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Precision therapy for epilepsy due to KCNT1 mutations: A randomized trial of oral quinidine.
Mullen, SA, Carney, PW, Roten, A, Ching, M, Lightfoot, PA, Churilov, L, Nair, U, Li, M, Berkovic, SF, Petrou, S, et al
Neurology. 2018;(1):e67-e72
Abstract
OBJECTIVE To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1. METHODS A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. RESULTS Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3-5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10-18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval -1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. CONCLUSION Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. CLINICAL TRIALS REGISTRATION Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). CLASSIFICATION OF EVIDENCE This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.
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Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies.
Giblett, JP, Axell, RG, White, PA, Clarke, SJ, McCormick, L, Read, PA, Reinhold, J, Brown, AJ, O'Sullivan, M, West, NE, et al
Cardiovascular diabetology. 2016;:99
Abstract
BACKGROUND Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. METHODS Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. RESULTS GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). CONCLUSIONS Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022.
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Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program.
Florez, JC, Jablonski, KA, Kahn, SE, Franks, PW, Dabelea, D, Hamman, RF, Knowler, WC, Nathan, DM, Altshuler, D
Diabetes. 2007;(2):531-6
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Abstract
The common polymorphisms KCNJ11 E23K and ABCC8 A1369S have been consistently associated with type 2 diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over approximately 3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at 1 year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-to-diabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation.
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The effect of an angiotensin-converting enzyme inhibitor and a K+(ATP) channel opener on warm up angina.
Edwards, RJ, Redwood, SR, Lambiase, PD, Marber, MS
European heart journal. 2005;(6):598-606
Abstract
AIMS: In various models, angiotensin-converting enzyme (ACE) inhibitors and K+(ATP) channel openers can potentiate and mimic ischaemic preconditioning, respectively. Our aim was to determine whether these characteristics are shared by the phenomenon of warm up in angina, often regarded as a surrogate of ischaemic preconditioning. METHODS AND RESULTS Twenty patients with ischaemic heart disease were assigned in a double blind, randomized cross-over design to equivalent pressor doses of nicorandil 20 mg bid, enalapril 10 mg bid, losartan 25 mg bid, or placebo for 3 days. Patients underwent three consecutive exercise tolerance tests on each medication separated by a 1-week interval. Each patient underwent 12 exercise tests in total and 13 patients completed the study. On each medication the second exercise was separated from the first by 15 min of rest and the third exercise was performed 90 min after the second to control for training. The time to 0.1 mV ST depression and rate pressure product at 0.1 mV ST depression increased significantly in all groups during exercise two compared with exercise one. Nicorandil reduced angina but did not attenuate this warm up effect. This benefit of first exercise waned by test three with placebo, losartan, and nicorandil, but not with enalapril. CONCLUSION In contrast to predictions based on ischaemic preconditioning the magnitude of the warm up was apparently unaltered by nicorandil, losartan, or enalapril, however its duration seemed to be extended by enalapril. Thus ischaemic preconditioning and warm up angina are likely to have differing pharmacological profiles suggesting a diverse underlying mechanism.
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Pharmacological modulation of the ATP sensitive potassium channels during repeated coronary occlusions: no effect on myocardial ischaemia or function.
Lindhardt, TB, Gadsbøll, N, Kelbaek, H, Saunamäki, K, Madsen, JK, Clemmensen, P, Hesse, B, Haunsø, S
Heart (British Cardiac Society). 2004;(4):425-30
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Abstract
BACKGROUND Repeated episodes of myocardial ischaemia may lead to ischaemic preconditioning. This is believed to be mediated by the ATP sensitive potassium channels. OBJECTIVE To examine the effect of pharmacological modulation of the ATP sensitive potassium channels during repeated coronary occlusions. DESIGN Double blind, double dummy study. METHODS 38 patients with a proximal stenosis of the left anterior descending coronary artery and no visible coronary collateral vessels underwent three identical 90 second balloon occlusions, each followed by five minutes of reperfusion. The patients were randomised to pinacidil 25 mg, glibenclamide 10.5 mg, or matching placebo 90 minutes before the start of the procedure. Myocardial ischaemia was measured by continuous monitoring of ECG ST segment changes. Changes in left ventricular function were recorded with a miniature radionuclide detector, and angina was scored on the Borg scale. RESULTS In all patients the first balloon occlusion led to significant ST segment elevation, a clear decrease in left ventricular ejection fraction, and angina pectoris. This response was not attenuated at the second or third balloon occlusion, either in the placebo group or in the patients pretreated with pinacidil or glibenclamide. CONCLUSIONS Under the given experimental conditions, this randomised and double blind study did not support the view that the human myocardium has an intrinsic protective mechanism that is activated by short lasting episodes of ischaemia.
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Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study.
Laukkanen, O, Pihlajamäki, J, Lindström, J, Eriksson, J, Valle, TT, Hämäläinen, H, Ilanne-Parikka, P, Keinänen-Kiukaanniemi, S, Tuomilehto, J, Uusitupa, M, et al
The Journal of clinical endocrinology and metabolism. 2004;(12):6286-90
Abstract
Type 2 diabetes is caused by defective insulin secretion and impaired insulin action. We investigated whether common polymorphisms in the SUR1 and Kir6.2 genes are associated with increased risk of type 2 diabetes in 490 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study. The 1273AGA allele of the SUR1 gene was associated with a 2-fold risk of type 2 diabetes [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.19-3.36; P = 0.009]. This silent polymorphism was in linkage disequilibrium with three promoter polymorphisms (G-2886A, G-1561A, and A-1273G), and they formed a high-risk haplotype having a 2-fold risk of type 2 diabetes (OR, 1.89; 95% CI, 1.09-3.27; P = 0.023). Subjects with both the high-risk haplotype of the SUR1 gene and the 23K allele of the Kir6.2 gene had a 6-fold risk for the conversion to diabetes compared with those without any of these risk genotypes (OR, 5.68; 95% CI, 1.75-18.32; P = 0.004). We conclude that the polymorphisms of the SUR1 gene predicted the conversion from impaired glucose tolerance to type 2 diabetes and that the effect of these polymorphisms on diabetes risk was additive with the E23K polymorphism of the Kir6.2 gene.
