技术领域technical field
本发明属于化学医药领域，具体涉及抗HIV蛋白酶抑制剂沙奎拉韦单用或沙奎拉韦和利托那韦的组合物与抗肿瘤药物伊立替康联合使用，减少伊立替康的毒性反应，增加肿瘤患者的体质，即提高肿瘤患者耐受伊立替康的使用剂量，延长肿瘤患者使用伊立替康的时间。The invention belongs to the field of chemical medicine, and specifically relates to anti-HIV protease inhibitor saquigravir used alone or a combination of saquigravir and ritonavir combined with antitumor drug irinotecan to reduce the toxicity of irinotecan , increase the physique of tumor patients, that is, increase the dosage of irinotecan tolerated by tumor patients, and prolong the time of using irinotecan for tumor patients.
背景技术Background technique
伊立替康临床用于治疗晚期结直肠癌，与5-氟尿嘧啶和亚叶酸(LV)联合治疗既往未接受化疗的晚期大肠癌患者；作为单一用药，治疗经含5-氟尿嘧啶化疗方案治疗失败的患者。盐酸伊立替康180mg/m2静脉滴注30-90分钟，第1天；LV 400mg/m2应该在盐酸伊立替康输注后立即给予，滴注时间相同，第1天；5-FU 400mg/m2静脉推注，第1天，然后1200 mg/m2/d×2天持续静脉输注(总量2400mg/m2,输注46-48小时)。每2周重复。伊立替康的剂量限制性毒性为延迟性腹泻(用药24小时后发生)。寻找与抗肿瘤药物伊立替康联合使用的药物，减少伊立替康导致的腹泻，减少因腹泻导致的肠功能障很有必要。Irinotecan is clinically used for the treatment of advanced colorectal cancer, combined with 5-fluorouracil and leucovorin (LV) in the treatment of patients with advanced colorectal cancer who have not received chemotherapy before; as a single drug, to treat patients who have failed treatment with 5-fluorouracil-containing chemotherapy regimens . Irinotecan hydrochloride 180mg/m2 intravenous infusion for 30-90 minutes, the first day; LV 400mg/m2 should be given immediately after irinotecan hydrochloride infusion, the same infusion time, the first day; 5-FU 400mg /m2 intravenous bolus injection on the first day, and then 1200 mg/m2 /d×2 days continuous intravenous infusion (total amount 2400mg/m2 , infusion for 46-48 hours). Repeat every 2 weeks. The dose-limiting toxicity of irinotecan was delayed diarrhea (onset 24 hours after dosing). It is necessary to find drugs that are used in combination with the antineoplastic drug irinotecan to reduce diarrhea caused by irinotecan and reduce intestinal dysfunction caused by diarrhea.
临床上抗HIV蛋白酶抑制剂(protease inhibitor)沙奎拉韦甲磺酸沙奎拉韦(Saquinavir mesylate，Invirase)为一高效高选择性的HIV蛋白酶抑制剂，作用于HIV繁殖的后期，与 HIV蛋白酶的激活点结合，使之失去结合和水解断裂多肽的功能，与其它药物合用治疗严重的HIV感染，增加CD4计数，降低血中HIV总量，但抗HIV蛋白酶抑制剂沙奎拉韦单用或沙奎拉韦和利托那韦的组合物与抗肿瘤药物伊立替康或其活性代谢物7-乙基-10羟基喜树碱 (SN-38)联合使用，预防或治疗减少伊立替康或SN-38的毒性反应，减少伊立替康或SN-38 导致的腹泻，减少因腹泻导致的肠功能障碍出现的饮食量下降，增加肿瘤患者的体质，提高肿瘤患者耐受伊立替康或SN-38的使用剂量，延长肿瘤患者使用伊立替康或SN-38时间的作用未见报道。本发明人通过大量的研究发现抗HIV蛋白酶抑制剂沙奎拉韦与抗肿瘤药物伊立替康或SN-38联合使用，可以明显减少伊立替康或SN-38的毒性反应，抑制抗肿瘤药物伊立替康或SN-38导致的腹泻，减少因腹泻导致的肠功能障，增加饮食量，增加肿瘤患者的体质，提高肿瘤患者耐受伊立替康或SN-38的使用剂量，延长肿瘤患者使用伊立替康或SN-38的时间。基于此，本发明人发明了抗HIV蛋白酶抑制剂沙奎拉韦单用或沙奎拉韦和利托那韦的组合物与伊立替康联合或SN-38使用，减少伊立替康或SN-38的毒性反应，减少伊立替康或 SN-38导致的腹泻，减少因腹泻导致的肠功能障碍出现的饮食量下降，增加肿瘤患者的体质，提高肿瘤患者耐受伊立替康或SN-38的使用剂量，延长肿瘤患者使用伊立替康或SN-38 的时间。Clinical anti-HIV protease inhibitor (protease inhibitor) Saquinavir mesylate (Saquinavir mesylate, Invirase) is a highly efficient and highly selective HIV protease inhibitor, acting on the late stage of HIV reproduction, and HIV protease Combining with the activation point of the anti-HIV protease inhibitor Saquigravir to lose the function of binding and hydrolyzing the broken polypeptide, it can be used in combination with other drugs to treat severe HIV infection, increase the CD4 