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Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects.
Midei, MG, Darpo, B, Ayers, G, Brown, R, Couderc, JP, Daly, W, Ferber, G, Sager, PT, Camm, AJ
Journal of clinical pharmacology. 2021;(12):1606-1617
Abstract
Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine-palmitoyltransferase-1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch-clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150-600 ng/mL) with IC50 for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline-treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel-designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119-0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration-JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.
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First Clinical Study with AP30663 - a KCa 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation.
Gal, P, Klaassen, ES, Bergmann, KR, Saghari, M, Burggraaf, J, Kemme, MJB, Sylvest, C, Sørensen, U, Bentzen, BH, Grunnet, M, et al
Clinical and translational science. 2020;(6):1336-1344
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Abstract
Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa 2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax ) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa 2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
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Grapefruit juice prolongs the QT interval of healthy volunteers and patients with long QT syndrome.
Chorin, E, Hochstadt, A, Granot, Y, Khoury, S, Schwartz, AL, Margolis, G, Barashi, R, Viskin, D, Ghantous, E, Schnapper, M, et al
Heart rhythm. 2019;(8):1141-1148
Abstract
BACKGROUND The list of medications linked to drug-induced long QT syndrome (LQTS) is diverse. It is possible that food products too have QT-prolonging potential. OBJECTIVE We tested the effects of grapefruit juice on the QT interval with the methodology used by the pharmaceutical industry to test new drugs. METHODS This was an open-label, randomized, crossover study with blinded outcome evaluation, a thorough QT study of grapefruit juice performed according to the Guidelines for the Clinical Evaluation of QT/QTc for Non-antiarrhythmic Drugs. Thirty healthy volunteers and 10 patients with congenital LQTS were studied. Healthy volunteers drank 2 L of grapefruit juice (in divided doses), or received 400 mg oral moxifloxacin, in a randomized crossover study. Patients with LQTS were tested with only grapefruit. Repeated baseline, off-drug, and on-drug (grapefruit or moxifloxacin) electrocardiograms were scanned and coded. QT measurements were done with electronic calipers. RESULTS In comparison to off-drug electrocardiograms, grapefruit juice led to significant rate-corrected QT (QTc) prolongation. The absolute net QTc prolongation from grapefruit was 14.0 ms (95% confidence interval 6.2-21.7 ms; P < .001). The QT-prolonging effects of grapefruit in healthy volunteers were comparable with those of moxifloxacin. The QT-prolonging effects of grapefruit juice were greater in female patients and particularly marked in patients with LQTS (net QTc prolongation 21.8 ms; 95% confidence interval 3.4-35.3 ms; P = .034). CONCLUSION Grapefruit juice, at doses tested, prolongs the QT interval. The effect is significant in healthy volunteers, greater in female patients, and more so in patients with LQTS.
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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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Estimation of the Power of the Food Effect on QTc to Show Assay Sensitivity.
Ferber, G, Fernandes, S, Täubel, J
Journal of clinical pharmacology. 2018;(1):81-88
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The most recent International Conference on Harmonisation E14 Q&A document states that a separate positive control would not be necessary provided sufficiently high exposures are achieved in the early-phase studies. Realistically, a phase 1 study is unlikely to include a pharmacological positive control, and in cases in which plasma levels of the drug exceeding therapeutic levels are not achieved, the lack of a positive control can constitute a limitation when excluding an effect of regulatory concern. It has been proposed to use the effect of a standardized meal on the estimate of the diurnal time course of QTc to show assay sensitivity. We conducted simulations by subsampling subjects from a 3 different studies and could show that the effect on food on QTc can be reliably prove assay sensitivity for sample sizes as low as 3 × 6 subjects with a power greater than 80%.
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Prognostic Value of Coronary Artery Calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).