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A phase II trial comparing five dose levels of BEC2 anti-idiotypic monoclonal antibody vaccine that mimics GD3 ganglioside.
Chapman, PB, Williams, L, Salibi, N, Hwu, WJ, Krown, SE, Livingston, PO
Vaccine. 2004;(21-22):2904-9
Abstract
In previous studies, we showed that immunization with 2.5 mg of BEC2, an anti-idiotypic MAb that mimics GD3 ganglioside, can induce antibodies against GD3 in approximately 25% of patients. In this trial, 50 melanoma patients at high risk for recurrence were randomly assigned to one of the five BEC2 dose levels (2.5 microg-10mg) to determine if lower or higher BEC2 doses are more immunogenic. We also tested whether prolonged booster immunizations can enhance the anti-GD3 antibody response. All patients developed detectable IgG against BEC2 except for one patient at the lowest BEC2 dose level. Six patients developed detectable antibody responses to GD3, all of them at the lower three dose levels of BEC2. We conclude that high doses of BEC2 are not necessary to induce anti-GD3 antibody responses and that lower doses may be more immunogenic than the 2.5 mg dose used in previous BEC2 trials. Prolonged booster immunizations did not induce or maintain antibody responses.
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Prophylactic effect of intravenous nicorandil on perioperative myocardial damage in patients undergoing off-pump coronary artery bypass surgery.
Ito, I, Hayashi, Y, Kawai, Y, Kamibayashi, T, Matsumiya, G, Takahashi, T, Matsuda, H, Mashimo, T
Journal of cardiovascular pharmacology. 2004;(4):501-6
Abstract
Nicorandil, ATP sensitive potassium channel opener, is shown to reduce coronary events for patients with stable angina. The present study was designed to examine the protective potential of nicorandil for patients undergoing off-pump coronary artery bypass grafting. Twenty-four patients undergoing off-pump coronary artery bypass grafting were randomly assigned to two groups, one receiving continuous infusion of nicorandil (1.0 microg.kg(-1).min(-1)) (n = 12) through anesthesia to next day and the other receiving no nicorandil for control (n = 12). For assessing myocardial injury, heart type fatty acid binding protein, troponin T, and creatine kinase MB isoform were determined during the first 15 hours after reperfusion. The concentration of heart type fatty acid binding protein in the nicorandil group was significantly lower than that in the control group. On the other hand, the concentrations of troponin T and creatine kinase MB isoform in the nicorandil group were lower than those in the control group, but the differences did not reach statistical significance. Furthermore, nicorandil did not affect the patients' hemodynamic variables. Our data suggest that the infusion of nicorandil provides small myocardial protection without affecting hemodynamic parameters during perioperative treatment of patients undergoing off-pump coronary artery bypass grafting.
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Lack of anti-ischemic efficacy of the potassium channel opener bimakalim in patients with stable angina pectoris.
Burian, M, Piske, M, Petkovic, D, Mitrovic, V
Cardiovascular drugs and therapy. 2004;(1):37-46
Abstract
UNLABELLED Aim of the study was to evaluate anti-ischemic, hemodynamic and neurohumoral effects of bimakalim, a novel selective K(+)-channel opener, in patients with stable angina pectoris and reproducible ST-segment depression. METHODS AND RESULTS 86 patients with angiographic signs of CAD were involved in two randomised, placebo-controlled, double-blind trials with single high (0.1, 0.3 or 0.6 mg) and low (0.025 or 0.05 mg) doses of oral bimakalim. The anti-anginal efficacy was evaluated by analysis of ST-segment depression within exercise or RV pacing. A parallel assessment of hemodynamic parameters was done by means of right-heart catheterization. Given in high doses, bimakalim acted as a potent vasodilator and decreased SBP by 15 mm Hg. This was associated with a reflex activation of sympathetic nervous system resulting in an increase in heart rate by 25 /min, a 14% rise of myocardial oxygen consumption and a 63% elevation of noradrenaline plasma level. Low doses of bimakalim had no significant effect on hemodynamics and oxygen consumption. In exercise-induced angina pectoris, administration of bimakalim was neither associated with attenuation of ST-segment depression nor resulted in prolongation of time to 0.1 mV ST-segment depression. CONCLUSION The results of the present study suggest that bimakalim has a dose-dependent vasodilatatory activity but exerts no anti-ischemic benefits in patients with exercise-induced angina pectoris due to coronary artery disease.
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Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women.
Pietilä, E, Fodstad, H, Niskasaari, E, Laitinen P, PJ, Swan, H, Savolainen, M, Kesäniemi, YA, Kontula, K, Huikuri, HV
Journal of the American College of Cardiology. 2002;(3):511-4
Abstract
OBJECTIVES The aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BACKGROUND The length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. METHODS QT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV(2), and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. RESULTS The allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 +/- 99 ms) and Tpeak-Tend intervals (143 +/- 95 ms) than females with the genotype AA (441 +/- 69 ms and 116 +/- 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. CONCLUSIONS; The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.