Evaluation of CYP2C9- and VKORC1-based pharmacogenetic algorithm for warfarin dose in Gaza-Palestine.

Future Sci OA. 2018 Mar;4(3):FSO276

Authors: Ayesh BM, Abu Shaaban AS, Abed AA

Abstract
Aim: To evaluate applicability of CYP2C9*2, *3 and VKORC1-1639G > A based algorithm to predict warfarin stable dose (WSD) in a group of Palestinian patients.
Patients & methods: Warfarin doses were retrospectively calculated for 101 Palestinian patients under warfarin therapy using three models. Performance of the three models was assessed in 47 patients found to take WSD.
Results: Frequency of CYP2C9*2, *3 and VKORC1-1639G > A alleles is 13.6, 0.0 and 46.5% respectively. The international warfarin pharmacogenetics consortium algorithm was more reliable (MAE = 8.9 ± 1.4; R2 = 0.350) than both the clinical algorithm (MAE = 10.4 ± 1.4; R2 = 0.128;) and the fixed-dose algorithm (MAE = 11.1 ± 1.7).
Conclusion: The international warfarin pharmacogenetics consortium algorithm can be reliably applied for predicting the WSD in Palestinian population.

PMID: 29568565 [PubMed]

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Neuron. 2018 Mar 21;97(6):1268-1283.e6

Authors: Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt JJFA, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A, ITALSGEN Consortium, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L, Genomic Translation for ALS Care (GTAC) Consortium, Moreno CAM, Kamalakaran S, Goldstein DB, ALS Sequencing Consortium, Gitler AD, Harris T, Myers RM, NYGC ALS Consortium, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC, Answer ALS Foundation, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E, Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J, SLAGEN Consortium, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C, French ALS Consortium, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, Sidle KC, Malaspina A, Hardy J, Singleton AB, Johnson JO, Arepalli S, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Al-Sarraj S, King A, Troakes C, Vance C, de Belleroche J, Baas F, Ten Asbroek ALMA, Muñoz-Blanco JL, Hernandez DG, Ding J, Gibbs JR, Scholz SW, Floeter MK, Campbell RH, Landi F, Bowser R, Pulst SM, Ravits JM, MacGowan DJL, Kirby J, Pioro EP, Pamphlett R, Broach J, Gerhard G, Dunckley TL, Brady CB, Kowall NW, Troncoso JC, Le Ber I, Mouzat K, Lumbroso S, Heiman-Patterson TD, Kamel F, Van Den Bosch L, Baloh RH, Strom TM, Meitinger T, Shatunov A, Van Eijk KR, de Carvalho M, Kooyman M, Middelkoop B, Moisse M, McLaughlin RL, Van Es MA, Weber M, Boylan KB, Van Blitterswijk M, Rademakers R, Morrison KE, Basak AN, Mora JS, Drory VE, Shaw PJ, Turner MR, Talbot K, Hardiman O, Williams KL, Fifita JA, Nicholson GA, Blair IP, Rouleau GA, Esteban-Pérez J, García-Redondo A, Al-Chalabi A, Project MinE ALS Sequencing Consortium, Rogaeva E, Zinman L, Ostrow LW, Maragakis NJ, Rothstein JD, Simmons Z, Cooper-Knock J, Brice A, Goutman SA, Feldman EL, Gibson SB, Taroni F, Ratti A, Gellera C, Van Damme P, Robberecht W, Fratta P, Sabatelli M, Lunetta C, Ludolph AC, Andersen PM, Weishaupt JH, Camu W, Trojanowski JQ, Van Deerlin VM, Brown RH, van den Berg LH, Veldink JH, Harms MB, Glass JD, Stone DJ, Tienari P, Silani V, Chiò A, Shaw CE, Traynor BJ, Landers JE

Abstract
To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

PMID: 29566793 [PubMed - in process]

Contractile reserve and the response to cardiac resynchronization therapy.

Int J Cardiol. 2018 02 01;252:234-235

Authors: Bristow MR

PMID: 29249434 [PubMed - indexed for MEDLINE]

Impact of BCL2 polymorphisms on survival in transitional cell carcinoma of the bladder.

