Gene-gene and gene-environment interactions influence platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients.

Sci Rep. 2017 Jul 11;7(1):5082

Authors: Cui JJ, Wang LY, Zhu T, Gong WJ, Zhou HH, Liu ZQ, Yin JY

Abstract
Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based chemotherapy response and drug toxicity. However, neither of the studies explored this association from SNP-SNP interaction perspective nor taking into effects of SNP-environment consideration simultaneously. We genotyped 504 polymorphisms and explore the association of gene-gene and gene-environment interactions with platinum-based chemotherapy response and toxicity in 490 NSCLC patients. 16 SNPs were found significantly associated with platinum-based chemotherapy, and they were picked out as study object in the validation cohort. We recruited 788 patients in the validation cohort. We found that HSPD1 rs17730989-SUMF1 rs2633851 interaction was associated with platinum-based chemotherapy-induced hematologic toxicity (adjusted OR = 0.233, P = 0.018). In addition, the combined effect of ABCG2 rs2231142-CES5A rs3859104 was significantly associated with overall toxicity (adjusted OR = 8.044, P = 4.350 × 10(-5)). Besides, the model of ARHGAP26 rs3776332-ERCC6 rs2228528-SLC2A1 rs4658-histology was associated with platinum-based chemotherapeutic response. Gene-gene and gene-environment interactions have been identified to contribute to chemotherapy sensitivity and toxicity. They can potentially predict drug response and toxicity of platinum-based chemotherapy in NSCLC patients.

PMID: 28698656 [PubMed - in process]

V-J combinations of T-cell receptor predict responses to erythropoietin in end-stage renal disease patients.

J Biomed Sci. 2017 Jul 11;24(1):43

Authors: Wong HS, Chang CM, Kao CC, Hsu YW, Liu X, Chang WC, Wu MS, Chang WC

Abstract
BACKGROUND: Anemia is common among end-stage renal disease (ESRD) patients who undergone hemodialysis. The total reduction of red blood cell (RBC) count is associated with poor prognosis in these patients. Although erythropoietin (EPO) has been used as an effective treatment for ESRD patients with anemia, a large number of patients still present poor responses to EPO treatment.
METHODS: We measured T-cell receptor sequencing profiles, including length of complementarity-deteremining region 3 (CDR3), intra- and inter-group (EPO resistant vs. responsive) clonotype diversity, V(D)J usage profiles and V-J combinations from ESRD patients and to investigate the correlation between these features and EPO treatment efficacy.
RESULTS: Our results revealed statistical significance in the top 3 ~ 15 most abundant joint distributions of Vβ/Jβ among the two groups, suggesting the importance of V or J gene utilization in the EPO response of ESRD patients.
CONCLUSIONS: In summary, we provided evidence addressing the potential correlation between the immune repertoire and EPO response in ESRD patients.
TRIAL REGISTRATION: TMU-JIRB 201309026. Registered 16 October 2013.

PMID: 28697735 [PubMed - in process]

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 2017/07/12

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.

MTRR rs1801394 and its interaction with MTHFR rs1801133 in colorectal cancer: a case-control study and meta-analysis.

Pharmacogenomics. 2017 Jul 10;:

Authors: Haerian MS, Haerian BS, Molanaei S, Kosari F, Sabeti S, Bidari-Zerehpoosh F, Abdolali E

Abstract
AIM: This study aims to evaluate the association between the MTRR rs1801394 alone or in interaction with the MTHFR rs1801133 and susceptibility to colorectal cancer (CRC) and its characteristics in Iranian population. Additionally, both a systematic review and meta-analysis were performed to derive a more precise assessment of this association.
MATERIALS & METHODS: Genomic DNA of 2332 subjects was genotyped for rs1801394. These data were pooled with 17 eligible studies for meta-analysis.
RESULTS: No significant association was found between the rs1801394 or rs1801394-rs1801133 and CRC risk. Meta-analysis results also demonstrated no significant relationship between the rs1801394 and CRC risk.
CONCLUSION: Results of this study showed that the rs1801394 alone or together with the rs1801133 is not a risk factor for CRC in Iranian population.

