| Purpose: According to WHO statistics, more than one thousand million new cancer cases worldwide each year, about 80% to 90% of patients with adanced cancer have different degree of pain. How to effectively alleviate or eliminate pain is doctors,very thorny problem.Traditional Chinese medicine external treatment has played a positive role in the process of pain treatment. Analgesic paste of TCM, which is based on years of clinical experience summary professor Wen-ping Wang. Babu agent made of Chinese herbal medicine, Corydalis,borneol and so on agent, promoting blood circulation to remove blood stasis and analgesic,which is clinically used in the treatment of cancer pain. Its curative effect, high safety, patient compliance is good. Since 2009, successively in Liaoning University of Traditional Chinese Medicine Hospital carried out a series of basic experiment and clinical observation, has published more than 10 references. For further confirmed that Chinese medicine analgesia on the safety and efficacy of cancerous pain, we has carried on the long-term toxicity test of the drug research according to the relevant regulations of the new drug development guiding principle, investigate analgesic paste external Chinese traditional medicine the main toxic effects on rats and its severity, and judge its reversibility and late-onset toxicity, non-toxic reaction doses, for clinical designer with dose and provides some references for the clinical monitoring of adverse reaction. In this study, the Affiliated Hospital of Liaoning University of traditional Chinese medicine to take the lead in 8 hospitals to carry out multi center,randomized, double-blind, placebo-controlled clinical study and evaluation of traditional Chinese medicine analgesic paste in the treatment of mild, moderate and severe pain( hepatocellular carcinoma, metastatic bone cancer) is effective and safety.Material and method:1.The first part Choose healthy SD rats SPF, 180, male and female half and half. 6 to 7 weeks. Female body weight 160-190 g, male weight 170-200 g, set up four groups in this experiment, respectively was blank control group, low, medium and high dose group. 40 animals in each group,Chinese medicine dose analgesic paste is low, medium and high dose group are: 31.25 g/m2,62.5 g/m2 and 125 g/m2 for external use only 3 months, for 7 days a week, for 1 times a day,each patches contact about 6 h. End of drug administration, the rest of the animals into the recovery time is 4 weeks, observe the toxic effects of reversibility, persistence, and late toxicity effect. The Whole to treatment and recovery period, animal body weight and food intake was measured every week. At the end of 6 weeks, 13 weeks and 4 weeks recovery final on anatomical animal blood, urine routine, blood chemistry, said to take absolute organ weight, calculate the relative organ weight(organ / body ratio and visceral brain ratio).2.The second part We adopt effective preparation of traditional Chinese medicine "Chinese medicine analgesic plaster, to evidence-based medicine theory as a guide, to comply with the principle of clinical trial quality management specification(GCP), according to clinical trial design requirements,develop treatment programs, mainly through a multi center, stratified random and double-blind, placebo parallel control clinical study, of traditional Chinese medicine for external use traditional Chinese medicine pain relieving paste in treating mild cancer pain clinical evaluation. Test scheme of external therapy of traditional Chinese medicine comprehensive treatment of cancer pain, provide clues and ideas for the future treatment of cancer research, to further improve the quality of clinical research on traditional Chinese medicine in treatment of cancer pain.3.The third part We adopt effective preparation of traditional Chinese medicine " Chinese medicine analgesic plaster, to evidence-based medicine theory as a guide, to comply with the principle of clinical trial quality management specification(GCP), according to clinical trial design requirements,develop treatment programs, mainly through a multi center, stratified random and double-blind, placebo parallel control clinical study, treatment of external therapy of traditional Chinese medicine and combined with morphine in treatment of severe cancer pain and effect evaluation. Test scheme of external therapy of traditional Chinese medicine comprehensive treatment of cancer pain, provide clues and ideas for the future treatment of cancer research, to further improve the quality of clinical study of TCM in the treatment of cancer.Results:1. The first part of research results1.1 Symptom observation Symptom observation and statistical results showing symptoms is episodic and can be recovered, no drug associated toxicity symptoms. Death of 3 animals respectively in the control group and middle dose group, possibly due to improper operation or long shackled,cleaning and other operations, due to differential tolerance to the animal autopsy results has nothing to do with drugs.1.2 Weight status Male rats in the low dose group, the average weight growth was inhibited, the average body weight of the female rats showed a long rise trend, but after the same period compared with each group, there was no dose effect relationship.1.3 Average food intake There were no differences in drug related among animals.1.4 Blood routine examination At the end of the middle, high dose groups of male animals eosinophils eosinophil count(EO)and eosinophil eosinophil percentage and the control group was significantly higher than that of; detection index of female animals administered group and control showed no significant differences.At the end of administration: the high dose group of male animal blood platelet(PLT) was significantly lower than the control group, there were statistical differences; the female animals of each test index to the drug group and the control group were not statistically significant differences.The final recovery indexes: male and female animal drug group compared with the control showed no statistically significant difference.1.5 Blood biochemical examination At the end of the middle: male in low and middle dose groups animals aspartate amino conversion enzyme(AST) was significantly higher than that of the control group; high dose group of creatinine(crea) is slightly higher than that of the control group, there wasstatistically significant difference; female low dose group of aspartic acid amino converting enzyme(AST) was significantly higher than that of the control group,At the end of the term of administration: the high dose group of male high dose of the enzyme(AST) was significantly higher than that of the control group, the high dose group of urea(UREA) was significantly higher than the control group.At the end of recovery period: male and female animal biochemical indexes the drug group compared with the control group had no significant