Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness.

Cancer Res. 2019 Nov 13;:

Authors: Patel VL, Busch EL, Friebel TM, Cronin A, Leslie G, McGuffog L, Adlard J, Agata S, Agnarsson BA, Ahmed M, Aittomäki K, Alducci E, Andrulis IL, Arason A, Arnold N, Artioli G, Arver B, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barnes DR, Barroso A, Barrowdale D, Belotti M, Benitez J, Bertelsen B, Blok MJ, Bodrogi I, Bonadona V, Bonanni B, Bondavalli D, Boonen SE, Borde J, Borg A, Bradbury AR, Brady A, Brewer C, Brunet J, Buecher B, Buys SS, Cabezas-Camarero S, Caldés T, Caliebe A, Caligo MA, Calvello M, Campbell IG, Carnevali I, Carrasco E, Chan TL, Chu ATW, Chung WK, Claes KBM, Collaborators GS, Collaborators E, Cook J, Cortesi L, Couch FJ, Daly MB, Damante G, Darder E, Davidson R, de la Hoya M, Della Puppa L, Dennis J, Díez O, Ding YC, Ditsch N, Domchek SM, Donaldson A, Dworniczak B, Easton DF, Eccles DM, Eeles RA, Ehrencrona H, Ejlertsen B, Engel C, Evans DG, Faivre L, Faust U, Feliubadaló L, Foretova L, Fostira F, Fountzilas G, Frost D, García-Barberán V, Garre P, Gauthier-Villars M, Géczi L, Gehrig A, Gerdes AM, Gesta P, Giannini G, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gutierrez-Barrera AM, Hahnen E, Hamann U, Hauke J, Herold N, Hogervorst FBL, Honisch E, Hopper JL, Hulick PJ, Investigators K, Investigators H, Izatt L, Jager A, James P, Janavicius R, Jensen UB, Jensen TD, Johannsson OT, John EM, Joseph V, Kang E, Kast K, Kiiski JI, Kim SW, Kim Z, Ko KP, Konstantopoulou I, Kramer G, Krogh L, Kruse TA, Kwong A, Larsen M, Lasset C, Lautrup C, Lázaro C, Lee J, Lee JW, Lee MH, Lemke J, Lesueur F, Liljegren A, Lindblom A, Llovet P, Lopez-Fernández A, Lopez-Perolio I, Lorca V, Loud JT, Ma ESK, Mai PL, Manoukian S, Mari V, Martin L, Matricardi L, Mebirouk N, Medici V, Meijers-Heijboer HEJ, Meindl A, Mensenkamp AR, Miller C, Molina Gomes D, Montagna M, Mooij TM, Moserle L, Mouret-Fourme E, Mulligan AM, Nathanson KL, Navratilova M, Nevanlinna H, Niederacher D, Cilius Nielsen FC, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Ong KR, Osorio A, Ott CE, Palli D, Park SK, Parsons MT, Pedersen IS, Peissel B, Peixoto A, Pérez-Segura P, Peterlongo P, Høgh Petersen A, Porteous ME, Pujana MA, Radice P, Ramser J, Rantala J, Rashid MU, Rhiem K, Rizzolo P, Robson ME, Rookus MA, Rossing CM, Ruddy KJ, Santos C, Saule C, Scarpitta R, Schmutzler RK, Schuster H, Senter L, Seynaeve CM, Shah PD, Sharma P, Shin VY, Silvestri V, Simard J, Singer CF, Skytte AB, Snape K, Solano AR, Soucy P, Southey MC, Spurdle AB, Steele L, Steinemann D, Stoppa-Lyonnet D, Stradella A, Sunde L, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tommasi S, Torres D, Toss A, Trainer AH, Tung N, van Asperen CJ, van der Baan FH, van der Kolk LE, van der Luijt RB, van Hest LP, Varesco L, Varon-Mateeva R, Viel A, Vierstraete J, Villa R, von Wachenfeldt A, Wagner P, Wang-Gohrke S, Wappenschmidt B, Weitzel JN, Wieme G, Yadav S, Yannoukakos D, Yoon SY, Zanzottera C, Zorn KK, D'Amico AV, Freedman ML, Pomerantz MM, Chenevix-Trench G, Antoniou AC, Neuhausen SL, Ottini L, Nielsen HR, Rebbeck TR

