Research On The Cardiac Toxicity And Attenuated Drug Screening Of Toad Venoms

In recent years,Chinese medicine toxic problem has caused wide attention of scholars,tradi tional Chinese medicine toxic toads is commonly used medicine clinical,Toad venom(called "Cansu" in China)is a TCM obtained from the skin and parotid venom glands of the toad,includ ing Bufo bufo gargarizans Cantor and B.melanostictus Schneider.It is frequently used in clinics in China to treat tonsillitis,sore throat,palpitation and so on.For drugs treatment of throat(liu shen pill,bezoar diminish inflammation pill,etc)and treatment of cancer drugs active ingredient(HuaChansu pill,xihuan pill,etc)Recent studies have found that toad venom has been used for tr eatment of cancer,tuberculosis,heart diseases,leukemia and so on.Meanwhile toad venom can cause toxicity,clinical excessive use can cause poisoning,especially cause arrhythmia and even death.The heart toxic seriously restricted the clinical drug safety.Therefore,this paper toads in t oxicity and its heart synergia from drug screening to reveal its clinical application to provide the basis for reasonable combination.The main contents include:1.The influence of toads to arrhythmia,cardiac function;2.screening of drugs which can reduce the heart toxicity of toads;3.The role of anti-arrhythmic drugs on toads venom-induced various types of arrhythmia,and the relationship of Na+,K+,Ca2+ and the arrhythmia inculed by toads venom;4.the influence of verapamil and phenytoin on the toad steroids composition in gui-nea pigmyocardial untake.The main research results as follows:1.To summarizes the Chinese traditional medicine the toads venom chemical constituents,pharmacological effects and clinical application of the advances research;And to the pathogene sis of arrhythmia,anti-arrhythmic drugs were reviewed in this paper.2.Study of toad venom induced rat arrhythmia.By using dynamic electrocardiogram(ECG)technology,rats one-time irrigation of crude toads(250/500 mg/kg),record normal and after the treatment 5,15,30,45,60,120,180,300,480,720 minutes of ECG,for all the electrocardiogram analysis,and the results show that:(1)of toads poisoning happened rats major arrhythmia(supra ventricular premature beats,supraventricula tachycardia,premature ventricular ventricular,vent ricular tachycardia,ventricular fibrillation,ventricular bradycardia)(2)The incidence of arrhyth mia in different time points;(3)the trend of arrhythmia extent in 720minutes.3.The influence of ECG and cardiac function by Crude toads(125/250 mg/kg).Through monitor the ECG and heart function of toads poisoning guinea pig,the results showed that:(1)toads can cause a variety arrhythmia of guinea pigs,compared with normal ECG,P-R interphase significantly extend,QRS schedule significantly increased width,and the heart rate increased re markably;(2)the toads inhibit the guinea pig left ventricular function(dp/dtmax,Pmax and RPP decreased significantly,the Pmin significantly increased).4.Screening traditional Chinese medicine which can reduce the toxicity of toads venom.Through document access,selecting 10 reports in the literature have antiarrhythmic effect of the Chinese medicine.By using dynamic electrocardiogram record 10 kinds of traditional Chinese medicine to the influence of the heart toxic to toads,after many index analysis,and the results showed that the Chinese native medicine ingredient astragaloside and compound ShengMaiYin have the most obvious role of attenuated,total ginsenoside,American ginseng total saponins,diosgenin,ginkgolide,taurine,berberine role is the second,and zhigancao soup and renshenshaoyao soup in the present condition,reduce the effect is not significant.5.the role of four types of anti-arrhythm drugs to the arrhythm of toads venom induced.Using mice in vivo and vitro experiment,found that phenytoin has significant inhibition on toads venom induced mice arrhythm,followed by lidocaine and propranolol,amiodarone is not obvious.Find verapamil has two different effects:on one hand,verapamil inhibit the ventricular arrhythmias induced by toad venom;On the other hand,verapamil increased atrioventricular block,live time is shortened,tip verapamil and toads drugs combined with need to be cautious.In vitro experiments,the Langendorff perfusion device,observe the drug to mice direct effect of heart,find phenytoin has the strongest protective effect of the poisoning isoolated mouse heart.followed by lidocaine,propranolol and amiodarone no significant reduction poison effect,verapamil reduced cumulative lethal dose of toad venom in the mouse heart.Statistical ECG indices(P-R interval,QRS duration,Q-T interval,T wave amplitude and HR)and all kinds of arrhythmia incidence,analysis the relationship between toads induction arrhythm types and the ion channels,the results showed that ventricular arrhythmias induced by toad venom in mice may be closely related to sodium channels,supraventricular arrhythmias may be close to the P-receptors,the atrioventricular block may be closely related to the calcium channel.6.Verapamil on the impact of the toad venom cardiotoxicity.Preliminary experiments showed that the verapamil on toads venom induced arrhythmias in both directions,and shorten the survival time of mice poisoned,further use guinea pig isolated heart perfusion and ECG monitoring technology,observe the influence of verapamil on toad venom induced isolated guinea pig heart arrhythmia,use the UPLC-MS analysis the intake leve of the heart toad venom components.The results show that verapamil inhibit the toads induced QRS wide,but increased P-R interval,and increased significantly intake of heart of the 6 kinds of toad steroidal composi-tions.Explain,increase the intake of toadsteroidal composition is a potential mechanism of its toxicity increased.7.Phenytoin on the impact of the toad venom cardiotoxicity.Preliminary experiments showed that the phenytoin on toads venom induced arrhythmias has significant effect.further use guinea pig isolated heart perfusion and ECG monitoring technology,observe the influence of phenytoin on toad venom induced isolated guinea pig heart arrhythmia,use the UPLC-MS analysis the intake leve of the heart toad venom components.The results show that phenytoin inhibit the toads induced QRS wide,and reduced significantly intake of heart of the 4 kinds of toad steroidal compositions.Explain,reduce the intake of toad steroidal composition is a potential mechanism of its toxicity lower.To sum up,this paper analyzes the total ginsenoside,american ginseng saponins,diosgenins,astragloside,taurine,gingolide,berberine,ShengMaiYin,zhigancao soup,renshenshaoyao soup,phenytoin,lidocaine,propranolol,amiodarone,verapamil on the role of toad venom cardiotoxicity respectively,the results show that:phenytoin against arrhythmia induced by toad venom is the most significan,this may be associated with reduced myocardial uptake on 4 kinds of toad steroids composition;Verapamil on toads venom induced arrhythmias in both directions,and shorten the survival time of mice poisoned,this may be assoeiated with increased myocardial uptake on 6 kinds of toad steroids composition;Relatively safe and stable to reduce the cardiac toxicity of toad venom is the astragaloside monomer and compound ShengMaiYin.arrhythmia induced byToad venom and Na+?Ca2+channels may have relatively close relationship.Through the experimental study of this paper,the hope can for the clinical application of toads and new medicine development to provide certain experimental basis.In the choice of arrhythmia drugs for arrhythmia properties,drug use aim must be clear,combination should be prudent.