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Aim: Selisistat (SEN0014196), a first-in-class SirT1 inhibitor, is being developed as a disease-modifying therapy for Huntington's disease. This first-in-human study investigated the safety, pharmacokinetics and pharmacogenomics of single and multiple doses of selisistat in healthy male and female subjects., Method: In this double-blind, randomized, placebo-controlled study, seven cohorts of eight subjects received a single dose of selisistat at dose levels of 5, 25, 75, 150, 300 and 600 mg and four cohorts of eight subjects were administered 100, 200 and 300 mg once daily for 7 days. Blood sampling and safety assessments were conducted throughout the study., Results: Selisistat was rapidly absorbed and systemic exposure increased in proportion to dose in the 5-300 mg range. Steady-state plasma concentrations were achieved within 4 days of repeated dosing. The incidence of drug related adverse events showed no correlation with dose level or number of doses received and was comparable with the placebo group. No serious adverse events were reported and no subjects were withdrawn due to adverse events. There were no trends in clinical laboratory parameters or vital signs. No trends in heart rate or ECG parameters, including the QTc interval and T-wave morphology, were observed. There were no findings in physical or neurological examinations or postural control. Transcriptional alteration was observed in peripheral blood., Conclusion: Selisistat was safe and well tolerated by healthy male and female subjects after single doses up to 600 mg and multiple doses up to 300 mg day(-1)., (© 2014 The British Pharmacological Society.)

The aim of the study was to evaluate the effect of preshock atrial pacing on the atrial defibrillation threshold (DFT) during internal cardioversion of AF. The implantable atrial defibrillator has been added to the therapeutic options for patients with recurrent episodes of persistent AF. Although the device is efficient in restoring sinus rhythm, patient discomfort is a limitation. Methods that lower the ADFT are needed. Eleven patients with AF underwent internal cardioversion. In a randomized, crossover design, ADFT testing was performed, applying a step-up protocol starting at 100 V. Rapid atrial pacing was performed with a right atrial catheter for 20 seconds at 90% of the average cycle length of the fibrillatory waves and was immediately followed by a biphasic defibrillation shock. At each energy level, pacing + shock was compared to shock only, until the level at which sinus rhythm was restored by both modes. The step-up protocol was thereafter repeated using the inverse sequence of the two modes. A total of 19 ADFTs were obtained. For 10 the ADFT was lower with pacing + shock, in 4 equal and in 5 higher, than with shock only. The ADFT (mean +/- SD) with pacing + shock was 260 +/- 84 V(3.4 +/- 2.9 J) and did not differ from shock only: 268 +/- 85 V(3.8 +/- 3.0 J) (P > 0.05). The coefficient of variation and the coefficient of reproducibility for pacing + shock was 16% and 60 V, respectively, and for shock only 17% and 61 V. Rapid atrial pacing did not influence the internal ADFT in AF. The randomized, crossover protocol used was reproducible between different modes, and seems useful when testing the impact of different interventions on the ADFT.