Study On The Phase Ⅱ (Early) Clinical Trial Of Traditional Chinese Medicine With Shuxuening Injection As An Example

Purpose:Based on the status quo of our country that new Traditional Chinese Medicine has a low rate of getting permission to the market and a high waste of its research fund, this paper explores how to evaluate the TCM’s effect during its early phase of clinical trials referring to the method of western medicine’s Phase 0 trials. It aims at improving the creation research of TCM by establishing a primary system of relative techniques and making its research and development meet the top level in the world.Material and method:1. By analyzing the relative handbooks and literatures about western medicine’s Phase 0clinical trial, the paper tries to find out the similarities and differences between TCM’s and western drugs’ research and development, and to establish key-technique standards that fit the evaluation on TCM’s early clinical behaviors.2. According to the ready research methods, we take Shuxuening Injection as an example to carry out Phase 0 clinical trials on some healthy volunteers. Then pharmacokinetics and pharmacodynamics of it are detected and discussed, which verify the possibility of TCM’s earlier clinical evaluation.Design of the pharmacokinetics experiment: Test the plasma concentration of volunteers after being injected micro-dose Shuxuening Injection by means of intravenous infusion. On condition that volunteers are sure to be well protected, we explore the minimum detectable dose of pharmacokinetics parameters according to the multiple distributions by increasing single dose, and calculate pharmacokinetics parameters. Choose the official test dosage for single dose and multiple dose, then test the plasma concentration and pharmacokinetics parameters in serum and plasma. Try to find out the pharmacokinetics law compared with the clinical dosage.Design of the pharmacodynamics experiment: Dose to the volunteers inside their body according to the test dosage set by pharmacokinetics. Choose the timing before and after dosing, then collect and prepare two groups of serum and plasma: one is mixed with the drug and the other isn`t. Assess the curative effect by organically combining the assessment criteria on body’s safe curative effect, the external cell experiment and selected results of high throughput of whole transcriptase. We take the clinical dosage as the control group in the experiment to survey the tendency consistency of pharmacokinetics and pharmacodynamics in low dose and clinical dose.3. According to the result of Phase 0 clinical trials of Shuxuening, we discuss the deficiency in the method design of clinical trials, and improve the evaluating method of TCM’s earlier clinical phase.Results:1. About pharmacokinetics: According to the results, the plasma concentrations of micro-dose group are all under the lower limit of detection, which cannot be put into data statistics. In single-dose climbing group, plasma concentration is tested out in the groups with 1/25,1/12.5and 1/6.25 of clinical dosage. In the groups of single dose and multiple doses with fixed concentration, the tested concentration is lower in serum than in plasma. Compared with the clinical group, low dose has similar metabolic tendency of drugs.2. About pharmacodynamics: there are no significant differences before and after being injected in evaluation indicator of safe curative effect. In the external experiment of H2O2 inducing endothelial cell damage, experimental groups can differently affect the cell proliferation, protect the shape of cells, reduce the release of Calcium ion owing to cell damages and influence the secretion of MDA, SOD, NO and ET in cells. After PAF induction of Medicated plasma, experimental groups can reduce the amount of TXB2 and rise6- Keto- PGF1α in different levels compared with model control group. Complete-sequence RNA gives differential multiterm expression before and after the low dose, but as the amount of differential genes is too large, it is difficult to find out valuable ones and the possible points that drugs may effect on, so there is still no complete evaluating ways. Compared with the clinical group, low dose has similar metabolic tendency of drugs.3. TCM`s Phase 0 trials are proved to be available in clinic that we can detect plasma concentration of pharmacokinetics by increasing the dosage step by step, and we can discuss the efficacy system by means of external induction to biological samples and serum pharmacology.Conclusion:1. Owing to TCM`s complex ingredients, we can simplify the issue to choose several active elements to study pharmacokinetics and pharmacodynamics under low dose.2. On condition that volunteers are well protected, we can adopt the way of increasing each dose step by step, so we can make the displaying degree of low dose clearer, and make it possible that plasma concentration could be tested in TCM`s Phase 0 trials of pharmacokinetics.3. TCM`s pharmacodynamics test with multi components and multiple target points should be a complex with a multi-factor and multivariable process. Specifically, we should work on it regardless of corresponding relations between components and target points. We can classify drugs according to their main functions, and set up an ideal and better improved evaluation system by means of molecular-biology-level experiments, including high throughput screening and serum pharmacology.