nitrophenols and cilnidipine

Sympathetic nerve activity is augmented by calcium-channel blocker treatment as a result of decreased blood pressure. Dihydropyridine calcium-channel blockers are divided into three different types. The purpose of the present study was to investigate whether treatment effects on hemodynamics, cardiac autonomic nerve activity and plasma norepinephrine levels differ among amlodipine (L type), efonidipine (L + T type) and cilnidipine (L + N type). We enrolled 14 hypertensive patients (seven males, seven females, 70 ± 6 years old) undergoing a monotherapy of amlodipine, efonidipine or cilnidipine into this prospective, open-labeled, randomized, crossover study. At baseline and every 6 months of the treatment period, we repeated the evaluation of hemodynamics, spectral analysis of heart rate variability and plasma norepinephrine levels. Blood pressure and pulse rate were comparable among the three treatments. The low-frequency (LF)/high-frequency (HF) power ratio, an index of cardiac sympathovagal balance, was significantly lower with efonidipine and cilnidipine than with amlodipine, while the HF/total power ratio, an index of cardiac vagal activity, revealed the opposite results. There was no significant correlation between the LF/HF ratio and plasma norepinephrine levels. Antihypertensive monotherapy with efonidipine or cilnidipine attenuates cardiac sympathetic nerve activity more effectively than amlodipine monotherapy.

Topics: Aged; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cross-Over Studies; Dihydropyridines; Female; Heart; Heart Conduction System; Hemodynamics; Humans; Hypertension; Male; Nitrophenols; Norepinephrine; Organophosphorus Compounds; Prospective Studies; Sympathetic Nervous System

Efonidipine hydrochloride is a new generation dihydropyridine Ca(2+) channel blocker designed to inhibit both T-type and L-type Ca(2+) channels. Efonidipine possesses a chiral carbon and is clinically administered as a racemate. In the present study, an enantioselective and sensitive LC-MS/MS method of determining efonidipine enantiomers in human plasma was developed and validated to characterize the stereoselective pharmacokinetics. Plasma samples were processed by liquid-liquid extraction (LLE). Chiral separation was optimized on a CHIRALPAK(®) ID column using an isocratic mobile phase of acetonitrile/water (60:40, v/v). Detection was using MS in multiple reaction monitoring (MRM) mode, using the transitions of m/z 632.3→91.1 for efonidipine enantiomers, and m/z 493.3→117.2 for cilnidipine (internal standard). The calibration curves were linear over 0.100-20.0 ng/mL for each enantiomer. The lower limit of quantification (LLOQ) for each enantiomer was established at 0.100 ng/mL. Intra- and inter-day precisions were less than 12.1% for each enantiomer in terms of relative standard deviation (RSD), and accuracies were between -5.0% and 5.0% in terms of relative error (RE) for each enantiomer. No chiral inversion was observed during sample storage, preparation procedure and analysis. The validated method was successfully applied to a stereoselective pharmacokinetic study of efonidipine in healthy subjects after oral administration of 40 mg (20 mg × 2) efonidipine hydrochloride tablets.

Topics: Administration, Oral; Chromatography, Liquid; Dihydropyridines; Humans; Liquid-Liquid Extraction; Nitrophenols; Organophosphorus Compounds; Plasma; Stereoisomerism; Tablets; Tandem Mass Spectrometry