Abstract
Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer (PCa). We evaluated whether PSVs in BRCA1/2 were associated with risk of overall PCa or high grade (Gleason 8+) PCa using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with PCa, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without PCa. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of PCa compared with reference bin c.1001-c.7913 (HR=1.78, 95%CI: 1.25-2.52, p=0.001), as well as elevated risk of Gleason 8+ PCa (HR=3.11, 95%CI: 1.63-5.95, p=0.001). c.756-c.1000 was also associated with elevated PCa risk (HR=2.83, 95%CI: 1.71-4.68, p=0.00004) and elevated risk of Gleason 8+ PCa (HR=4.95, 95%CI: 2.12-11.54, p=0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive PCa.

PMID: 31723001 [PubMed - as supplied by publisher]

Therapeutic drug monitoring-guided definition of adherence profiles in resistant hypertension and identification of predictors of poor adherence.

Br J Clin Pharmacol. 2018 11;84(11):2535-2543

Authors: Avataneo V, De Nicolò A, Rabbia F, Perlo E, Burrello J, Berra E, Pappaccogli M, Cusato J, D'Avolio A, Di Perri G, Veglio F

Abstract
AIMS: Arterial hypertension is an important cardiovascular risk factor. A substantial proportion of patients show resistance to antihypertensive treatment but poor adherence to medication regimens is also a significant cause of treatment failure. In this context, therapeutic drug monitoring (TDM) could be useful. The objective of this study was to assess adherence to treatment in patients with resistant hypertension by TDM and to identify parameters that predict nonadherence.
METHODS: Liquid chromatography tandem mass spectrometry was used to quantify a wide panel of antihypertensive drugs in human plasma to assess treatment compliance. Associations between TDM-determined adherence profiles, self-reported adherence and other patient-related clinical, anthropometric or demographic features were evaluated as potentially useful pre-TDM predictors of poor adherence.
RESULTS: TDM was performed on 50 patients with suspected resistant hypertension: 24% of patients partially complied to treatment and 18% were nonadherent. No concordance was observed with questionnaire results, while nonadherence was associated with high diastolic blood pressure, high heart rate, previous onset of stroke and previous use of invasive treatments, including renal denervation or baroreceptor stimulation.
CONCLUSIONS: This evidence highlights the high prevalence of poor adherence in patients with resistant hypertension and the need for caution in using invasive approaches. These preliminary data require validation in a larger cohort, to confirm the need for TDM in routine clinical practice.

PMID: 29971815 [PubMed - indexed for MEDLINE]

NIX-Mediated Mitophagy Promotes Effector Memory Formation in Antigen-Specific CD8+ T Cells.

Cell Rep. 2019 Nov 12;29(7):1862-1877.e7

Authors: Gupta SS, Sharp R, Hofferek C, Kuai L, Dorn GW, Wang J, Chen M

Abstract
Autophagy plays a critical role in the maintenance of immunological memory. However, the molecular mechanisms involved in autophagy-regulated effector memory formation in CD8+ T cells remain unclear. Here we show that deficiency in NIX-dependent mitophagy leads to metabolic defects in effector memory T cells. Deletion of NIX caused HIF1α accumulation and altered cellular metabolism from long-chain fatty acid to short/branched-chain fatty acid oxidation, thereby compromising ATP synthesis during effector memory formation. Preventing HIF1α accumulation restored long-chain fatty acid metabolism and effector memory formation in antigen-specific CD8+ T cells. Our study suggests that NIX-mediated mitophagy is critical for effector memory formation in T cells.

PMID: 31722203 [PubMed - in process]

Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial.

Braz J Psychiatry. 2019 Nov 11;:

Authors: Brunoni AR, Carracedo A, Amigo OM, Pellicer AL, Talib L, Carvalho AF, Lotufo PA, Benseñor IM, Gattaz W, Cappi C

Abstract
OBJECTIVE: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression.
METHODS: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately.
RESULTS: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group.
CONCLUSION: Larger, combined datasets are necessary to identify candidate genes for tDCS response.

PMID: 31721892 [PubMed - as supplied by publisher]

Impact of Pharmacogenomics on Clinical Outcomes for Patients Taking Medications With Gene-Drug Interactions in a Randomized Controlled Trial.

