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Objective:Considering the efficacy of Gegen Qinliantang （GQT） in releasing exterior and clearing interior to alleviate dampness-heat dysentery， we analyzed the mechanism of the chloroform extract of GQT in alleviating enterotoxicity caused by irinotecan to provide an experimental basis for the development of GQT. Method:Kunming mice （<italic>n</italic>=60） were randomly divided into a blank group， a model group， a loperamide group （positive drug of loperamide hydrochloride capsule， 0.4 mg·kg<sup>-1</sup>）， and high- （2.3 g·kg<sup>-1</sup>） and low-dose （1.16 g·kg<sup>-1</sup>） GQT chloroform extract groups. The mouse model of delayed diarrhea was established by intraperitoneal injection of irinotecan hydrochloride （CPT-11， 55 mg·kg<sup>-1</sup>） for four consecutive days， meanwhile， the mice in the blank group only received the same volume of normal saline. Corresponding drugs were administered by gavage on the fifth day， respectively， while the ones in the blank group and model group were given distilled water for five consecutive days. The general condition of mice in each group was observed， and diarrhea indexes of mice were recorded. Pathological changes in colon tissues of mice were observed by hematoxylin-eosin （HE） staining. The tumor necrosis factor （TNF）-<italic>α</italic>， interleukin （IL）-1<italic>β</italic>， cyclooxygenase （COX）-2， intercellular adhesion molecule （ICAM）-1， glutathione peroxidase （GSH-Px）， superoxide dismutase （SOD）， malondialdehyde （MDA） and nitric oxide （NO） levels in colon tissues were detected with the assay kits. Furthermore， the expression levels of Kelch sample epoxy chloropropane associated protein 1 （Keap1）， nuclear factor E<sub>2</sub> related factor 2 （Nrf2）， tight junction protein-1 （ZO-1）， heme oxygenase-1 （HO-1） and tight junction protein （Occludin） were detected by Western blot. Result:Compared with the blank group， the model group showed declined body weight and reduced contents of GSH-Px and SOD （<italic>P</italic><0.01）， whereas increased diarrhea indexes and TNF-<italic>α</italic>， IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO levels （<italic>P</italic><0.01）. Abundant inflammatory cells and colonic mucosa with defects， swelling， bleeding， and inflammatory exudation were revealed by HE staining in the mice of the model group. The expression levels of Keap1， Nrf2， ZO-1， HO-1 and Occludin in colon tissues significantly declined （<italic>P</italic><0.01）. Compared with the model group， the loperamide group and the high- and low-dose GQT chloroform extract groups exhibited improved weight loss， reduced diarrhea indexes， diminished TNF-<italic>α</italic>，<italic> </italic>IL-1<italic>β</italic>， COX-2， ICAM-1， MDA and NO， and elevated GSH-Px and SOD. HE staining indicated that the cells were compactly arranged with clear nuclei in the high- and low-dose GQT chloroform extract groups， and the expression levels of Keap1， Nrf2， HO-1， Occludin， and ZO-1 were up-regulated. Conclusion:GQT chloroform extract may alleviate CPT-11-induced delayed diarrhea by regulating inflammation and oxidative stress for enhancing the intestinal barrier function. These findings are expected to provide a reference for exploring the toxicity-attenuating effect of Chinese medicinals on chemotherapy drugs and for developing famous classical formulas.
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Objective@#To investigate the relationship between UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 polymorphisms and irinotecan-induced severe adverse reactions(grade 3-4 delayed diarrhea and neutropenia) in Chinese cancer patients.@*Methods@#A total of 141 cancer patients treated with irinotecan were enrolled in this study. Peripheral venous blood was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 were analyzed by PCR and direct sequencing. The adverse reactions during chemotherapy were observed and recorded. The incidence of severe adverse reactions was compared among patients with different genotypes.@*Results@#Among 141 patients, the cases with UGT1A1*6 GG, GA and AA genotypes were 71, 54 and 16, while those with UGT1A1*28 TA6/6, TA6/7 and TA7/7 genotypes were 105, 33 and 3, respectively. The cases with UGT1A1*60 AA, AC and CC genotypes were 52, 80 and 9, while those with UGT1A1*93 GG, GA and AA genotypes were 105, 32 and 4, respectively. The patients with grade 3-4 delayed diarrhea and neutropenia were 23 and 56, respectively. Multivariate logistic regression analysis showed that UGT1A1*6 and UGT1A1*60 genetic polymorphisms were independent factors influencing the occurrence of grade 3-4 delayed diarrhea. The risk of grade 3-4 delayed diarrhea in homozygous AA carriers of UGT1A1*6 increased 3.79 times compared with that in wild-type GG carriers (95%CI: 1.35-10.67). Moreover, the risk of grade 3-4 delayed diarrhea in homozygous CC carriers of UGT1A1*60 was 20.42 times compared with that in wild-type AA carriers (95%CI: 3.52-118.33). In addition, UGT1A1*28 genetic polymorphism was an independent factor of the occurrence of grade 3-4 neutropenia. The patients with homozygous TA7/7 carriers of UGT1A1*28 had an 1.61 times higher risk of grade 3-4 neutropenia compared with those with wild-type TA6/6 carriers (95%CI: 1.44-12.65). There was no correlation between UGT1A1*93 genetic polymorphism and severe adverse reactions caused by irinotecan.@*Conclusion@#The cancer patients who carried UGT1A1*6, UGT1A1*28 and UGT1A1*60 gene polymorphisms have high risk of severe adverse events caused by irinotecan-based chemotherapy.