PMID: 28691890 [PubMed - as supplied by publisher]

Feasibility of clinical pharmacist-led CYP2C19 genotyping for patients receiving non-emergent cardiac catheterization in an integrated health system.

Pharm Pract (Granada). 2017 Apr-Jun;15(2):946

Authors: Johnson SG, Shaw PB, Delate T, Kurz DL, Gregg D, Darnell JC, Aquilante CL

Abstract
OBJECTIVE: To assess the feasibility of clinical pharmacist-led CYP2C19 genotype-guided P2Y12 inhibitor antiplatelet drug therapy recommendations to cardiologists in an outpatient cardiology practice.
METHODS: This was a prospective, open-labeled, single-arm study conducted in an integrated healthcare delivery system between March 1, 2013 and January 23, 2014. Patients requiring non-emergent cardiac catheterization were included. A clinical pharmacist provided interpretation and recommendations from genotyping results. The feasibility of implementing CYP2C19 genotype-guided antiplatelet therapy was assessed by the: 1) percentage of patients approached who consented to CYP2C19 genotyping, 2) percentage of patients with CYP2C19 genotyping results available prior to cardiac catheterization, and 3) percentage of clinical pharmacist CYP2C19 genotype-based antiplatelet recommendations accepted by cardiologists.
RESULTS: Of the 43 patients identified for potential recruitment, 22 of these were eligible for study enrollment and 6 (27%) patients consented and received CYP2C19 genotyping. All patients had genotyping results available prior to catheterization and all clinical pharmacists' antiplatelet therapy recommendations were accepted by the patients' cardiologists. Three patients had the CYP2C19 wild-type (*1/*1) genotype and the clinical pharmacist recommended clopidogrel therapy. CYP2C19 variant genotypes (i.e., *1/*2, *1/*17, and *2/*17) were found in the other three patients; alternative antiplatelet therapy was recommended for the patient with the *1/*2 genotype, while clopidogrel was recommended for those with *1/*17 and *2/*17 genotypes.
CONCLUSION: A relatively small proportion of patients undergoing non-emergent cardiac catheterization consented to pharmacogenetic testing; however, their cardiologists were receptive to clinical pharmacists conducting such testing and providing corresponding pharmacotherapy recommendations. Future studies should identify patient barriers to pharmacogenetic testing.

PMID: 28690699 [PubMed - in process]

Role of Genetic Testing in Patients undergoing Percutaneous Coronary Intervention.

Expert Rev Clin Pharmacol. 2017 Jul 10;:

Authors: Moon JY, Franchi F, Rollini F, Rivas Rios JR, Kureti M, Cavallari LH, Angiolillo DJ

Abstract
INTRODUCTION: Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert Commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.

PMID: 28689434 [PubMed - as supplied by publisher]

Rivaroxaban non-responders: do plasma measurements have a place?

Clin Chem Lab Med. 2017 Jul 08;:

Authors: Dideriksen D, Damkier P, Nybo M

PMID: 28688225 [PubMed - as supplied by publisher]

14 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 2017/07/08

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.

Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models.

Br J Cancer. 2017 Jul 06;:

Authors: Belgiovine C, Bello E, Liguori M, Craparotta I, Mannarino L, Paracchini L, Beltrame L, Marchini S, Galmarini CM, Mantovani A, Frapolli R, Allavena P, D'Incalci M

Abstract
BACKGROUND: Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.
METHODS: In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice.
RESULTS: Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro, lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes.
CONCLUSIONS: The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology.British Journal of Cancer advance online publication, 6 July 2017; doi:10.1038/bjc.2017.205 www.bjcancer.com.

PMID: 28683469 [PubMed - as supplied by publisher]

Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Major Depressive Disorder.