J Clin Psychiatry. 2019 Oct 31;80(6):

Authors: Thase ME, Parikh SV, Rothschild AJ, Dunlop BW, DeBattista C, Conway CR, Forester BP, Mondimore FM, Shelton RC, Macaluso M, Li J, Brown K, Jablonski MR, Greden JF

Abstract
OBJECTIVE: The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions.
METHODS: Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD. Patients were randomized to treatment as usual (TAU) or the guided-care arm, in which clinicians had access to a combinatorial pharmacogenomic test report to inform medication selection. Patients and raters were blinded to study arm through week 8. The following outcomes were assessed using the 17-item Hamilton Depre​ssion Rating Scale (HDRS-17): symptom improvement (percent change in HDRS-17 score), response (≥ 50% decrease in HDRS-17 score), and remission (HDRS-17 score ≤ 7). In the GUIDED trial, the primary endpoint of symptom improvement did not reach significance in the intent-to-treat cohort (P = .069). Here, a post hoc analysis of patients who were taking medications subject to gene-drug interactions at baseline as predicted by combinatorial pharmacogenomic testing (N = 912) is presented.
RESULTS: Among participants taking medications subject to gene-drug interactions at baseline, outcomes at week 8 were significantly improved for those in the guided-care arm compared to TAU (symptom improvement: 27.1% versus 22.1%, P = .029; response: 27.0% versus 19.0%, P = .008; remission: 18.2% versus 10.7%, P = .003). When patients who switched medications were assessed, all outcomes were significantly improved in the guided-care arm compared to TAU (P = .011 for symptom improvement, P = .011 for response, P = .008 for remission).
CONCLUSIONS: By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02109939​.

PMID: 31721487 [PubMed - in process]

Precision medicine, agriculture, and genome editing: science and ethics.

Ann N Y Acad Sci. 2019 Nov 13;:

Authors: Moscoso CG, Potz KR, Tan S, Jacobson PA, Berger KM, Steer CJ

Abstract
The era of precision medicine has generated advances in various fields of science and medicine with the potential for a paradigm shift in healthcare delivery that will ultimately lead to an individualized approach to medicine. Such timely topics were explored in 2018 at a workshop held at the Third International Conference on One Medicine One Science (iCOMOS), in Minneapolis, Minnesota. A broad range of scientists and regulatory experts provided detailed insights into the challenges and opportunities associated with precision medicine and gene editing. There was a general consensus that advances in studying the genomic traits driving differential pharmacogenomics will undoubtedly enhance individualized treatments for a wide variety of diseases. Ethical considerations, societal implications, approaches for prioritizing safe and secure use of treatment modalities, and the advent of high-throughput computing and analysis of large, complex datasets were discussed. Large biobanks, such as the All of Us Research Program and the Veterans Affairs Million Veterans Program, can aid studies of various conditions in massive cohorts of patients. As the applications of precision medicine continue to mature, the full potential and promise of these individualized approaches will continue to yield important advances in transplant medicine, oncology, public health, agriculture, pharmacology, and bioinformatics.

PMID: 31721233 [PubMed - as supplied by publisher]

Pharmacogenetic analyses of variations of measures of cardiovascular risk in Alzheimer's dementia.

Indian J Med Res. 2019 Sep;150(3):261-271

Authors: de Oliveira FF, Berretta JM, de Almeida Junior GV, de Almeida SS, Chen ES, Smith MC, Bertolucci PHF