J Cancer Res Clin Oncol. 2017 Sep;143(9):1659-1670

Authors: Hess J, Stelmach P, Eisenhardt A, Rübben H, Reis H, Schmid KW, Bachmann HS

Abstract
PURPOSE: To evaluate the impact of three BCL2 single-nucleotide polymorphisms, i.e., c.-938C>A (rs2279115), c.21G>A (rs1801018), and c.*2203A>G (rs4987853) on survival in patients with transitional cell carcinoma of the bladder.
METHODS: We analyzed 179 patients who underwent surgical treatment for bladder cancer at the Clinic of Urology, University Hospital Essen, Germany. Genomic DNA was extracted and genotyped for the polymorphisms. For all polymorphisms, linkage analysis was performed. Kaplan-Meier and Cox regression analyses were used to determine the putative impact of the three polymorphisms on outcome.
RESULTS: c.-938C>A and c.21G>A, but not c.*2203A>G, are in strong linkage disequilibrium (D' 0.96). We found a significant association between c.-938C>A and relapse-free survival (p = 0.024) with an allele dose effect. In the same way, c.21G>A had a significant impact on both relapse-free survival (p = 0.009) and progression-free survival (p = 0.012), as well as a pronounced allele dose effect. Regression analysis proved c.21G>A and c.-938C>A, to be an independent risk factor in univariate and multivariable analyses.
CONCLUSIONS: In our cohort, both c.-938C>A and c.21G>A showed a significant impact on outcome with TCC of the bladder. Due to the linkage disequilibrium of both SNPs, maybe, only one of them could mediate this effect. In multivariable analysis, however, both proved to be independently associated with overall survival. Contrary to other findings which found the c.-938C>A mainly influencing outcome, our data may suggest that the main effect on TCC could be due to the c.21G>A polymorphism.

PMID: 28417194 [PubMed - indexed for MEDLINE]

Formyl peptide receptor 2 mediated chemotherapeutics drug resistance in colon cancer cells. Point of view from pharmacogenetics field.

Eur Rev Med Pharmacol Sci. 2018 Mar;22(5):1178-1179

Authors: Marotta G, Muto T, Benincasa G, De Monaco A

PMID: 29565471 [PubMed - in process]

Drug-Induced Skin Adverse Reactions: The Role of Pharmacogenomics in Their Prevention.

Mol Diagn Ther. 2018 Mar 21;:

Authors: Gerogianni K, Tsezou A, Dimas K

Abstract
Adverse drug reactions (ADRs) affect many patients and remain a major public health problem, as they are a common cause of morbidity and mortality. It is estimated that ADRs are responsible for about 6% of hospital admissions and about 9% of hospitalization costs. Skin is the organ that is most frequently involved in ADRs. Drug-induced skin injuries vary from mild maculopapular eruptions (MPE) to severe cutaneous adverse reactions (SCARs) that are potentially life threatening. Genetic factors have been suggested to contribute to these SCARs, and most significant genetic associations have been identified in the major histocompatibility complex (MHC) genes. Common drugs associated with SCARs connected with strong genetic risk factors include antiepileptic drugs (AEDs), allopurinol, abacavir, nevirapine, sulfonamides, dapsone, non-steroidal anti-inflammatory drugs (NSAIDs), and analgesic drugs. However, genetic associations vary between different ethnic populations. Differences may in part be explained by the different prevalence of HLA (human leukocyte antigen) alleles among ethnic groups. In this review, we present and discuss the recent advances in genetic associations with ADRs in the skin. Many of these ADRs are now preventable with pharmacogenetic screening.

PMID: 29564734 [PubMed - as supplied by publisher]

CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment.

Pharmgenomics Pers Med. 2018;11:23-33

Authors: Chen L, Prasad GVR

Abstract
Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between CYP3A5 genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear. CYP3A5 genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release. CYP3A5 genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of CYP3A5 genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.

PMID: 29563827 [PubMed]

Mebendazole, an antiparasitic drug, inhibits drug transporters expression in preclinical model of gastric peritoneal carcinomatosis.

