Nagatsuka K

Abstract
BACKGROUND: CYP2C19variants are associated with the antiplatelet effects of clopidogrel against recurrent cardiovascular events. However, it remains unknown whether the elapsed time from stroke onset affects the relationship between the genetic variants and such events. To address this, we conducted a prospective cohort study to determine the effect ofCYP2C19variants on clinical outcomes in the chronic phase.Methods and Results:In total, 518 Japanese non-acute stroke patients treated with clopidogrel were registered at 14 institutions. Patients were classified into 3 clopidogrel-metabolizing groups according toCYP2C19genotype: extensive metabolizer (EM:*1/*1), intermediate metabolizer (IM:*1/*2or*1/*3), and poor metabolizer (PM:*2/*2,*2/*3, or*3/*3). Antiplatelet effects of clopidogrel were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. The endpoint was composite cerebrocardiovascular events (CVEs). In 501 successfully followed-up patients, the median time from index stroke to enrollment was 181 days. There were 28 cardiovascular and 2 major bleeding events. There were no significant differences in the rates of cardiovascular events among the groups.
CONCLUSIONS: Despite associations betweenCYP2C19variants and on-clopidogrel platelet reactivity, there was no significant difference in rates of CVEs in the chronic stroke phase among the 3 clopidogrel-metabolizing groups ofCYP2C19variants.

PMID: 31006731 [PubMed - as supplied by publisher]

Insufficient harmonization of antibiotics assays - Polish experience with an external quality assessment program in the years 2011-2018.

Clin Biochem. 2019 Apr;66:91-94

Authors: Kowalski R, Ćwiklińska A, Lizakowski M, Kortas-Stempak B, Bednarczuk G, Fijałkowska A, Pikul P, Lewandowski K

Abstract
INTRODUCTION: Treatment with vancomycin and gentamycin requires strict monitoring of its serum concentration for proper dosage optimization. This study aimed to assess the quality and the harmonization of antibiotics assays in Polish laboratories.
MATERIALS AND METHODS: 413 results of vancomycin and 148 results of gentamycin assays obtained from Polish laboratories in 30 international external quality assessment (EQA) surveys carried out from March 2011 to May 2018 were analyzed.
RESULTS: Interlaboratory robust coefficients of variation (rCVs) in particular surveys comprised between 1.3 and 47.2% for vancomycin, and between 1.8 and 34.2% for gentamycin. The percentage of the results with the difference above acceptable limit ±10% from the target value established for own method group was 25.7% for vancomycin and 25.6% for gentamycin. When the difference was established according to target value for all methods, the percentage of results outside the acceptable limit was 2-fold higher on average (54.8% for vancomycin and 43.2% for gentamycin). The comparison of target values for methods revealed statistically significant differences between analytical systems used (p < .0001). The highest difference was 40% for vancomycin and 12% for gentamycin.
CONCLUSIONS: The present analysis revealed high dispersion of the antibiotics assays results in Polish laboratories. Moreover, vancomycin and gentamycin results differed significantly in a way dependent on the analytical system used. There appear to be an urgent need for harmonization of methods used for vancomycin and gentamycin measurement.

PMID: 30731069 [PubMed - indexed for MEDLINE]

Anticancer effects of alloxanthoxyletin and fatty acids esters - In vitro study on cancer HTB-140 and A549 cells.

Biomed Pharmacother. 2019 Feb;110:618-630

Authors: Jóźwiak M, Struga M, Roszkowski P, Filipek A, Nowicka G, Olejarz W

Abstract
Alloxanthoxyletin, a natural occurring pyranocoumarin isolated from a number of plant sources, such as family of Rutaceae, and its synthetic derivatives show cytotoxic and antitumor activities. In the present study new eleven esters of alloxanthoxyletin and fatty acids were synthesized and evaluated for their anticancer toxicity. The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR) and High Resolution Mass Spectrometry (HRMS) analyses. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effect on human melanoma cells (HTB-140), human epithelial lung carcinoma cells (A549) and human keratinocyte line (HaCaT). For the most active compounds (8-11) lactate dehydrogenase (LDH) assay to assess the level of cell damage as well as migration inhibition assay were performed. To explain the basic mechanism of cell death induction, the effect of derivatives 8-11 on early and late apoptosis in Annexin V-FITC/7-AAD flow cytometry analysis was investigated. The results indicate that human melanoma cells (HTB-140) and human epithelial lung carcinoma cells (A549) were more sensitive to new alloxanthoxyletin derivatives exposure compared to human keratinocytes (HaCaT). Both, the cytotoxicity and the migration tests showed a concentration-dependent inhibition of cell growth, although with a different degree of efficacy. Tested compounds induced apoptosis in cancer cells, however, derivatives 8, 9, 10 and 11 were found to be much more potent inducers of early apoptosis in HTB-140 cells than in A549 and HaCaT cells. To establish the potent mechanism of action of alloxanthoxyletin derivatives 8, 9, 10 and 11 on HaCaT, A549 and HTB-140 cells, the level of IL-6 was measured. Our results indicate, that tested compounds significantly decrease the release of IL-6 for all cancer cell lines.

PMID: 30544062 [PubMed - indexed for MEDLINE]

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-containing Antiretroviral Therapy.

Clin Pharmacol Ther. 2019 Apr 21;:

Authors: Desta Z, Gammal RS, Gong L, Whirl-Carrillo M, Gaur AH, Sukasem C, Hockings J, Myers A, Swart M, Tyndale R, Masimirembwa C, Iwuchukwu OF, Chirwa S, Lennox J, Gaedigk A, Klein T, Haas DW

Abstract
The human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes. This article is protected by copyright. All rights reserved.

PMID: 31006110 [PubMed - as supplied by publisher]

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture.

Calcif Tissue Int. 2019 Apr 20;:

Authors: Kharazmi M, Michaëlsson K, Schilcher J, Eriksson N, Melhus H, Wadelius M, Hallberg P

Abstract
Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n = 51) with population-based controls (n = 4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n = 324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p < 5 × 10-8 was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p < 5.7 × 10-6). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

PMID: 31006051 [PubMed - as supplied by publisher]

Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden.

Biochem Pharmacol. 2019 Apr 18;:

Authors: Zimdahl Kahlin A, Helander S, Skoglund K, Söderkvist P, Mårtensson LG, Lindqvist Appell M

Abstract
Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient's TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

PMID: 31005613 [PubMed - as supplied by publisher]