J Clin Psychiatry. 2017 Jun;78(6):703-713

Authors: McIntyre RS, Suppes T, Tandon R, Ostacher M

Abstract
OBJECTIVE: Herein we provide the 2015 update for the Florida Best Practice Psychotherapeutic Medication Guidelines (FPG) for major depressive disorder (MDD). The FPG represent evidence-based decision support for practitioners providing care to adults with MDD.
PARTICIPANTS: The consensus meeting included representatives from the Florida Agency for Health Care Administration (FAHCA), advocacy members, academic experts in MDD, and multidisciplinary mental health clinicians, as well as health policy experts. The FAHCA provided funding support for the FPG.
EVIDENCE: Evidence was limited to results from adequately powered, randomized, double-blind, placebo-controlled trials; in addition, pooled-, meta-, and network-analyses were included. Recommendations were based on consensus arrived at by the multistakeholder Florida Expert Panel. Articles selected were identified on the electronic search engine PubMed with the dates 2010 to present. The search terms were major depressive disorder, psychopharmacology, antidepressants, psychotherapy, neuromodulation, complementary alternative medicines, pooled-analysis, meta-analysis, and network-analysis. Bibliographies of the identified articles were manually searched for additional citations not identified in the original search.
CONSENSUS PROCESS: A consensus meeting comprising all representatives took place on September 25-26, 2015, in Tampa, Florida. Guiding principles (eg, emphasis on the most rigorous evidence for efficacy, safety, and tolerability) were discussed, defined, and operationalized prior to review of extant data. As MDD often pursues a recurrent and chronic course, principles of practice, measurement-based care, and comprehensive assessment and management of overall physical and mental health were emphasized. Evidence supporting pretreatment major depressive episode specifiers (eg, mixed features, anxious distress) and the role of pharmacogenomics (and other biological-behavioral markers) in informing treatment selection were comprehensively discussed. Algorithmic priority was assigned to agents with relatively greater therapeutic index (ie, efficacy) and minimal propensity for safety and tolerability disadvantages.
CONCLUSIONS: The updated 2015 FPG provide concise, pragmatic, evidence-based decision support for treatment selection and sequencing for adults with MDD. Principles of practice include measurement-based care, priority to both psychiatric and medical comorbidity, identification of DSM-5-defined specifiers (eg, mixed features), suicide risk assessment, and evaluation of cognitive symptoms. The FPG have purposefully aimed to minimize emphasis on "expert opinion" and instead differentially emphasized extant evidence for pharmacologic treatments.

PMID: 28682531 [PubMed - in process]

The Relationship of Genetics, Nursing Practice, and Informatics Tools in 6-Mercaptopurine Dosing in Pediatric Oncology.

J Pediatr Oncol Nurs. 2017 Jul 01;:1043454217713446

Authors: Haylett WJ

Abstract
An antileukemic agent prescribed for pediatric oncology patients during the maintenance phase of therapy for acute lymphoblastic leukemia, 6-mercaptopurine (6-MP), is highly influenced by genetic variations in the thiopurine S-methyltransferase enzyme. As such, 6-MP must be dosed so that patients with 1 or 2 inactive thiopurine S-methyltransferase alleles will not incur an increased risk for myelosuppression or other toxicities. Informatics tools such as clinical decision support systems are useful for the application of this and similar pharmacogenetics information to the realm of nursing and clinical practice for safe and effective patient care. This article will discuss pharmacogenetics and the associated use of 6-MP; present implications for nursing practice; identify informatics tools such as clinical decision support systems, which can greatly enhance the care of patients whose treatment is based on critical genetic information; and examine the relationship of genetics, nursing practice, and informatics for 6-MP dosing in pediatric oncology.

PMID: 28681659 [PubMed - as supplied by publisher]

Proposal for a Pharmacogenetic Decision Algorithm.