Toxicol In Vitro. 2017 Sep;43:87-91

Authors: Celestino Pinto L, de Fátima Aquino Moreira-Nunes C, Soares BM, Burbano RMR, de Lemos JAR, Montenegro RC

Abstract
The present study aimed to investigate whether MBZ down-regulates drug transporter expression (ABCB1, ABCC1, SLC47A1). mRNA expression level of ABCB1, ABCC1 and SLC47A1 was evaluated by qPCR and protein expression levels MDR-1 was performed by western blotting in malignant ascites cells (AGP-01) treated with MBZ for 24h. The mRNA expression level of ABCB1 and ABCC1 significantly decreased at a 1.0μM of MBZ compared to negative control, while SLC47A1 extremely decreased at all tested concentrations of MBZ. Protein expression levels MDR-1 significantly decreased at a 1.0μM of MBZ compared to negative control. Therefore, our results showed MBZ may play an important role in inhibiting MDR gene expression in malignant ascites cells.

PMID: 28606429 [PubMed - indexed for MEDLINE]

High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients.

Oncotarget. 2017 May 23;8(21):34387-34397

Authors: Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X, Li GC

Abstract
Transforming growth factor beta (TGF-β) promotes the pathogenesis of hepatocellular carcinoma (HCC). We evaluated the associations between TGF-β1 expression and clinicopathological parameters in HCC patients from The Cancer Genome Atlas (TCGA), as well as the prognostic power of TGF-β1 expression. Eligible studies were retrieved from several databases, and effects (hazard ratios (HRs) with 95% confidence intervals (CIs)) for overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), metastasis-free survival (MFS), and progression-free survival (PFS) were pooled to assess the prognostic ability of TGF-β1 expression in HCC patients. Twelve qualified articles and our TCGA data comprising 2,021 HCC patients were incorporated. In the TCGA analysis, HCC patients with higher TGF-β1 expression presented a shorter OS than those with lower TGF-β1 expression (HR = 1.42, p < 0.05). In the meta-analysis, univariate analyses showed that HCC patients with higher TGF-β1 expression had a shorter OS (pooling HR = 1.71, p < 0.01) and DFS/RFS/MFS/PFS (pooling HR = 1.60, p < 0.01) than those with lower TGF-β1 expression. In conclusion, our results suggested that high TGF-β1 expression promotes a poor prognosis in HCC patients.

PMID: 28415739 [PubMed - indexed for MEDLINE]

Immunological mutational signature in adenosquamous cancer of pancreas: an exploratory study of potentially therapeutic targets.

Expert Opin Ther Targets. 2018 Mar 21;:

Authors: Silvestris N, Brunetti O, Pinto R, Petriella D, Argentiero A, Fucci L, Tommasi S, Danza K, De Summa S

Abstract
OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP.
METHODS: We compared the mutational status of a customized gene panel, including 41 genes involved in immunity checkpoint, inflammation and control of leukocytes, B and T cells proliferation of PDAC and ASCP. Moreover, we evaluated the immunohistochemical expression of programmed death ligand 1 (PD-L1).
RESULTS: We observed a status of "hypermutation" of genes included in our panel in ASCP (22/41 mutated genes). Furthermore, PD-L1 resulted expressed only in 15% the squamous counterpart of ASCP tissue.
CONCLUSION: Due to genetic characteristics and to PD-L1 expression in ASCP compared to PDAC tissue, we can conclude that ASCP presents a potential sensitivity to immunological therapy.

PMID: 29561217 [PubMed - as supplied by publisher]

Association between Nonsteroidal Anti-inflammatory Drugs and Atrial Fibrillation among a Middle-aged Population: A Nationwide Population-based Cohort.