Budoff, MJ, Mayrhofer, T, Ferencik, M, Bittner, D, Lee, KL, Lu, MT, Coles, A, Jang, J, Krishnam, M, Douglas, PS, et al
Circulation. 2017;(21):1993-2005
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BACKGROUND Coronary artery calcium (CAC) is an established predictor of future major adverse atherosclerotic cardiovascular events in asymptomatic individuals. However, limited data exist as to how CAC compares with functional testing (FT) in estimating prognosis in symptomatic patients. METHODS In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain (or dyspnea) and intermediate pretest probability for obstructive coronary artery disease were randomized to FT (exercise electrocardiography, nuclear stress, or stress echocardiography) or anatomic testing. We evaluated those who underwent CAC testing as part of the anatomic evaluation (n=4209) and compared that with results of FT (n=4602). We stratified CAC and FT results as normal or mildly, moderately, or severely abnormal (for CAC: 0, 1-99 Agatston score [AS], 100-400 AS, and >400 AS, respectively; for FT: normal, mild=late positive treadmill, moderate=early positive treadmill or single-vessel ischemia, and severe=large ischemic region abnormality). The primary end point was all-cause death, myocardial infarction, or unstable angina hospitalization over a median follow-up of 26.1 months. Cox regression models were used to calculate hazard ratios (HRs) and C statistics to determine predictive and discriminatory values. RESULTS Overall, the distribution of normal or mildly, moderately, or severely abnormal test results was significantly different between FT and CAC (FT: normal, n=3588 [78.0%]; mild, n=432 [9.4%]; moderate, n=217 [4.7%]; severe, n=365 [7.9%]; CAC: normal, n=1457 [34.6%]; mild, n=1340 [31.8%]; moderate, n=772 [18.3%]; severe, n=640 [15.2%]; P<0.0001). Moderate and severe abnormalities in both arms robustly predicted events (moderate: CAC: HR, 3.14; 95% confidence interval, 1.81-5.44; and FT: HR, 2.65; 95% confidence interval, 1.46-4.83; severe: CAC: HR, 3.56; 95% confidence interval, 1.99-6.36; and FT: HR, 3.88; 95% confidence interval, 2.58-5.85). In the CAC arm, the majority of events (n=112 of 133, 84%) occurred in patients with any positive CAC test (score >0), whereas fewer than half of events occurred in patients with mildly, moderately, or severely abnormal FT (n=57 of 132, 43%; P<0.001). In contrast, any abnormality on FT was significantly more specific for predicting events (78.6% for FT versus 35.2% for CAC; P<0.001). Overall discriminatory ability in predicting the primary end point of mortality, nonfatal myocardial infarction, and unstable angina hospitalization was similar and fair for both CAC and FT (C statistic, 0.67 versus 0.64). Coronary computed tomographic angiography provided significantly better prognostic information compared with FT and CAC testing (C index, 0.72). CONCLUSIONS Among stable outpatients presenting with suspected coronary artery disease, most patients experiencing clinical events have measurable CAC at baseline, and fewer than half have any abnormalities on FT. However, an abnormal FT was more specific for cardiovascular events, leading to overall similarly modest discriminatory abilities of both tests. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT01174550.
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Effect of Intralipid® on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study.
Dureau, P, Charbit, B, Nicolas, N, Benhamou, D, Mazoit, JX
Anesthesiology. 2016;(3):474-83
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Abstract
BACKGROUND Rapid intravenous administration of lipid emulsion has become the standard treatment of severe local anesthetic systemic toxicity. This experiment in volunteers aimed at determining the effect of Intralipid® administration on the time to neurologic symptoms. METHODS Ropivacaine or levobupivacaine was infused intravenously in 16 volunteers (8 mg/min up to 120 mg) with 120 ml Intralipid® 20% (Fresenius, Paris France) or placebo infused at T + 2 min). Each subject received all four treatments in a crossover manner. The infusion was stopped after the intended dose had been administered or on occurrence of incipient neurologic signs of toxicity. The primary outcome was time-to-event. In addition, blood ropivacaine and levobupivacaine concentrations were measured. RESULTS The dose infused was not different whether volunteers received placebo (81.7 ± 22.3 vs. 80.8 ± 31.7 mg, ropivacaine vs. levobupivacaine) or Intralipid® (75.7 ± 29.1 vs. 69.4 ± 26.2 mg, ropivacaine vs. levobupivacaine), P = 0.755, Intralipid® versus placebo groups. Plasma concentrations were best modeled with an additional volume of distribution associated with Intralipid®. Simulations suggested that decreased peak concentrations would be seen if Intralipid® was given during a period of increasing concentrations after extravascular administration. CONCLUSIONS At modestly toxic doses of ropivacaine or levobupivacaine, we were unable to find any effect of the infusion of Intralipid® on the time to early signs of neurologic toxicity in volunteers. Peak concentration was decreased by 26 to 30% in the subjects receiving Intralipid®. Simulations showed that Intralipid® might prevent the rapid increase of local anesthetic concentration after extravascular administration.
