The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
J Seshagiri V L N Rao - One of the best experts on this subject based on the ideXlab platform.
-
highly sensitive uhplc ms ms method for the simultaneous estimation of propafenone and its metabolites 5 Hydroxypropafenone and n depropylpropafenone on human dried blood spots technique and application to a pharmacokinetic study
Journal of Pharmaceutical and Biomedical Analysis, 2017Co-Authors: Adinarayana Andy, Raja Reddy Kallem, Ramesh Mullangi, Divya Andy, J Seshagiri V L N RaoAbstract:A highly sensitive, rapid and selective UHPLC-MS/MS method has been developed and validated for quantification of the propafenone (PF), 5-Hydroxypropafenone (5-OHPF) and N-depropylpropafenone (N-DPF) on human dried blood spot (DBS). The assay procedure involves a solid-liquid extraction of PF, 5-OHPF and N-DPF and amlodipine (internal standard, I.S.) from dried human DBS cards using water and acetonitrile. The chromatographic resolution was achieved on a BEH C18 column using a gradient mobile phase consisting of 0.1% formic acid in water and acetonitrile with 0.1% formic acid at flow rate of 0.6mL/min. The UHPLC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Total run time of analysis was 1.1min and elution of PF, 5-OHPF, N-DPF and I.S. occurred at 0.69, 0.6, 0.68 and 0.73min, respectively. A detailed method validation was performed as per the regulatory guidelines and the standard curves found to be linear in the range of 5.11-1000ng/mL for PF and 5-OHPF and 0.51-100ng/mL for N-DPF with a correlation coefficient of ≥0.99 for all the drugs. The intra- and inter-day accuracies were in the range of 95.6-107 and 93.5-103; 93.4-106 and 96.3-107 and 87.9-103 and 96.5-102%, for PF, 5-OHPF and N-DPF, respectively. The intra- and inter-day precisions were in the range of 2.50-5.52 and 3.38-5.18; 2.16-6.34 and 3.23-4.94 and 2.63-7.55 and 1.56-10.2%, for PF, 5-OHPF and N-DPF, respectively. The validated assay method was successfully applied to a pharmacokinetic study in humans. The key pharmacokinetic parameters AUC0-∞ and Cmax were 6057±1526, 2002±515 and 525±202 ng*h/mL and 653±183, 295±37.5 and 68.4±13.6ng/mL for PF, 5-OHPF and N-DPF, respectively.
Paul I. Dargan - One of the best experts on this subject based on the ideXlab platform.
-
Propafenone poisoning: a case report with plasma propafenone concentrations
Journal of Medical Toxicology, 2010Co-Authors: Hanna Ovaska, Andrew Ludman, Edgar P. Spencer, David M. Wood, Alison L. Jones, Paul I. DarganAbstract:Propafenone is an anti-arrhythmic drug used in the management of supraventricular and ventricular arrhythmias. It is metabolised through cytochrome P450 2D6 pathways; the major metabolites possess anti-arrhythmic activity. The cytochrome P450 CYP2D6 is coded by more than 70 alleles resulting in great genetic polymorphism of CYP2D6 isoenzymes, and up to 7% of Caucasian population are poor metabolisers. This case report describes a patient with severe overdose of propafenone who presented with coma, seizures and cardiotoxicity. The patient was managed with intravenous glucagon, hypertonic sodium bicarbonate, hypertonic saline and inotropic support. The propafenone and its 5-Hydroxypropafenone (5-OHP) metabolite were measured by high-performance liquid chromatography with ultraviolet detection (no assay was available at the time to measure N-despropyl propafenone concentrations). Toxicological screen showed propafenone concentrations at a maximum of 1.26 mg/L at 9-10 h post-presentation, falling to 0.25 mg/L at 27-28 h post-presentation. No propafenone metabolite 5-OHP was detected in any sample analysed. No antidepressant or analgesic drugs were detected in toxicological screen. Propafenone overdose has been reported to be associated with features of severe cardiovascular and CNS toxicity. Aggressive treatment, meticulous monitoring and supportive care was associated with a good outcome in this case.