Abstract
Background & objectives: Neurodegeneration affects blood pressure variations, while renal function and cerebral perfusion are impaired by vascular risk factors. This study was aimed to estimate variations of measures of cardiovascular risk in Alzheimer's dementia by pharmacogenetic analyses of the effects of angiotensin-converting enzyme (ACE) inhibitors and statins.
Methods: Consecutive patients were prospectively followed to study variations of creatinine clearance and blood pressure for one year, estimated by correlating the effects of ACE inhibitors with the ACE Alu I/D polymorphism and genotypes or haplotypes of rs1800764 or rs4291, and the effects of statins with LDLR (low-density lipoprotein receptor) genotypes or haplotypes of rs11669576 (exon 8) or rs5930 (exon 10), or genotypes of rs2695121 (liver X receptor β gene). Variations of the coronary heart disease (CHD) risk according to these cardiovascular measures were also explored.
Results: All polymorphisms of the 193 patients were in Hardy-Weinberg equilibrium. Genetic determinants of cardiovascular effects affected the individual variability of the response to ACE inhibitors and statins. ACE inhibitors, but not statins, reduced blood pressure for all patients. ACE inhibitors protected carriers of alleles that supposedly decrease serum ACE levels (rs1800764-T, rs4291-A, Alu II) regarding creatinine clearance variations (P <0.005), but carriers of Alu DD (P <0.02), rs1800764-C (P <0.05), or rs4291-AT (P <0.04) showed better blood pressure lowering effects. The presence of rs2695121-T (P=0.007) or rs5930-A (P=0.039) was associated with systolic blood pressure lowering, whereas rs5930-AA was protective against decrease in creatinine clearance (P=0.019). Statins lowered creatinine clearance for carriers of rs2695121-CT (P=0.026).
Interpretation & conclusions: Pharmacological response of blood pressure and creatinine clearance to ACE inhibitors and statins may be genetically mediated.

PMID: 31719297 [PubMed - in process]

Perceptions and expectations of health care providers towards clinical pharmacy services at a tertiary cancer centre in Qatar.

J Oncol Pharm Pract. 2019 Nov 13;:1078155219882076

Authors: Omar NE, Elazzazy S, Abdallah O, Nashwan AJ, Eltorki Y, Afifi HM, Kassem N, Yassin M, Hamad A

Abstract
BACKGROUND: Clinical pharmacy services started in 2009 at the National Center for Cancer Care and Research, Qatar. Clinical pharmacy services was established to provide comprehensive prescription of drug management and support, and consulting services to build clinically efficient and cost-effective pharmacy program.
AIM: To determine perceptions and expectations of healthcare providers toward the clinical pharmacy services at the National Center for Cancer Care and Research.
METHODS: A cross-sectional survey of healthcare providers was conducted from January to May 2018. A self-administered electronic/paper survey containing four domains assessing healthcare providers' perceptions and expectations towards clinical pharmacy services, perceived barriers to clinical pharmacist role and suggested area for improvement was sent to 375 healthcare providers including physicians, operational pharmacists, nurses and dietitians.
RESULTS: The response rate was 112/375. Most of the healthcare providers (74%) perceived the increasing interest in clinical pharmacy services. Also, they expected (1) providing consultations regarding appropriate medication choices (82%); (2) providing information about medication availability and shortages (82%); (3) assisting in the prescribing of cost-effective drugs by providing pharmacogenomics information routinely (75%) and (4) Participating actively in research activities (74%). Overall, healthcare providers have a high level of trust in the clinical pharmacists' abilities (P < 0.01). Nurses were less appreciative (P < 0.002) of the positive role of clinical pharmacists in direct patient care as compared to both physicians and pharmacists (64.2%, 90% and 95.7%, respectively).
CONCLUSION: This study revealed a positive attitude towards the role of clinical pharmacists by healthcare providers at National Center for Cancer Care and Research. However, there is an area of improvement by empowering with privilege and staffing, elevating the awareness and expansion in the ambulatory care settings.

PMID: 31718469 [PubMed - as supplied by publisher]

HLA Alleles and CYP2C9*3 as Predictors of Phenytoin Hypersensitivity in East Asians.

Clin Pharmacol Ther. 2019 02;105(2):476-485

Authors: Su SC, Chen CB, Chang WC, Wang CW, Fan WL, Lu LY, Nakamura R, Saito Y, Ueta M, Kinoshita S, Sukasem C, Yampayon K, Kijsanayotin P, Nakkam N, Saksit N, Tassaneeyakul W, Aihara M, Lin YJ, Chang CJ, Wu T, Hung SI, Chung WH

Abstract
To develop a pre-emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin-related severe cutaneous adverse reactions (SCARs), three sets of patients with phenytoin-SCAR and drug-tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA-B*13:01, HLA-B*15:02, and HLA-B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA-B*13:01/HLA-B*15:02/HLA-B*51:01 from 30.5-71.9% for selecting the individuals with the risk of developing phenytoin-SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta-analysis of the four combined risk alleles showed significant associations with phenytoin-SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.

PMID: 30270535 [PubMed - indexed for MEDLINE]

Evaluation of current regulation and guidelines of pharmacogenomic drug labels; opportunities for improvements.