Br J Clin Pharmacol. 2018 Mar 20;:

Authors: Chuang SY, Hsu PF, Lin FJ, Huang YW, Wang GZ, Chang WC, Tsai HJ

Abstract
AIMS: It remains inconclusive whether the use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of atrial fibrillation (AF), especially in middle-aged Asian populations. In this study, we evaluated the association between NSAID use and the risk of AF in a nationwide population-based study of middle-aged individuals in Taiwan.
METHODS: A nested case-control study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan. We identified the cases with a diagnosis of AF (ICD-9-CM codes: 427.31) and the matched controls from three independent Longitudinal Health Insurance Databases (LHIDs) derived from the NHIRD from data collected from 2001 to 2013. Conditional logistic regression models with covariates adjustment were performed to evaluate the association between NSAID use and the risk of AF.
RESULTS: A total of 57,058 participants (28,529 AF cases and 28,529 matched controls) were included. Participants with NSAID use had an elevated risk of AF compared to non-users (adjusted odds ratio (AOR)=1.18, 95% confidence interval (CI): 1.14-1.23). When further assessing the effects of different classes of NSAIDs on the risk of AF, the results showed that participants who used non-selective NSAIDs had a significantly elevated risk of AF (AOR=1.18, 95%CI: 1.13-1.23), as did participants with a combined use of selective and non-selective NSAIDs (AOR=1.30, 95%CI: 1.21-1.39).
CONCLUSIONS: NSAID use was associated with an increased risk of AF occurrence among the participants included in our study cohort. Closely monitoring the adverse effects of NSAID treatment on the risk of AF will be important, particularly among individuals at high risk.

PMID: 29560612 [PubMed - as supplied by publisher]

Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder.

Front Psychiatry. 2018;9:65

Authors: Amare AT, Schubert KO, Tekola-Ayele F, Hsu YH, Sangkuhl K, Jenkins G, Whaley RM, Barman P, Batzler A, Altman RB, Arolt V, Brockmöller J, Chen CH, Domschke K, Hall-Flavin DK, Hong CJ, Illi A, Ji Y, Kampman O, Kinoshita T, Leinonen E, Liou YJ, Mushiroda T, Nonen S, Skime MK, Wang L, Kato M, Liu YL, Praphanphoj V, Stingl JC, Bobo WV, Tsai SJ, Kubo M, Klein TE, Weinshilboum RM, Biernacka JM, Baune BT

Abstract
Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.

PMID: 29559929 [PubMed]

Polymorphism genotyping based on loop-mediated isothermal amplification and smartphone detection.

Biosens Bioelectron. 2018 Mar 08;109:177-183

Authors: Yamanaka ES, Tortajada-Genaro LA, Pastor N, Maquieira Á

Abstract
The genotyping of a single-nucleotide polymorphism (SNP) is addressed through methods based on loop-mediated isothermal amplification (LAMP) combined with user-friendly optical read-outs to cover the current demand for point-of-care DNA biomarker detection. The modification of primer design and reaction composition improved the assay selectivity yielding allele-specific results and reducing false-positive frequency. Furthermore, the reduced cost, ease of use and effectiveness of colorimetric detection (solution and hybridisation chip formats) were availed for the image capture by a smartphone, reching high sensitivity. In order to evaluate their discriminating capacities, LAMP-based methods were applied to human samples to genotype a SNP biomarker (rs1954787) located in the GRIK4 gene and related to the treatment response to anti-depressants drugs. Sensitive (limit of detection: 100 genomic DNA copies), reproducible (< 15% error), fast (around 70 min) and low-cost assays were accomplished. Patient subgroups were correctly discriminated, agreeing with reference sequencing techniques. The achieved analytical performances using the developed amplification-detection principles confirmed the approach potential for point-of-care optical DNA testing.

PMID: 29558731 [PubMed - as supplied by publisher]

When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children.

Front Pharmacol. 2018;9:148

Authors: Rodieux F, Vutskits L, Posfay-Barbe KM, Habre W, Piguet V, Desmeules JA, Samer CF

Abstract
Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children's inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP) 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.

PMID: 29556194 [PubMed]

Pharmacokinetic Study of 7 Compounds Following Oral Administration of Fructus Aurantii to Depressive Rats.