-
Propafenone Poisoning—A Case Report with Plasma Propafenone Concentrations
Journal of Medical Toxicology, 2010Co-Authors: Hanna Ovaska, Andrew Ludman, Edgar P. Spencer, David M. Wood, Alison L. Jones, Paul I. DarganAbstract:Propafenone is an anti-arrhythmic drug used in the management of supraventricular and ventricular arrhythmias. It is metabolised through cytochrome P450 2D6 pathways; the major metabolites possess anti-arrhythmic activity. The cytochrome P450 CYP2D6 is coded by more than 70 alleles resulting in great genetic polymorphism of CYP2D6 isoenzymes, and up to 7% of Caucasian population are poor metabolisers. This case report describes a patient with severe overdose of propafenone who presented with coma, seizures and cardiotoxicity. The patient was managed with intravenous glucagon, hypertonic sodium bicarbonate, hypertonic saline and inotropic support. The propafenone and its 5-Hydroxypropafenone (5-OHP) metabolite were measured by high-performance liquid chromatography with ultraviolet detection (no assay was available at the time to measure N -despropyl propafenone concentrations). Toxicological screen showed propafenone concentrations at a maximum of 1.26 mg/L at 9–10 h post-presentation, falling to 0.25 mg/L at 27–28 h post-presentation. No propafenone metabolite 5-OHP was detected in any sample analysed. No antidepressant or analgesic drugs were detected in toxicological screen. Propafenone overdose has been reported to be associated with features of severe cardiovascular and CNS toxicity. Aggressive treatment, meticulous monitoring and supportive care was associated with a good outcome in this case.
J. Evers - One of the best experts on this subject based on the ideXlab platform.
-
Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its Phase I and Phase II metabolites
European Journal of Clinical Pharmacology, 1995Co-Authors: M. F. Fromm, S. Botsch, G. Heinkele, H. K. Kroemer, J. EversAbstract:The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5-Hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol · ml^−1 · mol^−1; R-PPFG: 576 vs. 304 nmol · ml^−1 · mol^−1). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol · ml^−1 · mol^−1; R-PPFG: 7340 nmol · ml^−1 · mol^−1). In summary, the disposition of propafenone and of its active metabolite 5-Hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.
Ferenc Follath - One of the best experts on this subject based on the ideXlab platform.
-
Concentration-effect relations of 5-Hydroxypropafenone in normal subjects☆
American Journal of Cardiology, 1991Co-Authors: Walter E. Haefeli, Walter Taeschner, Huy Riem Ha, S Vozeh, Ferenc FollathAbstract:Abstract To evaluate the pharmacologic activity of 5-Hydroxypropafenone, electrocardiographic changes (PQ and QRS duration) and blood pressure levels were measured in 6 healthy extensive metabolizers of debrisoquine after a single oral dose of 300 mg of this metabolite as a solution in a placebo-controlled, double-blind crossover study. Well-absorbed, with a lag time of 4.4 to 9.8 minutes, 5-Hydroxypropafenone reached peak concentrations of 153 to 337 ng/ml after 20 to 51 minutes. The terminal half-life was 506 to 963 minutes. To describe the temporal aspects of the concentration-effect relation, a pharmacokinetic-pharmacodynamic model with a hypothetical effect compartment was applied. The relation between electrocardiographic changes and drug concentration at the effect site could be described by a linear regression model. Significant prolongations of PQ and QRS duration were found in 5 of 6 subjects. There were no changes in QTc interval, blood pressure measurements and heart rate in the supine position. However, blood pressure measurements in the upright position revealed a greater percent decrease of systolic blood pressure than with placebo (mean ± standard deviation −25.6 ± 13.8% vs −3.4 ± 13.1%, p
-
Nonlinear kinetics of propafenone metabolites in healthy man
European Journal of Clinical Pharmacology, 1990Co-Authors: S Vozeh, Walter E. Haefeli, J. Vlcek, Ferenc FollathAbstract:The pharmacokinetics of oral and i. v. propafenone and its major metabolites have been investigated in 8 healthy subjects. The total body clearance of propafenone was 963 ml/min, the terminal half-life 198 min and its absolute bioavailability was 15.5%. The two active metabolites (5-Hydroxypropafenone and N-depropylpropafenone) showed non-linear kinetics in that both the dose-corrected area under the serum concentration-time curve and the amount excreted in the urine were larger after oral dosing. This resulted in considerably higher serum concentrations of the metabolites despite comparable serum concentrations of the parent compound. Thus, the concentration-effect relationship in the same patient may differ after oral and intravenous doses if concentrations of the active metabolite(s) are not taken into consideration. Although the mechanism of the nonlinearity is not clear, the data indicate that it may be due to saturable biliary excretion of the metabolites.