count, and reduce the total amount of HIV in the blood, but the anti-HIV protease inhibitor Saquigravir alone or The composition of saquigravir and ritonavir is used in combination with the antineoplastic drug irinotecan or its active metabolite 7-ethyl-10 hydroxycamptothecin (SN-38), to prevent or treat the reduction of irinotecan or The toxic reaction of SN-38 can reduce the diarrhea caused by irinotecan or SN-38, reduce the decrease in diet due to intestinal dysfunction caused by diarrhea, increase the physical fitness of tumor patients, and improve the tolerance of tumor patients to irinotecan or SN-38. The dose of 38 and the effect of prolonging the time of using irinotecan or SN-38 in cancer patients have not been reported. The inventor found through a large number of studies that the anti-HIV protease inhibitor saquigravir combined with the anti-tumor drug irinotecan or SN-38 can significantly reduce the toxicity of irinotecan or SN-38, and inhibit the anti-tumor drug irinotecan. Diarrhea caused by rinotecan or SN-38, reduce intestinal dysfunction caused by diarrhea, increase food intake, improve the physique of tumor patients, improve the tolerance of tumor patients to the dose of irinotecan or SN-38, and prolong the use of irinotecan in tumor patients time for rinotecan or SN-38. Based on this, the inventors have invented the anti-HIV protease inhibitor saquigravir alone or the combination of saquigravir and ritonavir combined with irinotecan or SN-38 to reduce irinotecan or SN-38. 38 toxicity, reduce the diarrhea caused by irinotecan or SN-38, reduce the decrease in diet due to intestinal dysfunction caused by diarrhea, increase the physique of tumor patients, and improve the tolerance of tumor patients to irinotecan or SN-38 Use dosage to prolong the time of using irinotecan or SN-38 in tumor patients.
发明内容Contents of the invention
本发明提供了抗HIV蛋白酶抑制剂沙奎拉韦单用或沙奎拉韦和利托那韦的组合物与抗肿瘤药物伊立替康或SN-38联合使用，减少伊立替康或SN-38的毒性反应，即减少伊立替康或 SN-38导致的腹泻，减少因腹泻导致的肠功能障碍，增加肿瘤患者对伊立替康或SN-38的耐受，延长肿瘤患者使用伊立替康或SN-38的时间，增加伊立替康或SN-38的使用剂量。The present invention provides anti-HIV protease inhibitor saquigravir alone or the composition of saquigravir and ritonavir combined with antineoplastic drug irinotecan or SN-38, reducing irinotecan or SN-38 Toxic reactions, that is, reduce diarrhea caused by irinotecan or SN-38, reduce intestinal dysfunction caused by diarrhea, increase the tolerance of tumor patients to irinotecan or SN-38, and prolong the use of irinotecan or SN-38 in tumor patients -38, increase the dose of irinotecan or SN-38.
本发明提供的沙奎拉韦的使用剂量范围是120mg～6000mg，优选120mg～3000mg。The dosage range of saquigravir provided by the present invention is 120mg-6000mg, preferably 120mg-3000mg.
具体实施例specific embodiment
实验例1抗HIV蛋白酶抑制剂沙奎拉韦对伊立替康用药导致的毒性的影响Experimental Example 1 Effect of Anti-HIV Protease Inhibitor Saquigravir on the Toxicity Caused by Irinotecan Administration
1.1药品与试剂1.1 Drugs and reagents
甲磺酸沙奎拉韦(纯度99.5％，购买于上海翰香生物科技有限公司)Saquigravir mesylate (purity 99.5%, purchased from Shanghai Hanxiang Biotechnology Co., Ltd.)
利托那韦(纯度99.4％，购买于上海翰香生物科技有限公司)Ritonavir (purity 99.4%, purchased from Shanghai Hanxiang Biotechnology Co., Ltd.)