Cureus. 2017 May 30;9(5):e1289

Authors: Alzghari SK, Blakeney L, Rambaran KA

Abstract
Personalized medicine is playing an ever-increasing role in patient care. Over the past decade, awareness of the role of pharmacogenetics and its benefits is leading to its growing acceptance among providers. Though providers are using pharmacogenetics in practice, the decision-making process of when to use this tool can be ambiguous. Herein, we propose an algorithm to help guide providers on when to use pharmacogenetics for patient care.

PMID: 28680777 [PubMed - in process]

Bioavailability and pharmacokinetic comparison of tanshinones between two formulations of Salvia miltiorrhiza in healthy volunteers.

Sci Rep. 2017 Jul 05;7(1):4709

Authors: Xing L, Tan ZR, Cheng JL, Huang WH, Zhang W, Deng W, Yuan CS, Zhou HH

Abstract
Salvia miltiorrhiza (SM) is widely used to treat microcirculatory disturbance-related diseases; its lipophilic components play important roles in this application. Cryptotanshinone (CTS), tanshinone I (TSI) and tanshinone IIA (TSA) are the most widely-studied lipophilic ingredients, but low oral bioavailability limits their clinical application. It has been proven that micronization could improve the bioavailability of some drugs, so we've conducted this randomized study to investigate whether micronized granular powder (GP) of SM could improve the bioavailability of tanshinones compared with traditional decoction (TD). An oral dose of TD or GP of SM was administrated to subjects and blood samples were collected at predetermined time points. The plasma concentrations of tanshinones were detected by a validated method and pharmacokinetic parameters were calculated using a non-compartmental model. GP of SM resulted in a significant increase in mean maximum plasma concentration (C max ), elimination half-life and area under concentration-time curve (AUC) of tanshinones, with the plasma AUC of CTS, TSI and TSA in GP 5-184, 4-619 and 5-130 times higher than TD. In addition, the individual variances of C max and AUC were much lower after GP administration. Summarily, tanshinones in micronized GP of SM had higher oral bioavailability and lower individual variances, thus we speculate that it may indicate a better clinical efficacy and be a better choice than current treatments.

PMID: 28680091 [PubMed - in process]

Polymorphisms within Genes Involved in Regulation of the NF-κB Pathway in Patients with Rheumatoid Arthritis.

Int J Mol Sci. 2017 Jul 04;18(7):

Authors: Gębura K, Świerkot J, Wysoczańska B, Korman L, Nowak B, Wiland P, Bogunia-Kubik K

Abstract
Genes involved in regulation of the nuclear factor-κB (NF-κB)-pathway are suggested to play a role in pathogenesis of rheumatoid arthritis (RA). In the present study, genetic polymorphisms of TLR2, TLR4, TLR9 and NF-κB1 genes were investigated to assess their associations with RA susceptibility, progression and response to anti-TNF-α therapy. A group of 110 RA patients and 126 healthy individuals were genotyped for TLR2 (rs111200466), TLR4 (rs4986790, rs4986791), TLR9 (rs5743836, rs187084) and NF-κB1 (rs28362491) alleles. The presence of the TLR9 -1486 T variant (p < 0.0001) and its homozygosity (p < 0.0001) were found to be associated with disease susceptibility. The TLR9 -1237 C allele was associated with predisposition to RA in females only (p = 0.005). Moreover, the TLR4 rs4986791 G (rs4986790 T) alleles were more frequently detected among patients with the stage IV disease (p = 0.045), and were associated with more effective response to anti-TNF-α therapy (p = 0.012). More efficient response to anti-TNF-α treatment was also observed in patients with del within the NF-κB1 gene (p = 0.047), while for the TLR9 -1486 T homozygotes, the treatment was ineffective (p = 0.018). TLR polymorphisms affect disease susceptibility and response to therapy with TNF-α inhibitors in RA patients of Caucasian origin.

PMID: 28677621 [PubMed - in process]

DNA methylation and DNA methyltransferases.

