A conscious rat model involving bradycardia and hypotension after oral administration: a toxicokinetical study of aconitine.

1. A model of aconitine-induced bradycardia and hypotension, which is similar to aconitine poisoning in humans, was constructed in conscious rats by oral administration. 2. Blood pressure (BP) and heart rate (HR) of Sprague-Dawley rats were measured using a volume pressure recording (VPR) system. The pharmacokinetics of toxic doses of aconitine and its metabolites were analyzed using UPLC-MS/MS. 3. The HR was significantly decreased by 29% at 2 h after oral administration of 200 µg/kg aconitine. When the dose was increased to 400 µg/kg, systolic BP and diastolic BP were significantly decreased by 11% and 12% at 2 h after the administration, except when bradycardia occurred at 2 h and 4 h. The drug concentration-time curve showed a double-peak phenomenon in rats administered a 400 µg/kg dose. The AUC0-12 h value in the 400 µg/kg group significantly increased 0.8-fold compared to the 200 µg/kg group. Moreover, a high plasma concentration of 16-O-demethyaconitine was found in the rats that received two toxic doses. 4. In conclusion, bradycardia and hypotension are induced in conscious rats by a toxic dose of aconitine (400 µg/kg), and there was no significant difference in dose-normalized AUC0-12 h values between oral administrations of 200 µg/kg and that of 400 µg/kg. However, the dose-normalized Cmax and AUC0-12 h values in 200 µg/kg and 400 µg/kg groups were significantly smaller than those in 100 µg/kg group. The metabolites of aconitine, 16-O-demethyaconitine, and benzoylaconitine may also contribute to the hypotensive response.

[Search for new drugs with antiarrhythmic properties among derivatives of adamant-2-ylamides of alkylamidocarbonic acids].

The experiments on white outbred awaken male rats have shown that derivatives of adamant-2-ylamides of alkylamidocarbonic acids exhibit prominent antiarrhythmic (antifibrillatory) effect on the model of calcium chloride arrhythmia. The most pronounced effect was demonstrated by N-[2(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide. This compound was also active on the model of aconitine arrhythmia, which is characteristic of class-I antiarrhythmic agents. It is established that N-[2-(adamant-2-yl)aminocarbonylmethyl]-N'-[3-(diethylamino)propyl]-4-nitrobenzamide has prominent antiarrhythmic activity and is more safe than other antiarrhythmic drugs of class I (lidocaine, ethmosine, novocainamide), class IV (verapamil), and class III (cardiocyclide).