-
The relative potency of major metabolites and enantiomers of propafenone in an experimental reperfusion arrhythmia model
Journal of Cardiovascular Pharmacology, 1990Co-Authors: Kwame Oti-amoako, S Vozeh, Ferenc FollathAbstract:We used isolated rat hearts subjected to coronary artery ligation and reperfusion to study the antiarrhythmic activity of 5-Hydroxypropafenone (5OHP) and N-depropylpropafenone (NDPP), major metabolites of propafenone (P) in humans, and of the two enantiomers (R)- and (S)-propafenone. 5OHP suppressed reperfusion arrhythmias similar to the parent drug in a concentration-dependent manner. The concentration of 5OHP needed to prevent ventricular fibrillation in 50% of experiments (EC50) was significantly higher than that of P (0.186 +/- 0.05 vs. 0.153 +/- 0.005 mg/L, mean +/- SEM, p less than 0.05). 5OHP had a relative potency of 80% compared to P. When 5OHP and P were administered together, their antiarrhythmic effect appeared to be supra-additive. The NDPP metabolite showed very little antiarrhythmic potency and was about four times less active than P. The two enantiomers (R) and (S) were equipotent and showed antiarrhythmic activities similar to racemic P.
Carmen Valenzuela - One of the best experts on this subject based on the ideXlab platform.
-
effects of propafenone and its main metabolite 5 Hydroxypropafenone on herg channels
Cardiovascular Research, 2003Co-Authors: Cristina Arias, Teresa Gonzalez, Ignacio Moreno, Ricardo Caballero, Eva Delpon, Juan Tamargo, Carmen ValenzuelaAbstract:Objectives: Propafenone is a class Ic antiarrhythmic drug used to maintain sinus rhythm in patients with atrial fibrillation. During chronic therapy, it undergoes extensive first-pass hepatic metabolism to 5-Hydroxypropafenone. In the present study we have analysed the effects of propafenone and 5-Hydroxypropafenone on HERG current. Methods: The whole-cell configuration of the patch-clamp technique was used in CHO cells stably transfected with the gene encoding HERG channels. Results: Propafenone and 5-Hydroxypropafenone (2 μM) inhibited HERG current by 78.7±2.3% ( n =7) and 71.1±4.1% ( n =7, P 0.05) when measured at the end of 5-s depolarizing pulses to −10 mV. Block measured at the maximum peak of tail currents recorded at −60 mV was similar for propafenone (78.3±2.0%, n =7, P 0.05) and higher for 5-Hydroxypropafenone (79.3±1.5%, n =7, P <0.05). Propafenone and 5-Hydroxypropafenone shifted the midpoint of the activation curve by −10.2±0.9 mV ( n =7, P <0.01) and −7.4±1.1 mV ( n =10, P <0.01), respectively. Both drugs accelerated the deactivation and the inactivation process of HERG current. Propafenone, but not 5-Hydroxypropafenone, inhibited to a higher extent HERG current at the end of 5-s depolarizing pulses to 0 mV than after promoting the transition of HERG channels from the inactivated to the opened state. Conclusions: These results indicate that propafenone and its main active metabolite, 5-Hydroxypropafenone, block HERG channels to a similar extent by binding predominantly to the open state of the channel.
-
Effects of propafenone and its main metabolite, 5-Hydroxypropafenone, on HERG channels.
Cardiovascular Research, 2003Co-Authors: Cristina Arias, Teresa Gonzalez, Ignacio Moreno, Ricardo Caballero, Eva Delpon, Juan Tamargo, Carmen ValenzuelaAbstract:Objectives: Propafenone is a class Ic antiarrhythmic drug used to maintain sinus rhythm in patients with atrial fibrillation. During chronic therapy, it undergoes extensive first-pass hepatic metabolism to 5-Hydroxypropafenone. In the present study we have analysed the effects of propafenone and 5-Hydroxypropafenone on HERG current. Methods: The whole-cell configuration of the patch-clamp technique was used in CHO cells stably transfected with the gene encoding HERG channels. Results: Propafenone and 5-Hydroxypropafenone (2 μM) inhibited HERG current by 78.7±2.3% ( n =7) and 71.1±4.1% ( n =7, P 0.05) when measured at the end of 5-s depolarizing pulses to −10 mV. Block measured at the maximum peak of tail currents recorded at −60 mV was similar for propafenone (78.3±2.0%, n =7, P 0.05) and higher for 5-Hydroxypropafenone (79.3±1.5%, n =7, P