Epigenetics Chromatin. 2017;10:23

Authors: Edwards JR, Yarychkivska O, Boulard M, Bestor TH

Abstract
The prevailing views as to the form, function, and regulation of genomic methylation patterns have their origin many years in the past, at a time when the structure of the mammalian genome was only dimly perceived, when the number of protein-encoding mammalian genes was believed to be at least five times greater than the actual number, and when it was not understood that only ~10% of the genome is under selective pressure and likely to have biological function. We use more recent findings from genome biology and whole-genome methylation profiling to provide a reappraisal of the shape of genomic methylation patterns and the nature of the changes that they undergo during gametogenesis and early development. We observe that the sequences that undergo deep changes in methylation status during early development are largely sequences without regulatory function. We also discuss recent findings that begin to explain the remarkable fidelity of maintenance methylation. Rather than a general overview of DNA methylation in mammals (which has been the subject of many reviews), we present a new analysis of the distribution of methylated CpG dinucleotides across the multiple sequence compartments that make up the mammalian genome, and we offer an updated interpretation of the nature of the changes in methylation patterns that occur in germ cells and early embryos. We discuss the cues that might designate specific sequences for demethylation or de novo methylation during development, and we summarize recent findings on mechanisms that maintain methylation patterns in mammalian genomes. We also describe the several human disorders, each very different from the other, that are caused by mutations in DNA methyltransferase genes.

PMID: 28503201 [PubMed - indexed for MEDLINE]

First molecular epidemiology of Entamoeba histolytica, E. dispar and E. moshkovskii infections in Yemen: different species-specific associated risk factors.

Trop Med Int Health. 2017 Apr;22(4):493-504

Authors: Al-Areeqi MA, Sady H, Al-Mekhlafi HM, Anuar TS, Al-Adhroey AH, Atroosh WM, Dawaki S, Elyana FN, Nasr NA, Ithoi I, Lau YL, Surin J

Abstract
OBJECTIVES: To investigate the molecular epidemiology of Entamoeba histolytica, E. dispar and E. moshkovskii infections among rural communities in Yemen.
METHODS: In a community-based study, faecal samples were collected from 605 participants and examined by wet mount, formalin-ether sedimentation, trichrome staining and nested multiplex PCR techniques. Demographic, socio-economic and environmental information was collected using a pre-tested questionnaire.
RESULTS: Overall, 324 (53.6%) of the samples were positive for Entamoeba cysts and/or trophozoites by microscopic examination. Molecular analysis revealed that 20.2%, 15.7% and 18.2% of the samples were positive for E. histolytica, E. dispar and E. moshkovskii, respectively. Multivariate analysis showed different sets of species-specific risk factors among these communities. Educational level was identified as the significant risk factor for E. histolytica; age and gender were the significant risk factors for E. moshkovskii; and sources of drinking water and consumption of unwashed vegetables were the significant risk factors for E. dispar. Moreover, living in coastal/foothill areas and presence of other infected family members were risk factors for both E. histolytica and E. moshkovskii infections.
CONCLUSION: The study reveals that Entamoeba spp. infection is highly prevalent among rural communities in Yemen, with E. histolytica, E. dispar and E. moshkovskii differentiated for the first time. Identifying and treating infected family members, providing health education pertinent to good personal and food hygiene practices and providing clean drinking water should be considered in developing a strategy to control intestinal parasitic infections in these communities, particularly in the coastal/foothill areas of the country.

PMID: 28151567 [PubMed - indexed for MEDLINE]

Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women.

Malar J. 2017 Jul 03;16(1):267

Authors: Mutagonda RF, Kamuhabwa AAR, Minzi OMS, Massawe SN, Asghar M, Homann MV, Färnert A, Aklillu E

Abstract
BACKGROUND: Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women.
METHODS: Pregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol.
RESULTS: In total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4-17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in pregnant women followed up for 28 days (P = 0.018).
CONCLUSIONS: Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women.