difference.1.6Blood coagulation index At the end of recovery period: female low dose group of activated partial thromboplastin time(APTT) compared with the control group decreased significantly.Other each time statistics of prothrombin time(PT), activation of fibrinogen(FIB) content in activated partial thromboplastin time(APTT) and fibrin treatment group and the control group showed no significant difference.1.7 Urine routine examination Urine routine examination at each time period, the visual examination of the urine of male and female animals were normal. At the end of the middle: semifinal animal urine routine examination of the treatment group and the control group showed no abnormal.Administration final: semifinal animal urine routine examination of the treatment group and the control group showed no abnormal. Recovery period at the end: male middle dose group,the urine ketone body value(ket) had significant difference compared with the control group.The administration group and control group comparison of each index showed no significant difference.1.8 Organ weight In the end, between the dose groups of absolute organ weight, relative organ weight(BW ratio and dirty brain ratio) showed no statistically significant difference. The final delivery:the high dose group of liver in low absolute organ weight of male animal was lower than the control group, there were significant differences in the male animal; high dose group of epididymis, kidney, heart absolute organ weight lower than the control group, there were significant differences; the male animal is low, high dose group, spleen organ weight lowerthan the control group, there is significant difference between the low dose group; male animal thymus absolute organ weight lower than the control group, there is statistical difference. The male animal low in the high dose group of brain organ body ratio was significantly lower than control group. Low, high dose group of adrenal viscera were significantly higher than that of control group, low dose group of testicular organ body ratio was significantly higher than the control group. The male animal in the high dose group of liver and brain is significantly lower than the control group, high dose group and the spleen,Compared with the control group, the heart of the heart was significantly lower than the control group.Final recovery: male animals in the low dose group of epididymal absolute organ weight higher than control group, there was statistically significant difference; male animals. Low dose group of adrenal absolute organ weight higher than the control group, there was statistically significant difference. The female animals dose group of adrenal absolute organ weight below to contrast group, there were significant differences. Females dose group, the thyroid dirty body ratio and visceral brain ratio is lower than that of the control group,significant difference; female animals high dose group adrenal dirty body ratio was significantly higher than that of the control group.Second 2 part research results2.1Baseline Were randomly enrolled 264 cases of mild pain patients(132 cases of liver cancer, bone metastasis cancer in 132 cases) for demographic data, baseline disease, effect of baseline statistics results show between group difference no statistical significance(P > 0.05). The baseline equalization comparable.2.2 Effectiveness evaluation Comparison between the degree of efficacy of hepatocellular carcinoma in mild pain, bone metastatic carcinoma were analyzed in general the same. In the NRS(static), NRS(movement)score, complained of pain, pain, sleep time, analgesic onset time, traditional Chinese medicine syndrome efficiency, pain score, analgesic satisfaction, satisfaction with treatment, the test group and the control group before and after treatment the difference between group comparison and after administration of beta endorphin peptide content and baseline differencewas statistically significant(P < 0.05). The difference is, the outbreak of pain frequency in the experimental group and the control group, liver cancer level differences had no statistical significance(P > 0.05), bone metastasis cancer level difference was statistically significant(P< 0.05)2.3 Safety assessment Patients with blood routine, urine routine, liver and kidney function, electrocardiogram(ECG)not found changes associated with the drug, no pain medicine paste the adverse reactions,clinical medication safety.Third 3 part research results3.1 Baseline Were randomly enrolled 264 cases severe cancer pain patients(132 cases of liver cancer, bone metastasis cancer in 132 cases), demographic data, baseline disease, clinical baseline statistics showed that group among difference no statistical significance(P > 0.05). The baseline equalization comparable.3.2 Effectiveness evaluation Severe pain in bone metastasis of hepatocellular carcinoma, the overall clinical efficacy cancer statistics were similar. In NRS(static), NRS(motion) score, pain time, TCM syndrome rate, patient satisfaction between the groups showed no significant difference(P> 0.05),treatment satisfaction, burst pain frequency, comparing beta endorphin content and baseline difference after treatment, showed a significant difference between the two groups(P<0.05).The difference is, the experimental group and the control group complained of pain between the two groups, there were statistically significant differences in the level of hepatocellular carcinoma(P<0.05); bone metastasis cancer level difference was not statistically significant(P > 0.05). On the contrary, sleep time, pain score in experimental group and control group comparison, no statistically significant difference between liver cancer levels(P> 0.05); bone metastasis cancer level was statistically significant difference(P<0.05).3.3 Safety assessment Patients with blood routine, urine routine, liver and kidney function, electrocardiogram(ECG)not found changes associated with the drug, no pain medicine paste the adverse reactions,clinical medication safety.Conclusion:1. Traditional Chinese medicine pain relieving plaster on the SD rats was repeated 3 months,the recovery period was 4 weeks, and no visible harmful effect level(NOAEL) was 62.5g/m2.2. Simple application of traditional Chinese medicine analgesic plaster can quickly and effectively alleviate the mild pain(liver cancer, bone metastases).3. Traditional Chinese medicine plaster and combined with morphine to relieve the severe pain(hepatocellular carcinoma, metastatic bone cancer), can reduce the outbreak frequency of pain, reduce pain, improve treatment satisfaction and safety.4.Simple application of traditional Chinese medicine analgesic plaster can reduce the frequency of the pain of bone metastatic cancer pain.5. The analgesic effect of traditional Chinese medicine can be improved by increasing the level of beta- EP in the body.
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