Study Of Tetrodotoxin And Lidocaine Compound Preparation For Anti-arrhythmia

Over the past twenty years, the effects of anti-arrhythmic drugs are not ideal, and have no improvement in reducing mortality that caused by severe arrhythmia.Compound preparations have the advantages of efficiency, convenient use, good patient compliance and so on. Tetrodotoxin, as a highly selective sodium(Na+)channel blocker, has the function of analgesia, anti-arrhythmic and so on. However,the high activity, toxicity and low therapeutic index of tetrodotoxin impose restriction on the application in clinical research. Lidocaine hydrochloride, as the best choice for clinical ventricular arrhythmia treatment, the effect of which is not well when used alone and might aggravate cardiac insufficiency in some case. Therefore, it is of great application value to study the interation of tetrodotoxin with lidocaine hydrochloride,and develop the compound preparation for the puporse of enhancing the anti-arrhythmic effect and decreasing the toxicity of tetrodotoxin.In this paper, based on the model drugs of tetrodotoxin and lidocaine, we studied the compound preparation’s anti-arrhythmic effect using aconitine arrhythmia models in rats. The results showed that tetrodotoxin and lidocaine have synergistic anti-arrhythmic effect. After a series of screening, we obtained the optimal prescription that contains 1μg of TTX and 5 mg of lidocaine hydrochloride.Compared with monotherapy, it has the advantages of significantly delaying the arrhythmia starting time of the model rat, shortening the duration of arrhythmia,completely reversing the mortality which caused by ventricular arrhythmia and so on.The compound preparation is especially suitable for the treatment of fatal ventricular arrhythmia. Then, we have established a high-performance liquid chromatography(HPLC) method to determine the content and related substances of tetrodotoxin and lidocaine in compound preparations. The test results showed that the linear scope of tetrodotoxin and lidocaine were 0.1024 ~ 10.24 μg ? m L-1 and 0.5010 ~ 15.0324mg?m L-1, the average recovery were 100.48% and 99.78%, the RSD were 1.13% and0.65%, respectively(n = 9). In brief, the method was easy to perform and can effectively control the quality of the compound preparations. Furthermore, we chosethe content and relate substances content of tetrodotoxin and lidocaine with the appearance as the detection index, studying the effect of different excipients on the stability of compound preparations. Finally, we selected citrate as cosolvent, dextran40 as stabilizer and mannitol as excipient, developing the compound preparation of tetrodotoxin and lidocaine. After the influencing factor test and accelerated stability test, we conclued that the stability of the compound preparations is good.