Front Pharmacol. 2018;9:131

Authors: Zhang X, Han L, Liu J, Xu Q, Guo Y, Zheng W, Wang J, Huang X, Ren P

Abstract
In the present study, the pharmacokinetics of multi-components (naringenin, nobiletin, meranzin hydrate, narirutin, naringin, hesperidin, and neohesperidin) were investigated in acute depressive rats following oral administration of Fructus Aurantii (Zhi-Qiao, ZQ) extract (20 g/kg). A rapid and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established to quantitatively or qualitatively analyze the 7 absorbed ingredients in the plasma, hippocampus and cortex of acute depressive rats. Biological samples were separated on a 300SB-C18 column, and the 7 compounds were detected with sequential positive and negative ionization modes. Our results confirmed that ZQ has antidepressant effects by decreasing the immobility time. In addition, this validated method showed good linearity (r ≥ 0.9987), and the lower limits of quantification were 2.73-16.38 ng/mL for the 7 analytes. This method successfully determined the pharmacokinetics of the 7 compounds and separated two pairs of isomers in plasma of acute depressive rats following oral administration of ZQ extracts. The 7 active ingredients were also identified as marked compounds in target tissues and should be further examined in pharmacokinetic studies with acute depressive rats. So, pharmacokinetic compounds were precisely linked with the antidepressant effect of ZQ in our study. This relationship is well-understood and contributes to the application of Traditional Chinese Medicine (TCM).

PMID: 29556193 [PubMed]

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CYP2D6 Pharmacogenetics Testing and Post-Cesarean Section Pain Scores-a Preliminary Study.

Pain Med. 2018 Mar 12;:

Authors: Ribeiro C, Quinta R, Raposo A, Valentim A, Albuquerque J, Grazina M

Abstract
Objective: Prospective observational study to analyze CYP2D6 pharmacogenetics in 55 Portuguese adult parturients undergoing elective cesarean section and to investigate the association between CYP2D6 alleles and pain score.
Methods: DNA was extracted from peripheral blood by standard methods. Genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number determination with TaqMan probes by real-time polymerase chain reaction (PCR). Allele duplications were confirmed (long PCR and PCR-restriction fragment length polymorphism). Theoretical metabolic profiles prediction was based on genetic data and activity scores. Association was investigated between genotypes and predicted phenotypes with pain scores. Statistical analysis was performed by using a χ2 test, and significance was set at P < 0.05.
Results: The percentage of poor, intermediate, extensive, and ultrarapid metabolizers found were 9%, 38%, 46%, and 7%, respectively. The results reveal a positive association between alleles *4, *10, and pain.
Conclusions: A positive association was found between predicted reduced or null activity of CYP2D6 and increased pain. It can be hypothesized that if CYP2D6 activity is reduced, tyramine metabolism will decrease, resulting in reduced formation of endogenous dopamine. Consequently, activation of the signal transduction pathways that controls pain and analgesic effect may be reduced, leading to an increase in pain. Therefore, we would recommend CYP2D6 genotyping to anticipate the needs for analgesia, which will help to adjust opioid dose and maximize clinical efficacy while reducing side effects.

PMID: 29546421 [PubMed - as supplied by publisher]

Association between HLA-B Alleles and Carbamazepine-Induced Maculopapular Exanthema and Severe Cutaneous Reactions in Thai Patients.

J Immunol Res. 2018;2018:2780272

Authors: Sukasem C, Chaichan C, Nakkrut T, Satapornpong P, Jaruthamsophon K, Jantararoungtong T, Koomdee N, Sririttha S, Medhasi S, Oo-Puthinan S, Rerkpattanapipat T, Klaewsongkram J, Rerknimitr P, Tuchinda P, Chularojanamontri L, Tovanabutra N, Puangpetch A, Aekplakorn W

