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Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CiPA Phase I ECG Biomarker Validation Study.
Vicente, J, Zusterzeel, R, Johannesen, L, Ochoa-Jimenez, R, Mason, JW, Sanabria, C, Kemp, S, Sager, PT, Patel, V, Matta, MK, et al
Clinical pharmacology and therapeutics. 2019;(4):943-953
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Abstract
Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J-Tpeak (J-Tpeak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10-subject-per-drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ-Tpeak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether-à-go-go related gene (hERG), prolonged ΔΔQTc and ΔΔJ-Tpeak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced ΔQTc prolongation, but shortened ΔJ-Tpeak c and prolonged ΔTpeak -Tend . Absence of J-Tpeak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases.
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Effect of Zingiber officinale Supplementation on Obesity Management with Respect to the Uncoupling Protein 1 -3826A>G and ß3-adrenergic Receptor Trp64Arg Polymorphism.
Ebrahimzadeh Attari, V, Asghari Jafarabadi, M, Zemestani, M, Ostadrahimi, A
Phytotherapy research : PTR. 2015;(7):1032-9
Abstract
The present study aimed to investigate the effect of ginger (Zingiber officinale) supplementation on some obesity-associated parameters, with nutrigenetics approach. Accordingly, 80 eligible obese women (aged 18-45 years) were randomly assigned to receive either ginger (2-g ginger rhizomes powder as two 1-g tablets per day) or placebo supplements (corn starch with the same amount) for 12 weeks. Subjects were tested for changes in body weight, body mass index, waist and hip circumferences, body composition, appetite score, and dietary intake. Moreover, participants were genotyped for the -3826A>G and Trp64Arg polymorphisms of uncoupling protein 1 and ß3-adrenergic receptor genes, respectively. Over 12 weeks, ginger supplementation resulted in a slight but statistically significant decrease in all anthropometric measurements and total appetite score as compared with placebo group, which were more pronounced in subjects with the AA genotype for uncoupling protein 1 and Trp64Trp genotype for ß3-adrenergic receptor gene. However, there was no significant difference in changes of body composition and total energy and macronutrients intake between groups. In conclusion, our findings suggest that ginger consumption has potential in managing obesity, accompanying with an intervention-genotype interaction effect. However, further clinical trials need to explore ginger's efficacy as an anti-obesity agent in the form of powder, extract, or its active components.
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Association between UCP2 A55V polymorphism and risk of cardiovascular events in patients with multi-vessel coronary arterial disease.
Gioli-Pereira, L, Santos, PC, Sugaya, LS, Ferreira, NE, Krieger, JE, Pereira, AC, Hueb, WA
BMC medical genetics. 2013;:40
Abstract
BACKGROUND UCP2 (uncoupling protein 2) plays an important role in cardiovascular diseases and recent studies have suggested that the A55V polymorphism can cause UCP2 dysfunction. The main aim was to investigate the association of A55V polymorphism with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease and preserved left ventricular function. METHODS The participants of the MASS II were genotyped for the A55V polymorphism using allele-specific PCR assay. Survival curves were calculated with the Kaplan-Meier method and evaluated with the log-rank statistic. The relationship between baseline variables and the composite end-point of cardiac death, acute myocardial infarction (AMI), refractory angina requiring revascularization and cerebrovascular accident were assessed using a Cox proportional hazards survival model. RESULTS There were no significant differences for baseline variables according genotypes. After 2 years of follow-up, dysglycemic patients harboring the VV genotype had higher occurrence of AMI (p=0.026), Death+AMI (p=0.033), new revascularization intervention (p=0.009) and combined events (p=0.037) as compared with patients carrying other genotypes. This association was not evident in normoglycemic patients. CONCLUSIONS These findings support the hypothesis that A55V polymorphism is associated with UCP2 functional alterations that increase the risk of cardiovascular events in patients with previous coronary artery disease and dysglycemia.
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Modulation of insulin concentrations and metabolic parameters in obese patients by -55CT polymorphism of the UCP3 gene secondary to two hypocaloric diets.
Luis, DA, Aller, R, Izaola, O, Gonzalez Sagrado, M, Conde, R
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2009;(1):62-6
Abstract
Decreased expression or function of UCP3 could reduce energy expenditure and increase the storage of energy. The aim of our study was to investigate the influence of -55CT polymorphism of the UCP3 gene on insulin concentrations and metabolic parameters secondary to two hypocaloric diets in obese patients. A population of 131 obese (body mass index >30), nondiabetic outpatients was analyzed in a prospective way. Before and after 2 months on two different hypocaloric diets, bipolar electrical bioimpedance, blood pressure measurement, serial assessment of nutritional intake with 3 d of written food records, and biochemical analysis were performed. The statistical analysis was performed based on a dominant model. With diet type I (low fat) and diet type II (low carbohydrate) in probands with both wild-type alleles, we observed decreases in BMI, weight, fat mass, systolic blood pressure, leptin levels, and insulin concentrations. In addition, with diet type II, a decrease in diastolic blood pressure, total cholesterol, and triglyceride levels was detected. Secondary to diet type I, a decrease in waist circumference and TNF-alpha was observed. Carriers of the T variant experienced decreases in BMI, weight, and fat mass on both diets, without statistical changes in biochemical parameters. In probands with both C alleles, both diets decreased insulin concentrations, blood pressure, and leptin concentrations. Weight reduction was similar with C and T alleles, independent of macronutrient distribution.