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Sex differences in drug-induced changes in ventricular repolarization.
Vicente, J, Johannesen, L, Mason, JW, Pueyo, E, Stockbridge, N, Strauss, DG
Journal of electrocardiology. 2015;(6):1081-7
Abstract
INTRODUCTION Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs. METHODS AND RESULTS Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p=0.045) but lesser Tpeak-Tend prolongation (p=0.006) and lesser decrease of T wave amplitude (p=0.003) in women compared to men. CONCLUSIONS There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation.
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[Effect of L-Carnitine on QT Dispersion in Patients With Acute Coronary Syndrome].
Gleser, MG, Kiseleva, AE, Astashkin, EI
Kardiologiia. 2015;(3):4-9
Abstract
to evaluate the impact of L-carnitine on the dispersion of the interval QT (AQTc) in patients with acute coronary syndrome (ACS). In a prospective, randomized, double-blind, placebo-controlled study included 58 patients with ACS who have not had surgery (29 in group receiving L-carnitine, and 29 in the placebo group). L-carnitine was administered intravenously during the first 3 days to 2 g, 2 times a day, with 4 on the 15th day (or until discharge, if it occurred earlier)--for 1 g of 2 times per day. AQTc defined as the difference between the maximum and minimum duration of the QT interval in each of the 12 standard ECG leads surface--ECG (ΔQT = QTmax-QTmin) on the 1st, 2, 3, 5, 7 and 12-14th day. Compared groups did not differ in their baseline characteristics. Under the influence of L-carnitine reduction ΔQTc was more pronounced and significantly decreased since the 1st day of treatment. Thus, the group of patients treated with L-carnitine, ΔQTc decreased from 79.9 ± 19.9 to 60.4 ± 17.5 ms (p < 0.0001) and amounted to 12-14-th day of treatment 41.1 ± 7.6 ms (p < 0.0001) in the placebo group-respectively from 74.9 ± 23.2 to 68.3 ± 22.4 ms (p = 0.277) and 53.5 ± 15.0 ms (p = 0.0003). In the group of patients treated with L-carnitine, a decrease ΔQTc wore authentic character from the first day of the disease and unstable angina, and myocardial infarction. In the group of patients treated with placebo in unstable angina were not significant changes in the nature and in MI--reliability is marked only by the 7th day of the disease. Decrease in initial ΔQTc ΔQTc > 80 ms was more pronounced than in patients with ΔQTc < 80 ms. In the group of patients treated with L-carnitine, marked reduction ΔQTc less dependent on its initial value and was statistically significant in patients c great and not so great source ΔQTc. Thus, L-carnitine in patients with ACS reduces the severity of myocardial electrical instability.
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[Evaluation of Anti-Ischemic and Cardioprotective Effects of Nicorandil in Patients With Stable Angina].
Rezvanova, YA, Adamchik, AS
Kardiologiia. 2015;(8):21-5
Abstract
The aim of our study was to assess the anti-ischemic and cardiouprotective efficiency of the activator of potassium channels nicorandil in patients with stable angina during long-term intake on the background of standard therapy of coronary heart disease (CHD), including aspirin, rosuvastatin, valsartan and bisoprolol in comparison with standard therapy and long-acting form of nitrates. We compared the dynamics of nitroglycerine consumption, frequency of angina attacks, carried veloergometry, daily monitoring of an electrocardiogram by Holter, echocardiography, assess the state of lipid and carbohydrate metabolism, were determined concentrations of certain markers of systemic inflammation. The results showed that the inclusion of nicorandil into the standard therapy CHD leads to more significant changes in indicators of clinical evaluation of angina pectoris, myocardial remodeling, inflammatory markers.