Clin Pharmacol Ther. 2019 Nov 12;:

Authors: Shekhani R, Steinacher L, Swen JJ, Ingelman-Sundberg M

Abstract
Pharmacogenomic drug labels in summary of product characteristics (SmPCs) provide an instrument for clinical implementation of pharmacogenomics. We compared pharmacogenomic guidance by CPIC, DPWG, FDA, and by the European agencies EMA, CBG-MEB and FIDMD, collectively assigned as EMA/FM. Out of 54 drugs with an actionable gene-drug interaction in the CPIC and DPWG guidelines, only 50 % had actionable pharmacogenomic information in the SmPCs and the agencies were in agreement in only 18 % of the cases. We further compared 450 additional drugs, lacking CPIC or DPWG guidance, and found 126 actionable gene-drug labels by FDA and/or EMA/FM. Based on these 126 drugs in addition to the 54 above the consensus of actionable pharmacogenomic labelling between FDA and EMA/FM was only 54 %. In conclusion, guidelines provided by CPIC/DPWG are only partly implemented into the SmPCs and the implementation of pharmacogenomic drug labels into the clinics would strongly gain from a higher extent of consensus between agencies.

PMID: 31715018 [PubMed - as supplied by publisher]

CORRIGENDUM: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes.

Clin Pharmacol Ther. 2019 Dec;106(6):1408

Authors:

PMID: 31713238 [PubMed - in process]

Design and Implementing Pharmacogenomics Study in Cancer.

Adv Exp Med Biol. 2019;1168:43-77

Authors: Romero Lagunes ML, Vera Badillo FE

Abstract
The advances in technology has shifted healthcare from a "one size fits all" model to focus on personalized therapy. Understanding the relationship of genome variations and its effect on drug response has led to individualized drug selection, maximizing drug efficacy and improving toxicity profile. The developments in pharmacogenomics has led to the discovery of predictive and prognostic biomarkers, and has transformed cancer research leading to the creation of pharmacogenomics databases. While challenges associated with the implementation of pharmacogenomics based medicine exist, integrating data amongst collaborative networks will be crucial for researchers to identify all the functional elements of the human genome sequence. Future advances in the area of pharmacogenomics research will eventually lead to the identification of the right therapeutic drug for the right patient.

PMID: 31713164 [PubMed - in process]

Next Generation Sequencing (NGS): A Revolutionary Technology in Pharmacogenomics and Personalized Medicine in Cancer.

Adv Exp Med Biol. 2019;1168:9-30

Authors: Morganti S, Tarantino P, Ferraro E, D'Amico P, Duso BA, Curigliano G

Abstract
Following the completion of the Human Genome Project in 2003, research in oncology has progressively focused on the sequencing of cancer genomes, with the aim of better understanding the genetic basis of oncogenesis and identifying actionable alterations. The development of next-generation-sequencing (NGS) techniques, commercially available since 2006, allowed for a cost- and time-effective sequencing of tumor DNA, leading to a "genomic era" of cancer research and treatment. NGS provided a significant step forward in Personalized Medicine (PM) by enabling the detection of somatic driver mutations, resistance mechanisms, quantification of mutational burden, germline mutations which settled the foundation of a new approach in cancer care. In this chapter we discuss the history, available techniques and applications of NGS in oncology, with a particular referral to the PM approach and the emerging role of the research field of pharmacogenomics.

PMID: 31713162 [PubMed - in process]

Pharmaco-Geno-Proteo-Metabolomics and Translational Research in Cancer.

Adv Exp Med Biol. 2019;1168:1-7

Authors: Fernández-Figueroa EA, Lino-Silva S, Peña-Velasco JE, Rangel-Escareño C

Abstract
The diagnosis, prognosis and treatment of cancer has had a great improvement due to the "omics" technologies such as genomics, proteomics, epigenomics, pharmacogenomics, and metabolomics. The technological progress of these technologies has allowed precision medicine to become a clinical reality. The study of different biomolecules such as DNA, RNA and proteins has helped to detect alterations in genes, changes in gene expression profiles and loss or gain of protein function, which allows us to make associations and better understand the cancer biology. Data obtained from different "omics" technologies gives a complementary spectrum of information that helps us to understand and unveil new information for a better diagnosis, prognosis, prediction of new molecular targets of anticancer therapies, etc. This chapter presents a general landscape of the interaction between the Pharmaco-Geno-Proteo-Metabolomic and translational medicine research in cancer.

