| Aidi injection, a traditional Chinese medicine injection, is an extraction obtained from Cantharidin, Ginseng, Astragalus, and Acanthopanax, with effects such as heat-clearing, detoxification, and swelling reduction. It is also the anti-tumor traditional Chinese medicine injection with Fuzheng and quxie effects. Aidi injection is often used to malignant tumors in conjunction with cisplatin, which can enhance the efficacy and decreases adverse effects.Cisplatin is one of the commonly used chemotherapy drugs for the treatment of cancer with wide anticancer spectrum. However it can cause adverse reactions in patients including liver and kidney toxicity, bone marrow suppression and gastrointestinal reactions, which greatly limit its clinical application. Therefore, it is necessary to prevent and reduce the side effects especially cisplatin-induced hepatic and renal toxicity to ensure its security. In recent years, traditional Chinese medicine has made great progress in the clinical application and experimental research on the adverse effects of radiotherapy and chemotherapy. We aimed to study the effect of Aidi injection on liver and kidney toxicity induced by cisplatin, to lay a foundation on the clinical application of the combination of Aidi injection and cisplatin. In addition, because of the longer half-life of cisplatin, the change of blood drug concentration is bound to affect its safety and effectiveness. Therefore, the changes of the serum concentration of cisplatin in combined with Aidi injection were studied in this paper, which were used to guide clinical rational drug use. The main experiments and results were as follows:1. High performance liquid chromatography (HPLC) method was established to the determination of cisplatin of rat plasma. The methodology verification results showed that the method met the requirements of biological sample analysis. Specific, day RSD values were less than 15%, and recovery of low, medium and high concentrations were greater than 80%. The result indicated that the method could be used in the study of cisplatin pharmacokinetics.2. In combination with Aidi injection for cisplatin influence of drug metabolism in normal rats:healthy Sprague-Dawley (SD) rats were randomly divided into 3 groups, including the cisplatin group (tail vein injection of cisplatin 3 mg/kg), simultaneous group (after tail vein injection of cisplatin 3 mg/kg and immediate intraperitoneal injection of Aidi injection 10 ml/kg) and 30min combination group (intraperitoneal injection of Aidi injection 10 ml/kg, followed by tail vein injection of cisplatin 3 mg/kg after 30 min). Blood samples were collected from the orbital venous blood at different times after administration. The samples of each time point were determined by HPLC. Through the analysis of all pharmacokinetic parameters by non-compartmental analysis using Kinetica 5.1 software, the differences between the pharmacokinetic parameters were processed by SPSS 17.0. Compared pharmacokinetic parameters among the groups:Compared with the administration of cisplatin alone, there was a significant increase in T1/2 (P< 0.05) and Vd (P<0.01) of the simultaneous group, and no obvious difference in Cmax, Tmax, AUC, CL, MRT (P>0.05); While there was a significant increase in Tm (P<0.05), Cmax (P<0.01) and MRT (P< 0.05) of 30min combination group, and no obvious difference in Vd, Tmax, AUC, CL (P>0.05). Compared with simultaneous group, pharmacokinetic parameters of Cmax and AUC were increased significantly (P<0.01), CL was decreased significantly (P<0.01), T1/2, Tmax, Vd and MRT were no statistically significance in 30min combination group.The results showed that cisplatin combined with Aidi injection could increase cisplatin in vivo absorption rate, the maximum plasma concentration and half-life. From the point of view of pharmacokinetics, it provided a certain experimental basis for Aidi injection to increase the efficacy of cisplatin. The effects of 30min combination on animal metabolism were better than the simultaneous, especially in the increase of blood drug concentration. It was suggested that the interval of time was necessary to improve the clinical therapeutic effect of cisplatin. In order to prevent the occurrence of side effects, the plasma concentration of cisplatin should be monitored dynamically.3. Protective effect of Aidi injection on nephrotoxicity induced by cisplatin in rats:40 male Sprague-Dawley rats were randomly divided into 5 groups, including the control group, CDDP group, the low, medium and high dose Aidi injection group (5 ml/kg,10 ml/kg,15 ml/kg). Except the rats in control group, the rats of other groups were injected with CDDP on the third day. Aidi injection groups were administered to the rats once daily for 7 consecutive days. The control and CDDP groups were given corresponding regime of saline. On the eighth day, determine the content of serum creatinine (Scr) and blood urea nitrogen (BUN) in the rat, detect the level of superoxide dismutase (SOD), glutathione reductase (GSH-Px) and malondialdehyde (MDA) in the kidney tissue; observe HE staining slices of rats and find the renal pathological changes.Compared with control group, the levels of Scr, BUN and MDA content were increased significantly in CDDP group (P<0.01),whereas the contents of SOD and GSH-Px were decreased significantly (P<0.05). There were serious, renal tubular epithelial cell apoptosis and inflammation in the kidney tissue. Kidney histopathology indicated that Aidi injection alleviated CDDP-induced tissue damage. The levels of Scr, BUN were decreased significantly in the low dose Aidi injection group (5 ml/kg) (P<0.01), whereas the activity of SOD and GSH-Px were increased significantly (P<0.05).The medium dose of Aidi injection (10 ml/kg) could increase the level of SOD and GSH-Px (P<0.05). The high dose of Aidi injection (15ml/kg) could enhance the activity of GSH-Px (P<0.05), without statistically significant effect on other indicators. The results indicated that the low and middle dose of Aidi injection might protect the renal tissue from nephrotoxicity induced by cisplatin through anti-oxidation.4. Protective effect of Aidi injection on liver injury induced by cisplatin in rats:40 male Sprague-Dawley rats were randomly divided into 5 groups, including the control group, CDDP group, the low, medium and high dose Aidi injection group (5 ml/kg,10 ml/kg,15 ml/kg). Except the rats in control group, the rats of other groups were injected with CDDP on the third day. Aidi injection groups were administered to the rats once daily for 7 consecutive days. The control and CDDP groups were given corresponding regime of saline. On the eighth day, determine the content of serum alanine aminotransferase (ALT) and aspartate transaminase (AST) in the rat, detect the level of superoxide dismutase (SOD), glutathione reductase (GSH-Px) and malondialdehyde (MDA) in the liver tissue; observe HE staining slices of rats and find the liver pathological changes.Compared with control group, the levels of Scr, BUN and MDA were increased significantly in CDDP group (P<0.01), while the contents of SOD and GSH-Px were decreased significantly (P<0.01). The liver histopathology indicated that Aidi injection alleviated CDDP-induced tissue damage. The middle and high dose of Aidi injection significantly inhibited the elevations of serum ALT, and AST levels (P<0.05), alleviated the formation of MDA (P<0.05), and increased the level of SOD and GSH-Px in liver in cisplatin intoxicated rats (P<0.05). The protective effect of the middle dose of Aidi injection was better than the high dose. The results suggested that the middle and high dose of Aidi injection might protect the liver tissue from liver damage induced by cisplatin through anti-oxidation.In this paper, based on clinical application, we explored the effects of Aidi injection on the pharmacokinetics of cisplatin and its effect on liver and kidney toxicity induced by cisplatin. It provided a reference for the rational use of Aidi injection combined with cisplatin in the future, and laid the foundation for further research on drug interactions. |
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