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AIM To observe the therapeutic effects of Shengjiang Xiexin Decoction (Zingiberis recens Rhizoma,Zingiberis Rhizoma,Coptidis Rhizoma,etc.) on irinotecan (CPT-11)-induced delayed diarrhea in colorectal carcinoma mice and to discuss its possible action mechanism.METHODS The AOM/DSS-induced female colorectal carcinoma mice were randomly divided into normal group,model group and Shengjiang Xiexin Decoction group.The Shengjiang Xiexin Decoction group was intragastrically administered with Shengjiang Xiexin Decoction,the normal group and the model group were intragastrically administered with normal saline.The diarrhea index and rectum pathologic morphology were measured,and the β-glucuronide activity,IL-15 content and UGT1A1 expression were detected.RESULTS The diarrhea index of Shengjiang Xiexin Decoction group was significantly lower than that of the model group,which might be related to the significant inhibition of β-glucuronide activity,and sig-nificant improvement of IL-15 content and UGT1A1 expression.CONCLUSION Shengjiang Xiexin Decoction shows therapeutic effects on irinotecan-induced delayed diarrhea in AOM/DSS-induced colorectal carcinoma mice.
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OBJECTIVE:To investigate the prevention and treatment effect of Xiaochaihu decoction on irinotecan(CPT-11)-in-duced bloodystool in model mice with delayed diarrhea. METHODS:40 mice were randomly divided into normal control group (equal volume of normal saline),model control group(equal volume of normal saline),Xiaochaihu decoction group(1500 mg/kg, calculated by crude drug)and loperamide group(positive control,0.5333 mg/kg),ig,once a day,for 17 days. Except for normal control group,other groups were intraperitoneally injected CPT-11 to induce delayed diarrhea in 4th-10th day. Body mass changes, bloodystool rate of mice were determined,and pathological changes in large intestine and small intestine were observed. RE-SULTS:After 17 days of administration,compared with normal control group,the body mass in modeling groups was obviously declined (P<0.05),while body mass in Xiaochaihu decoction group was higher than model control group (P<0.05). In the 11th-17th day,bloodystool rate in Xiaochaihu decoction group and loperamide group were significantly lower than model control group(P<0.01),and bloodystool rate in Xiaochaihu decoction group was lower than loperamide group(P<0.05). Pathological re-sults showed,obvious diffuse necrosis and inflammatory cell infiltration were observed in mucosal epithelial cells of large intestine and small intestine in model control group,and the intestinal mucosal tissue in administration groups tended to be normal. CON-CLUSIONS:Xiaochaihu decoction can effectively reduce bloodystool rate,improve intestinal mucosa injury,and has prevention and treatment effect on CPT-11-induced bloodystool in mice,with superior effect to loperamide.
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Objective:To analyze one case of delayed diarrhea caused by irinotecan. Methods:The pathogeny, mechanism, ge-netics and treatment of the case were analyzed. Results:Delayed diarrhea was the dose-limited toxicity of irinotecan, which was related with the cytotoxicity of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Genetic polymorphism was one of important risk factors, especially UGT1A1 polymorphisms could be used as a predictor for the diarrhea. The pharmacotherapy of the diarrhea was ef-fective and rational, and the clinical pharmacist provided rational pharmaceutical care for the patient. Conclusion:It is very important to enhance pharmaceutical care for the patients treated with irinotecan.
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Objective To elaborate the progress on prevention and treatment of Chinese medicine to delayed diarrhea induced by Irinotecan. [Methods] In recent 5 years, traditional Chinese medicine treatment of the disease literature was reviewed . [Results] Traditional Chinese Medicine in prevention and treatment of this disease has unique advantages.[Conclusion] Traditional Chinese Medicine in prevention and treatment of this disease should be unified on syndrome type and evaluation criteria,enhance the efficacy, accepted by the majority of patients.
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Objective:To observe modulation of gut functions and intestinal mucosal immune barrier by ShengJiangXieXinTang in rats receiving Irinotecan(CPT-11).Methods:Sprague Dawley male rats(n=18)were randomly assigned to three groups:(1)herb group (using ShengJiangXieXinTang by oral administration once a day from day 1 to day 9 and being injected with 150 mg/kg?d CPT-11 on day 4 and 5 into the tail vein); (2)diarrhea control group: using distilled water instead of ShengJiangXieXinTang,with the same treatment of CPT-11 as the herb group; (3)normal control group: using normal saline instead of CPT-11, distilled water instead of ShengJiangXieXinTang,and with the same treatment of as the CPT-11 herb group.The animals were scored in terms of delayed-onset of diarrhea. Rats were killed on day 10,collecting ileum,cecum and colon for pathological examination.The damages in intestinal mucosa were assessed under light microscope according to the criterion of chiu's score.CD4+,CD8+T-lymphocytes and SIgA were enumerated by immunohistochemical staining and calculated by imaging analyzer.Results:Compared with diarrhea control group,the incidence of diarrhea and the damage in intestinal mucosa of the herb group was milder(P