PMID: 31713161 [PubMed - in process]

Formulation of Direct Compression Zidovudine Tablets to Correlate the SeDeM Diagram Expert System and the Rotary Press Simulator Styl'ONE Results.

AAPS PharmSciTech. 2019 Nov 11;21(1):1

Authors: Nofrerias I, Nardi A, Suñé-Pou M, Suñé-Negre JM, García-Montoya E, Pérez-Lozano P, Miñarro M, Bataille B, Ticó JR

Abstract
The SeDeM diagram expert system has been applied to study Zidovudine and some excipients. From the obtained diagrams, a pharmaceutical formula has been designed. SeDeM diagram ascertains the critical parameters that are suitable for a direct compression. The formula is compressed using a rotary tablet press simulator which emulates rotary tablet press' compression profiles. From these compressions, we study the formula behavior under different industrial production conditions but saving a huge amount of material. The study is done at different compression forces and compression speeds and taking into account the influence of the pre-compression force. The differences observed between the compression profiles are hereby described. The results indicate that the formulation is able to be compressed adequately with the emulated compression profiles and no differences are observed between the final products. Therefore, we can assure that the SeDeM diagram expert system is accurate and robust. Moreover, its results are comparable with the compression results in a rotary tablet press, which has never been described in the pharmaceutical literature before. From the obtained results, it is possible to select the best rotary press to scale-up this formulation.

PMID: 31712905 [PubMed - in process]

Population pharmacokinetics and pharmacogenetics of ethambutol in adult patients co-infected with tuberculosis and HIV.

Antimicrob Agents Chemother. 2019 Nov 11;:

Authors: Sundell J, Bienvenu E, Birgersson S, Äbelö A, Ashton M

Abstract
This study aimed to characterize the population pharmacokinetics and pharmacogenetics of ethambutol in co-infected tuberculosis/HIV adult patients. Ethambutol plasma concentrations, determined by LC-MS/MS, in 63 patients receiving ethambutol as part of a rifampicin based fixed-dose combination therapy for tuberculosis were analysed using nonlinear mixed-effects modelling. A one-compartment disposition model with first order elimination, and four transit compartments prior to first-order absorption was found to adequately describe the concentration - time profiles of ethambutol in plasma. Bodyweight was implemented as an allometric function on the clearance and volume parameters. Estimates of oral clearance and volume of distribution were 77.4 L/h and 76.2 L, respectively. G/A mutation with regard to CYP1A2 2159 G>A was associated with a 50 % reduction in relative bioavailability. Simulations revealed that 30 mg/kg and 50 mg/kg doses for G/G and G/A carriers, respectively would result in a clinically adequate exposure. The results presented here suggest that CYP1A2 polymorphism affects ethambutol exposure in this population and that current treatment guidelines may result in underexposure in patients co-infected with tuberculosis and HIV. Based on simulations, a dose increase from 15-20 mg/kg to 30 mg/kg is suggested. However, the 50 mg/kg dose required to reach therapeutic exposure in G/A carriers may be inappropriate due to the dose dependent toxicity of ethambutol. Additional studies are required to further investigate CYP450 polymorphism effects on ethambutol pharmacokinetics.

PMID: 31712201 [PubMed - as supplied by publisher]

[Efficiency of pharmacogenetic approach to anticoagulant therapy in patients with prosthetic heart valves].