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Variation in the UCP2 and UCP3 genes associates with abdominal obesity and serum lipids: the Finnish Diabetes Prevention Study.
Salopuro, T, Pulkkinen, L, Lindström, J, Kolehmainen, M, Tolppanen, AM, Eriksson, JG, Valle, TT, Aunola, S, Ilanne-Parikka, P, Keinänen-Kiukaanniemi, S, et al
BMC medical genetics. 2009;:94
Abstract
BACKGROUND We explored the associations of three variants in the uncoupling protein 2 (UCP2) gene, one variant in the UCP2-UCP3 intergenic region and five variants in the uncoupling protein 3 (UCP3) gene with obesity and diabetes related traits in subjects with impaired glucose tolerance participating in Finnish Diabetes Prevention Study. Altogether 507 overweight individuals (body mass index: 31.2 +/- 4.5 kg/m2, age: 55 +/- 7 years) for whom DNA was available were randomized to either an intensified diet and physical activity group or to a conventional care control group. METHODS We analysed the data from the baseline and annual follow-up visits from years 1, 2 and 3. Measurements of anthropometry, plasma glucose and serum insulin in oral glucose tolerance test, serum total cholesterol, HDL-cholesterol and triglycerides were included. The median follow-up time for type 2 diabetes incidence was 7 years. Genetic variants were screened by restriction fragment length polymorphism or Illumina method. RESULTS UCP3 gene variant rs3781907 was associated with increased serum total and LDL-cholesterol levels, at baseline and during the follow-up period. The same variant was associated with a higher risk of type 2 diabetes. Variants rs1726745, rs11235972 and rs1800849 in the UCP3 gene associated with serum total and LDL-cholesterol at baseline. Haploblock including variants rs659366, rs653529, rs15763, and rs1726745 was associated with measures of abdominal obesity at baseline and in the longitudinal analysis. The haplotype comprising alleles rs659366-G, rs653529-A, rs15763-G and rs1726745-A was associated with higher waist-to-hip ratio, and haplotype comprising alleles rs3781907-G, rs11235972-A, and rs1800849-T was associated with increased serum total and LDL-cholesterol concentrations. CONCLUSION Genetic variation in the UCP2-UCP3 gene cluster may act as a modifier increasing serum lipid levels and indices of abdominal obesity, and may thereby also contribute to the metabolic aberrations observed in obesity and type 2 diabetes.
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Levetiracetam influences human motor cortex excitability mainly by modulation of ion channel function--a TMS study.
Reis, J, Wentrup, A, Hamer, HM, Mueller, HH, Knake, S, Tergau, F, Oertel, WH, Rosenow, F
Epilepsy research. 2004;(1):41-51
Abstract
PURPOSE Levetiracetam (LEV) is a new compound with anticonvulsive efficacy in focal and generalized epilepsies. Recent in vitro studies suggest LEV to act as a selective N-type-calcium-channel blocker. METHODS We used transcranial magnetic stimulation (TMS) in order to investigate if ion-channel blockade is relevant to the inhibitory CNS effects of LEV in vivo and if motor thresholds (MTs) are a valid TMS parameter to detect this mode of action. In a double blind, placebo-controlled, crossover study, the effects of single oral doses of 500 and 2000 mg LEV on motor thresholds, recruitment curves (REC), cortical induced silent period (CSP) and on intracortical inhibition (ICI) and facilitation (ICF) were studied in 10 healthy subjects. RESULTS A significant increase of motor thresholds was noticed after 2000 mg LEV as compared to placebo. The recruitment curve showed a trend towards motor evoked potential (MEP) amplitude reduction after LEV. LEV had no significant effect on CSP or on intracortical excitability as measured by inhibition and facilitation. CONCLUSIONS We conclude that the modulation of ion-channel function, reflected by motor threshold elevation and a trend towards recruitment curve suppression, is relevant to the inhibitory CNS effects of LEV in vivo, and therefore, may contribute to the anticonvulsive efficacy of LEV. GABAergic or glutamatergic mechanisms seem to be less important in vivo as measured by TMS.