PMID: 28673292 [PubMed - in process]

Antimicrobial and Anti-biofilm Activity of Thiourea Derivatives Bearing 3-amino-1H-1,2,4-triazole Scaffold.

Med Chem. 2016;12(5):478-88

Authors: Stefanska J, Stepien K, Bielenica A, Szulczyk D, Miroslaw B, Koziol AE, Sanna G, Iuliano F, Madeddu S, Jozwiak M, Struga M

Abstract
A set of 21 thiourea derivatives were prepared through reacting 3-amino-1H-1,2,4-triazole with the commercial aliphatic and aromatic isothiocyanates. The aliphatic isothiocyanate was used as reagent leading to substitution on NH atom of 3-aminotriazole ring, whereas the triazole amino group was substituted when isothiocyanate group was bonded to the Csp2 hybridized atom, e.g. an aryl or C=O fragment. All compounds were evaluated in vitro for the antimicrobial activity. The derivatives 1, 2, 4, 8, 9, 10 and 12 showed the highest inhibition against Gram-positive cocci (S. aureus and S. epidermidis). The observed MIC values were in the range of 4-32 μg/mL. Compounds were also tested for their in vitro antimicrobial activity against the hospital methicillin-resistant strains of S. aureus. The observed MIC values varied from 4 to 64 μg/mL. The products 4 and 10 effectively inhibited the formation of biofilms of the methicillin-resistant and standard strains of S. epidermidis. The compound 10 was found to be more promising with IC50 values of 2-6 μg/mL as compared to the control. Moreover, the cytotoxicity against the MT-4 cells of all studied thioureas was evaluated. The compound 18 was significantly cytotoxic (CC50 = 8 μM).

PMID: 26648331 [PubMed - indexed for MEDLINE]

Warfarin Pharmacogenomics in Diverse Populations.

Pharmacotherapy. 2017 Jul 03;:

Authors: Kaye JB, Schultz LE, Steiner HE, Kittles RA, Cavallari LH, Karnes JH

Abstract
Genotype-guided warfarin dosing algorithms are a rational approach to optimize warfarin dosing and potentially reduce adverse drug events. Diverse populations, such as African-Americans (AAs) and Latinos, have greater variability in warfarin dose requirements and are at greater risk for experiencing warfarin-related adverse events compared with individuals of European ancestry. Although these data suggest that patients of diverse populations may benefit from improved warfarin dose estimation, the vast majority of literature on genotype-guided warfarin dosing, including data from prospective randomized trials, is in populations of European ancestry. Despite differing frequencies and effects of variants by race/ethnicity, most evidence in diverse populations evaluates variants that are most common in populations of European ancestry. Algorithms that do not include variants important across race/ethnic groups are unlikely to benefit diverse populations. In some race/ethnic groups, development of race-specific or admixture-based algorithms may facilitate improved genotype-guided warfarin dosing algorithms above and beyond that seen in individuals of European ancestry. These observations should be considered in the interpretation of literature evaluating the clinical utility of genotype-guided warfarin dosing. Careful consideration of race/ethnicity and additional evidence focused on improving warfarin dosing algorithms across race/ethnic groups will be necessary for successful clinical implementation of warfarin pharmacogenomics. The evidence with warfarin pharmacogenomics has a broad significance for pharmacogenomic testing, emphasizing the consideration of race/ethnicity in discovery of gene-drug pairs and development of clinical recommendations for pharmacogenetic testing. This article is protected by copyright. All rights reserved.

PMID: 28672100 [PubMed - as supplied by publisher]

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

Pharmacotherapy. 2017 Jul 03;:

Authors: Maxwell WD, Ramsey LB, Johnson SG, Moore KG, Shtutman M, Schoonover JH, Kawaguchi-Suzuki M

Abstract
Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. A summary of the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy is provided. This article is protected by copyright. All rights reserved.

PMID: 28672099 [PubMed - as supplied by publisher]