盐酸伊立替康(纯度99.5％，购买于上海翰香生物科技有限公司)Irinotecan hydrochloride (purity 99.5%, purchased from Shanghai Hanxiang Biotechnology Co., Ltd.)
实验动物：SPF级C57小鼠，雄性，体重20g-22g，北京维通利华实验动物技术有限公司实验动物中心提供，动物合格证号为：SCXK(京)2012-0001。Experimental animals: SPF grade C57 mice, male, weighing 20g-22g, provided by the Experimental Animal Center of Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., the animal qualification certificate number is: SCXK (Beijing) 2012-0001.
1.2实验方法与结果1.2 Experimental methods and results
1.2.1伊立替康连续用药导致的毒性模型小鼠制备、分组及给药1.2.1 Preparation, grouping and administration of toxicity model mice caused by continuous administration of irinotecan
雄性小鼠70只，体重20-22g，取70只，分为7组，即正常组，伊立替康组，伊立替康 +沙奎拉韦24mg/kg组，伊立替康+沙奎拉韦60mg/kg组，伊立替康+沙奎拉韦60mg/kg+利托那韦10mg/kg、伊立替康+沙奎拉韦600mg/kg组，伊立替康+沙奎拉韦1200mg/kg组，每只小鼠腹腔注射伊立替康50mg/kg，各沙奎拉韦组在给予伊立替康50mg/kg同时给予相应剂量的沙奎拉韦。伊立替康连续腹腔注射4天，各沙奎拉韦组连续给药5天，计算给药期间体重与摄食量，统计伊立替康致小鼠迟发性腹泻的评分，评价量表如下:大便正常:0分；大便稀软：1分；湿的和未成形的大便，有moderateperianal的包衣着色：2分；水样，水样伴肛周严重的着色：3分，计算造模5天的平均分数。比较伊立替康组与伊立替康+沙奎拉韦各组的差异，组间进行T检验。70 male mice, weighing 20-22g, were taken and divided into 7 groups, namely normal group, irinotecan group, irinotecan + saquigravir 24mg/kg group, irinotecan + saquigravir 60mg/kg group, irinotecan+saquigravir 60mg/kg+ritonavir 10mg/kg, irinotecan+saquigravir 600mg/kg group, irinotecan+saquigravir 1200mg/kg group, Each mouse was intraperitoneally injected with irinotecan 50 mg/kg, and each saquigravir group was administered with irinotecan 50 mg/kg and a corresponding dose of saquigravir at the same time. Continuous intraperitoneal injection of irinotecan for 4 days, continuous administration of each saquigravir group for 5 days, calculation of body weight and food intake during administration, statistics of irinotecan-induced delayed diarrhea scores in mice, evaluation scale is as follows: stool Normal: 0 points; Loose and soft stools: 1 point; Wet and unformed stools, with moderateperianal coating and coloring: 2 points; Watery samples, watery samples with severe perianal coloring: 3 points, calculated for 5 days after modeling average score. The differences between the irinotecan group and the irinotecan + saquigravir groups were compared, and the T test was performed between the groups.
1.2.2实验结果1.2.2 Experimental results
表1和表2结果显示伊立替康腹腔注射50mg/kg，连续注射4天，可明显减轻模型小鼠的体重、摄食量，增加5天平均腹泻分数(与正常组比较，p<0.01)；伊立替康+沙奎拉韦24mg/kg灌胃给药组、伊立替康+沙奎拉韦60mg/kg灌胃给药组、伊立替康+沙奎拉韦60mg/kg+利托那韦10mg/kg、伊立替康+沙奎拉韦600mg/kg灌胃给药组、伊立替康+沙奎拉韦1200 mg/kg灌胃给药组明显增加模型小鼠的体重、摄食量，降低5天平均腹泻分数(与伊立替康组比较，p<0.5或p<0.01)。伊立替康+沙奎拉韦600mg/kg灌胃给药组与伊立替康+沙奎拉韦1200mg/kg灌胃给药组比较，无明显增加模型小鼠的体重、摄食量，降低5天平均腹泻分数(p>0.05)。The results in Table 1 and Table 2 show that irinotecan intraperitoneal injection of 50mg/kg, continuous injection for 4 days, can significantly reduce the body weight and food intake of model mice, and increase the average diarrhea score in 5 days (compared with the normal group, p<0.01); Irinotecan + saquigravir 24mg/kg intragastric administration group, irinotecan + saquigravir 60mg/kg intragastric administration group, irinotecan + saquigravir 60mg/kg + ritonavir 10mg /kg, irinotecan+saquigravir 600mg/kg intragastric administration group, irinotecan+saquigravir 1200 mg/kg intragastric administration group significantly increased the body weight and food intake of model mice, and decreased by 5 Daily average diarrhea score (p<0.5 or p<0.01 compared with irinotecan group). Compared with the irinotecan + saquigravir 1200mg/kg intragastric administration group, the irinotecan + saquigravir 600mg/kg intragastric administration group did not significantly increase the body weight and food intake of the model mice, and decreased for 5 days Mean diarrhea score (p>0.05).