Abstract
The HLA-B∗15:02 allele has been reported to have a strong association with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Thai patients. The HLA-B alleles associated with carbamazepine-induced maculopapular exanthema (MPE) and the drug reaction with eosinophilia and systemic symptoms (DRESS) among the Thai population have never been reported. The aim of the present study was to carry out an analysis of the involvement of HLA-B alleles in carbamazepine-induced cutaneous adverse drug reactions (cADRs) in the Thai population. A case-control study was performed by genotyping the HLA-B alleles of Thai carbamazepine-induced hypersensitivity reaction patients (17 MPE, 16 SJS/TEN, and 5 DRESS) and 271 carbamazepine-tolerant controls. We also recruited 470 healthy Thai candidate subjects who had not taken carbamazepine. HLA-B∗15:02 showed a significant association with carbamazepine-induced MPE (P = 0.0022, odds ratio (OR) (95% confidence interval [CI]) = 7.27 (2.04-25.97)) and carbamazepine-induced SJS/TEN (P = 4.46 × 10-13; OR (95% CI) = 70.91(19.67-255.65)) when compared with carbamazepine-tolerant controls. Carbamazepine-induced SJS/TEN also showed an association with HLA-B∗15:21 allele (P = 0.013; OR (95% CI) = 9.54 (1.61-56.57)) when compared with carbamazepine-tolerant controls. HLA-B∗58:01 allele was significantly related to carbamazepine-induced MPE (P = 0.007; OR (95% CI) = 4.73 (1.53-14.66)) and DRESS (P = 0.0315; OR (95% CI) = 7.55 (1.20-47.58)) when compared with carbamazepine-tolerant controls. These alleles may serve as markers to predict carbamazepine-induced cADRs in the Thai population.

PMID: 29546073 [PubMed - in process]

Prediction of platinum-based chemotherapy efficacy in lung cancer based on LC-MS metabolomics approach.

J Pharm Biomed Anal. 2018 Feb 23;154:95-101

Authors: Peng F, Liu Y, He C, Kong Y, Ouyang Q, Xie X, Liu T, Liu Z, Peng J

Abstract
Lung cancer is the common cause of cancer-related death worldwide. Platinum-based chemotherapy is the cornerstone of treatment for lung cancer. Platinum sensitivity is a major possibility for effective cancer treatment. In this study, several potential biomarkers were identified for evaluating and predicting the response to platinum-based chemotherapy. LC-MS-based metabolomics was performed on plasma samples from 43 lung cancer patients with different chemotherapy efficacy. By combing multivariate statistical analysis, pathway analysis with correlation analysis, 8 potential biomarkers were significantly associated with platinum chemotherapy response. Moreover, a prediction model with these biomarkers involved in citric acid cycle, glutamate metabolism and amino acid metabolism, showed 100% sensitivity and 100% specificity for predicting chemotherapy response in a validation set. Interestingly, 2-hydroxyglutaric acid (2-HG) as an oncometabolite accumulated in lung cancer was remarkably elevated in the partial response (PR) patients. Collectively, our findings implicated that metabolomics can serve as a potential tool to select lung cancer patients that are more likely to benefit from the platinum-based treatment.

PMID: 29544107 [PubMed - as supplied by publisher]

Rationale, design and preliminary results of the Quebec Warfarin Cohort Study.

Clin Cardiol. 2018 Mar 15;:

Authors: Perreault S, Shahabi P, Côté R, Dumas S, Rouleau-Mailloux É, Feroz Zada Y, Provost S, Mongrain I, Dorais M, Huynh T, Kouz S, Diaz A, Blostein M, de Denus S, Turgeon J, Ginsberg J, Lelorier J, Lalonde L, Busque L, Kassis J, Talajic M, Tardif JC, Dubé MP

Abstract
BACKGROUND: Over- and under-coagulation with warfarin is associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control.
METHODS: The Quebec Warfarin Cohort (QWC) comprises 1,059 new warfarin users, with prospective follow up using telephone questionnaires every 3 months for one year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5-year prior to cohort entry and up to 10-years following active patient participation. Genetic material was collected and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report the baseline characteristics and outcomes after 1-year of follow-up. Poor anticoagulation control was defined as TTR <60% in 3- to 12-month interval.
RESULTS: Participants had a mean age of 71 years and 62% were men. The most common indication for warfarin was atrial fibrillation. Mean time in the therapeutic range (TTR) was 56% (±25) in the 3-month following warfarin initiation, and 70% (±21) in the 3- to 12-month interval. During follow up, the rate of stroke or systemic embolism was 1.8 events per 100 person-years and 3.3 events per 100 person-years for major bleeding events. Independent predictors of poor anticoagulation control were chronic kidney disease, heart failure, dyslipidemia, and age.
CONCLUSIONS: The QWC represents a good research opportunity to investigate clinical and genetic factors in a warfarin anticoagulated population.

PMID: 29542828 [PubMed - as supplied by publisher]