Kardiologiia. 2019 Aug 06;59(9S):25-30

Authors: Gorbunova EV, Rozhnev VV, Ponasenko AV, Barbarash OL

Abstract
BACKGROUND: This study examined clinical, demographic, anthropometric, and inheritance factors that influence individual sensitivity to warfarin therapy after heart valve surgery. The clinical significance of the pharmacogenetic approach was assessed using the individual time frame and time spent in the INR therapeutic range.
AIMS: We determined the clinical outcome of the pharmacogenetic approach at the start of warfarin therapy in patients with prosthetic heart valves.
MATERIALS AND METHODS: The study included 915 patients, of which 512 women and 403 men (mean age 56±10 years), living in Western Siberia. Rheumatic heart disease was the main diagnosis that caused the acquired defect. Mechanical prostheses were used in 70% of cases of cardiac surgery. Real-time polymerase chain reaction used for molecular genetic testing.
RESULTS: The frequencies of the alleles and genotypes of CYP2C9 and VKORC1 in the study population of patients with heart valves prosthetic correspond to the distribution in Caucasoid populations. The use of pharmacogenetic testing results at the beginning of warfarin therapy reduced the time required for selecting a therapeutic dose of anticoagulant by 2 times and increased the duration of stay in the INR therapeutic range by 20.2%.
CONCLUSION: The use of the pharmacogenetic approach at the begin‑ ning of warfarin therapy contributes to the effectiveness and safety of anticoagulant therapy in this category of patients.

PMID: 31644414 [PubMed - indexed for MEDLINE]

Computational/in silico methods in drug target and lead prediction.

Brief Bioinform. 2019 Nov 10;:

Authors: Agamah FE, Mazandu GK, Hassan R, Bope CD, Thomford NE, Ghansah A, Chimusa ER

Abstract
Drug-like compounds are most of the time denied approval and use owing to the unexpected clinical side effects and cross-reactivity observed during clinical trials. These unexpected outcomes resulting in significant increase in attrition rate centralizes on the selected drug targets. These targets may be disease candidate proteins or genes, biological pathways, disease-associated microRNAs, disease-related biomarkers, abnormal molecular phenotypes, crucial nodes of biological network or molecular functions. This is generally linked to several factors, including incomplete knowledge on the drug targets and unpredicted pharmacokinetic expressions upon target interaction or off-target effects. A method used to identify targets, especially for polygenic diseases, is essential and constitutes a major bottleneck in drug development with the fundamental stage being the identification and validation of drug targets of interest for further downstream processes. Thus, various computational methods have been developed to complement experimental approaches in drug discovery. Here, we present an overview of various computational methods and tools applied in predicting or validating drug targets and drug-like molecules. We provide an overview on their advantages and compare these methods to identify effective methods which likely lead to optimal results. We also explore major sources of drug failure considering the challenges and opportunities involved. This review might guide researchers on selecting the most efficient approach or technique during the computational drug discovery process.

PMID: 31711157 [PubMed - as supplied by publisher]

Vasopressin SNP pain factors and stress in sickle cell disease.

PLoS One. 2019;14(11):e0224886

Authors: Powell-Roach KL, Yao Y, Jhun EH, He Y, Suarez ML, Ezenwa MO, Molokie RE, Wang ZJ, Wilkie DJ

Abstract
PURPOSE: Frequencies of single nucleotide polymorphisms (SNPs) from pain related candidate genes are available for individuals with sickle cell disease (SCD). One of those genes, the arginine vasopressin receptor 1A gene (AVPR1A) and one of its SNPs, rs10877969, has been associated with pain and disability in other pain populations. In patients with SCD, clinical factors such as pain and stress have been associated with increased health care utilization, but it is not known if the presence of the AVPR1A SNP plays a role in this observation. The study purpose was to explore the relationships between rs10877969 and self-reported pain, stress, and acute care utilization events among individuals with SCD.
METHODS: In a cross-sectional investigation of outpatients with SCD, participants completed PAINReportIt®, a computerized pain measure, to describe their pain experience and contributed blood or saliva samples for genetic analysis. We extracted emergency department and acute care utilization from medical records.
RESULTS: The SNP genotype frequencies (%) for this sample were CC 30 (28%), CT 44 (41%), TT 33 (31%). Acute care utilization and stress as an aggravator of pain were significantly associated with the rs10877969 genotype (p = .02 and p = .002, respectively). The CT genotype had the highest mean utilization and CC genotype was associated with not citing stress as a pain aggravator. Chronic pain was not associated with rs10877969 (p = .41).
CONCLUSION: This study shows that rs10877969 is related to indicators of stress and acute pain. Further research is recommended with other measures of stress and acute pain.

PMID: 31710639 [PubMed - in process]

The Promise of Pharmacogenomics: Genetic variation can be used to individualize drug therapy, and is an integral component of genomic medicine.

Am J Med Genet A. 2019 Dec;179(12):2324-2325

Authors:

PMID: 31709748 [PubMed - in process]