表1沙奎拉韦对伊立替康连续用药导致的毒性模型小鼠体重和摄食量的影响Table 1 Effect of saquigravir on body weight and food intake of toxicity model mice caused by continuous administration of irinotecan
#，p<0.01，与正常组比较；*，p<0.05，**，p<0.01，与伊立替康组比较# , p<0.01, compared with normal group;* , p<0.05,** , p<0.01, compared with irinotecan group
表2沙奎拉韦对伊立替康连续用药导致的毒性模型小鼠腹泻评分的影响Table 2 The effect of saquigravir on the diarrhea score of toxicity model mice caused by continuous administration of irinotecan
#，p<0.01，与正常组比较；*，p<0.05，**，p<0.01，与伊立替康组比较# , p<0.01, compared with normal group;* , p<0.05,** , p<0.01, compared with irinotecan group
实验例2抗HIV蛋白酶抑制剂沙奎拉韦对伊立替康用药的荷瘤裸鼠生存期影响Experimental example 2 Effect of anti-HIV protease inhibitor saquigravir on the survival period of tumor-bearing nude mice treated with irinotecan
2.1药品与试剂2.1 Drugs and reagents
甲磺酸沙奎拉韦(纯度99.5％，购买于上海翰香生物科技有限公司)Saquigravir mesylate (purity 99.5%, purchased from Shanghai Hanxiang Biotechnology Co., Ltd.)
利托那韦(纯度99.4％，购买于上海翰香生物科技有限公司)Ritonavir (purity 99.4%, purchased from Shanghai Hanxiang Biotechnology Co., Ltd.)
盐酸伊立替康(纯度99.5％，购买于上海翰香生物科技有限公司)Irinotecan hydrochloride (purity 99.5%, purchased from Shanghai Hanxiang Biotechnology Co., Ltd.)
实验动物：BALB/c裸鼠SPF级，雄性，体重20g-22g，北京维通利华实验动物技术有限公司实验动物中心提供，动物合格证号为：SCXK(京)2012-0001。Experimental animals: BALB/c nude mice SPF grade, male, weighing 20g-22g, provided by the Experimental Animal Center of Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., the animal qualification certificate number is: SCXK (Beijing) 2012-0001.
2.2实验方法与结果2.2 Experimental methods and results
2.2.1伊立替康连续用药的荷瘤裸鼠分组及给药2.2.1 Grouping and administration of tumor-bearing nude mice with continuous administration of irinotecan
荷瘤裸鼠70只，体重20-22g，取70只，分为7组，即正常组，伊立替康组，伊立替康 +沙奎拉韦24mg/kg组，伊立替康+沙奎拉韦60mg/kg组，伊立替康+沙奎拉韦60mg/kg+利托那韦10mg/kg，伊立替康+沙奎拉韦600mg/kg组，伊立替康+沙奎拉韦1200mg/kg组，除正常组动物外，各组小鼠均腹腔注射伊立替康60mg/kg，各沙奎拉韦组在给予伊立替康60 mg/kg同时给予相应剂量的沙奎拉韦。伊立替康连续腹腔注射4天，各沙奎拉韦组连续给药7 天，计算动物存活时间，7天结束时，动物未死亡，记为144小时。比较伊立替康组与伊立替康+沙奎拉韦各组的动物存活时间差异。组间进行T检验。70 tumor-bearing nude mice, weighing 20-22g, were taken and divided into 7 groups, namely the normal group, irinotecan group, irinotecan+saquigravir 24mg/kg group, irinotecan+saquilavir group Wei 60mg/kg group, irinotecan+saquigravir 60mg/kg+ritonavir 10mg/kg, irinotecan+saquigravir 600mg/kg group, irinotecan+saquigravir 1200mg/kg group In addition to the normal group of animals, mice in each group were intraperitoneally injected with irinotecan 60 mg/kg, and each saquigravir group was administered with irinotecan 60 mg/kg and a corresponding dose of saquigravir at the same time. Irinotecan was injected intraperitoneally for 4 consecutive days, and each saquigravir group was administered continuously for 7 days, and the survival time of the animals was calculated. At the end of the 7 days, if the animals did not die, it was recorded as 144 hours. The differences in the survival time of animals in the irinotecan group and the irinotecan+saquigravir groups were compared. T test was performed between groups.
