Evaluation On "Toxicity-Efficacy" Correlation Of Radix Aconite Lateralis Based On Target Organ Of Heart

Objective: On the basis of the acute toxicity data of different samples from Radix AconiteLateralis, and the"dosage-efficacy-toxicity"relationship with Radix Aconite Lateralis basedon the changes of ECG and the function of isolated heart, in order to study myocardialelectrical activity, the cardiac systolic function, the heart of target organs of poison, sideeffects, dosage ranges, and damage mechanism. Through the relevance evaluation about"efficacy-toxicity"relationship based on target organs of heart, in order to further lock the "effective dose window" of Radix Aconite Lateralis and provides the experimental basis for" toxic safety window ", lay a foundation for the clinical safe drug use in the future.Methods: The extract technology of water extraction, alcohol extraction component fromRadix Aconite Lateralis were studied and referenced on the literature; its acute toxicity ofintragastric administration in mice was researched by the classical acute toxicity testmethod; mice were gavaged certain dose extracts one time or repeatedly, to monitor of thechanges of the electrocardiogram (ECG) before or after the dosage, and study the"dosage-efficiency-toxicity" relationship based on the changes of P wave, QRS complex, PRinterval period, QT interphase and S-T period, detective the index of serum aspertateaminotransferase (AST), lactate dehydrogenase (LDH) and cardiac troponin (cTn-I) afterdrug, and study the cardiac toxicity mechanism about different extracts; and through themyocardial perfusion experiment named Langedorff to observe the changes of cardiacoutput, myocardial contractility and heart rate in isolated heart with different doses, usingmathematics method to carry out the " efficiency-toxicity " relationship of target organs ofheart.based on aconiteResults: The intragastric administration of water extraction and alcohol extractioncomponent can cause fairly acute toxicity to mice. The LD50and its95%confident limit ofalcohol extract were11.7(11.1～12.4)g·kg-1·d-1. The water extraction components inRadix Aconite Lateralis was unable to make LD50, the MTD results calculated in accordance with crude drug content was14.4g·kg-1·d-1, the equivalent of clinical dosageof adult per kilogram of body weight70.0kg67.2times; nausea, convulsions, tetraplegia,prone fixed are main toxic aymptoms,most death of mice in water and alcohol extractgroups occurred in the time quantum from3minite to6h, and found the death of micecertain toxic injury with heart. A widening of the QRS complex and a prolongation of the Pwave, P-R and Q-T intervals on ECG were observed after intragastric administration ofalcohol extract in the dose1.17g·kg-1，which are espectively equal to9.00g of ChinesePharmacopoeia dose, from30to60min. After intragastric administration the water extractin the dose7.20g·kg-1, which are espectively equal to55.38g of Aconite, can observed thea prolongation of the P wave, P-R, Q-T and QRS intervals on EKG from30to120min.The water extract in the dose from1.17to1.95g kg-1can cause the increase of Pwave.In AST, LDH, cTn-I concentration, the effect was found to be insignificant.Conclusion: Different extraction component of Radix Aconite Lateralis can cause fairlyacute toxicity to mice and the toxicity of alcohol extract> water extract, the main targetorgans damage was to the heart. Based on the change of ECG, identify the efficacy index ofheart rate and R wave amplitude, toxicity associated indicators for QRS interphase and S-T period of change, and cTn-I was to prompt the heart toxicity early sensitive indicators,prompt severe myocardial damage.Based on the change of the activity of the isolated heart,confirm the myocardial contraction force is a sensitive cardiac index, it can directly effectintensity. At the same time, the dose is the key to evaluate efficacy and toxicity,preliminary lock water extraction of Aconite within the doses from9to47.55g wererelatively safe and effective doses, alcohol extraction components within the doses from3to9g were relatively safe and effective doses,12to18g were toxic doses. Based on thetarget organs heart, respectively from the efficacy and toxicity dosage, as well as theexperimental exploration about the changes of wave form electrocardiogram (ecg) and theactivity of the isolated heart, illustrates the relevance of the efficacy and toxicity of RadixAconite Lateralis, preliminary establishde the evaluation model with efficacy and toxicity,provide a certain experimental data for the reasonable clinical safe drug use in the future.