| ObjectivePreclinical cardiac safety evaluation system of International Conference onHarmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) wasused to study the preclinical cardiac electrophysiology physiological characteristics ofSalvia polyphenols salt injection so as to evaluate the cardiac safety of it, which canprovide theoretical basis and security guarantee for its clinical application in the treatmentof heart, brain, liver, kidney and other diseases.Method:1. ECG record of guinea pig in vivo:Ⅱ lead ECG was recorded by conventional guinea pig in vivo ECG technique toanalyze the heart rate, PR interval QRS duration and QTc interval.2. ECG record of guinea pig in vitro:Improved Langendoff perfusion system was used to performed isolated heartperfusion via aorta. Three silver electrodes were put under epicardium to guide the ECG ofthe isolated heart after the heart rate of guinea pig is stable. The positive electrode wasplaced at the apex, the negative electrode was placed in the right atrium, and the groundelectrode was placed in the aortic root. The signal entered into the computer record throughfour-channel polygraph to analyze Heart rate, PR interval, QRS duration and QTc interval.3. Papillary muscle action potentials record of guinea pig:Guinea pigs were anesthetized via intraperitoneal injection, and the heart was takenout to be immersed in0℃Tyrode’s solution; the left ventricular papillary muscle isseparated and placed in muscle tank (tank temperature was (35.0±0.5)℃), perfused withTyrode’s solution which was filled with95%O2and5%CO2gas mixture. Conventionalintracellular action potential record method was used to analyze the process of actionpotential duration at50%repolarize level (APD50) and action potential duration at90%repolarization level (APD90).Result1. The effect of Salvia polyphenol salt injection on ECG of guinea pigs in vivo ECG of guinea pigs in vivo showed that the PR interval of ECG was prolonged after5minutes that Salvia polyphenol salt injection was given by459mg/kg, increasing from(60.8±3.1) ms prior to the administration to (71.0±0.8ms)(P<0.05, n=10), while QRSduration was significantly prolonged from (15.5±1.5) ms prior to the administration to(17.3±1.9) ms (P<0.05, n=10). There was no significant change in HR and QTc amongthe groups.15minutes after the injection of Salvianolate459mg/kg, there appears thetypical conduction block.2. The effect of SN Injection on ECG of guinea pigs in vitroECG of guinea pigs in vitro showed that after perfusion of0.498mg/ml Salviapolyphenol salt injection, heart rate (HR) of guinea pigs in vitro significantly slowed downfrom (182.0±10.1) bpm to (152.0±1.7) bpm (P<0.05, n=10), and the heart rate of elutinggroup slightly restored. There was no significant change in PR, QRS and QTc among thegroups.3. The effect of SN Inj on papillary muscle action potentials of guinea pigsVarious concentrations of Salvia polyphenol salt injection has no effect on the actionpotential APD50, APD90and action potential amplitude (APA), whether before or afteradministration.Conclusion1. The effect of low-dose SN Inj on ECG of guinea pigs in vivo is not obvious, butthere are risks of bradycardia caused by high-dose SN Inj, mainly manifesting asatrioventricular block.2. The heart rate of guinea pig in vitro significantly slowed down after high-dose SNInj, but arrhythmia didn’t appear. The effect is independent of the allergic reaction.3. Each concentration group of SN Inj had no effect on action potential repolarization.4. Injection-used salvianolate under Clinical dose was found safe for heart of guineapig, and no cardiac adverse events were observed. But there is progressive arrhythmia riskunder the high-doses SN Inj, one consequence may be its direct role in slowing the heartrate. |
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