2.2.2实验结果2.2.2 Experimental results
表3结果显示伊立替康腹腔注射60mg/kg，连续注射4天，可明显增加动物死亡，减少存活时间(与正常组比较，p<0.01)；伊立替康+沙奎拉韦24mg/kg灌胃给药组、伊立替康+沙奎拉韦60mg/kg灌胃给药组、伊立替康+沙奎拉韦60mg/kg+利托那韦10mg/kg灌胃给药组、伊立替康+沙奎拉韦600mg/kg灌胃给药组、伊立替康+沙奎拉韦1200mg/kg灌胃给药组明显减少动物死亡，增加存活时间(与伊立替康组比较，p<0.5或p<0.01)，伊立替康+沙奎拉韦300mg/kg灌胃给药组、伊立替康+沙奎拉韦600mg/kg灌胃给药组无动物死亡。Table 3 results show that irinotecan intraperitoneal injection 60mg/kg, continuous injection 4 days, can obviously increase animal death, reduces survival time (compared with normal group, p<0.01); Stomach administration group, irinotecan+saquigravir 60mg/kg intragastric administration group, irinotecan+saquigravir 60mg/kg+ritonavir 10mg/kg intragastric administration group, irinotecan+ Saquigravir 600mg/kg intragastric administration group, irinotecan+saquigravir 1200mg/kg intragastric administration group significantly reduced animal death and increased survival time (compared with irinotecan group, p<0.5 or p <0.01), irinotecan+saquigravir 300mg/kg intragastric administration group, irinotecan+saquigravir 600mg/kg intragastric administration group had no animal death.
表3沙奎拉韦对伊立替康连续用药的荷瘤裸鼠存活时间影响Table 3 Effect of saquigravir on the survival time of tumor-bearing nude mice with continuous administration of irinotecan
#，p<0.01，与正常组比较；*，p<0.05，**，p<0.01，与伊立替康组比较。# , p<0.01, compared with normal group;* , p<0.05,** , p<0.01, compared with irinotecan group.
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| CN201710719424.7ACN107281462A (en) | 2017-08-21 | 2017-08-21 | Sha Kuilawei mitigates the new medical use of toxicity of irinotecan |
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| CN201710719424.7ACN107281462A (en) | 2017-08-21 | 2017-08-21 | Sha Kuilawei mitigates the new medical use of toxicity of irinotecan |
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| CN (1) | CN107281462A (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325305A (en)* | 1998-06-18 | 2001-12-05 | 乔治华盛顿大学 | Method of administering camptothecin compounds for the treatment of cancer with reduced side effects |
| CN1909919A (en)* | 2004-01-19 | 2007-02-07 | 瑞泰克公司 | Composition for the treatment of digestive pathologies |
| CN102131501A (en)* | 2008-08-01 | 2011-07-20 | 加尼尔免疫治疗公司 | Antitumor properties of no modified protease inhibitors |
| CN105797132A (en)* | 2016-05-03 | 2016-07-27 | 滨州医学院 | New application of saquinavir to medicines |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325305A (en)* | 1998-06-18 | 2001-12-05 | 乔治华盛顿大学 | Method of administering camptothecin compounds for the treatment of cancer with reduced side effects |
| CN1909919A (en)* | 2004-01-19 | 2007-02-07 | 瑞泰克公司 | Composition for the treatment of digestive pathologies |
| CN102131501A (en)* | 2008-08-01 | 2011-07-20 | 加尼尔免疫治疗公司 | Antitumor properties of no modified protease inhibitors |
| CN105797132A (en)* | 2016-05-03 | 2016-07-27 | 滨州医学院 | New application of saquinavir to medicines |
| Title |
|---|
| 杨雷等: "伊立替康致迟发性腹泻的机制和治疗进展", 《中国医药导报》* |
| Publication | Publication Date | Title |
|---|---|---|
| WO2004045617A1 (en) | Combination chemotherapy comprising a mek inhibitor and capecitabine for treating cancer | |
| CN109985237B (en) | Pharmaceutical composition for treating colorectal cancer and application thereof | |
| TW201513864A (en) | Antitumor agent containing low dose of irinotecan hydrochloride hydrate | |
| JP2016505050A5 (en) | ||
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| Date | Code | Title | Description |
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| PB01 | Publication | ||
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| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | Application publication date:20171024 |