CN107375287B - 一种硫酸阿托品在制备治疗原发性肝癌药物中的用途 - Google Patents
一种硫酸阿托品在制备治疗原发性肝癌药物中的用途 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明提供了一种硫酸阿托品在制备治疗原发性肝癌药物中的用途，静脉应用维拉帕米达不到有效逆转肿瘤细胞耐药浓度，且具有心脏毒性。阿托品通过解除解除迷走神经对心脏的抑制，使心跳加快，缓解维拉帕米使用可能导致的心律失常，从而最终提高了维拉帕米联合化疗药物治疗原发性肝癌的治疗疗效。
Description
技术领域
本发明涉及硫酸阿托品在制备治疗原发性肝癌药物中的用途。
背景技术
维拉帕米(Verapamil)是一种临床广泛用于心脏疾患的钙离子通道阻滞剂，具有逆转肿瘤细胞MDR(多药耐药)的作用，维拉帕米体外有效逆转肿瘤MDR的浓度为6～10μmol/L(2.94～4.91μg/mL)，而其在外周静脉血中的浓度达到1～2μmol/L(0.49～0.98μg/mL)时就会出现严重心律失常、房室传导阻滞等，因此，静脉应用达不到有效逆转耐药浓度。
尽管早期在乳腺癌和卵巢癌的临床队列研究中证实维拉帕米可以抑制肿瘤化疗耐药性并延长患者生存时间，但是其心脏毒性风险阻碍了进一步深入的临床应用研究。
发明内容
本发明要解决的技术问题是静脉应用维拉帕米达不到有效逆转肿瘤细胞耐药浓度，且具有心脏毒性。本发明提供的技术方案是提供一种硫酸阿托品在制备治疗原发性肝癌药物中的用途。经过临床研究表明阿托品通过解除解除迷走神经对心脏的抑制，使心跳加快，缓解维拉帕米使用可能导致的心律失常，从而最终提高了维拉帕米联合化疗药物治疗原发性肝癌的治疗疗效。
本发明通过应用维拉帕米联合动脉化学栓塞疗法(transarterialchemoembolization，TACE)提高中晚期肝癌患者的化疗疗效，且未出现静脉应用的心脏毒性。但是，维拉帕米抗ABCB1作用的临床应用受到其心脏毒性的限制。体外实验证明，浓度为6～10mol/L(2.94～4.91g/mL)的维拉帕米可以完全抑制ABCB1活性并逆转肿瘤细胞耐药性。但是，维拉帕米血清浓度仅1～2mol/L时，其钙通道抑制作用即可产生心血管系统的不良反应，如低血压、心动过缓等。
本发明在前期临床研究中发现，使用经动脉化学栓塞疗法(transarterialchemoembolization，TACE)或经靶血管灌注给药的方式进行维拉帕米和标准化疗药物的联合治疗，可以在避免全身不良反应的同时，保证局部维拉帕米达到抑制ABCB1的阈值。本发明在犬类和人体的药物安全观察性实验中，使用TACE进行维拉帕米的肝定向给药，检测发现肝脏局部微环境的维拉帕米浓度是血液的3～10倍，远超过抑制ABCB1活性的临界值。利用这一策略，本发明率先完成了肝细胞癌(HCC)患者中维拉帕米抗耐药治疗效果的验证，有效率达到71.4％，患者肝功能较非维拉帕米联合治疗组恢复迅速，而且均未出现心血管毒性引发的不良反应，心电图和血压无显著变化。
阿托品(atropine)是从植物颠茄、洋金花或莨菪等提出的生物碱，也可人工合成。天然存在于植物中的左旋莨菪碱很不稳定；在提取过程中经化学处理得到稳定的消旋莨菪碱，即阿托品，其硫酸盐为无色结晶或白色结晶性粉末，易溶于水，是第3号抢救药。用于抢救感染中毒性休克、有机磷农药中毒、缓解内脏绞痛、麻醉前给药及减少支气管粘液分泌等治疗。药理作用为阻断M胆碱受体的抗胆碱药，能解除平滑肌的痉挛(包括解除血管痉挛，改善微血管循环)；抑制腺体分泌；解除迷走神经对心脏的抑制，使心跳加快；散大瞳孔，使眼压升高；兴奋呼吸中枢。
阿托品通过解除解除迷走神经对心脏的抑制，使心跳加快，从而缓解维拉帕米使用可能导致的心律失常。从而最终提高了维拉帕米联合化疗药物治疗原发性肝癌的治疗疗效。一方面通过针对心率低于正常的原发性肝癌患者，采用阿托品联合维拉帕米及化疗药物，提高了患者心率；另一方面针对心率正常的原发性肝癌患者，在阿托品使用前提下，提高维拉帕米使用剂量，从而提高了维拉帕米使用疗效。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本
发明而不用于限制本发明的范围。
1.病例选择
1.1纳入标准
所有患者均符合原发性肝癌的临床诊断标准(2001年中国抗癌协会肝癌专业委员会制定标准)；KPS评分≥70分；患者年龄18～70岁；心功能0～I级；肝功能CHILD分级B级或B级以上；预计生存期超过3月，Seldinger导管能进入恶性肿瘤供养动脉内的患者。所有患者均自愿接受应用此方案治疗，并签署知情同意书，且该研究获得了医院伦理委员会批准；
1.2排除标准
有外科手术指证者；有碘药物过敏史；孕妇及哺期妇女；精神病患者及智力发育不全者；急性感染、有中枢神经系统症状者；WBC<4.0×109/L、BPC<10.0×109/L、Hb<60g/L，凝血机制障碍者。
1.3剔除标准
未严格执行治疗方案；因严重不良反应被停药者的结果记录在不良反应的评价报告中；资料不全，无法进行不良反应评估和疗效评价者。
2研究方法
2.1临床病例
2004年10月至2014年5月入院患者100例，其中男性76例，女性24例，平均年龄48.8岁；每位患者介入治疗2个周期以上。治疗前通过化学发光法(CLIA)定量检测AFP，其中AFP＜20μg/L的患者为48例；20μg/L＜AFP≤200μg/L为45例；200μg/L＜AFP≤400μg/L为59例；AFP＞400μg/L为121例。
2.2治疗方法
每月介入治疗1次，每例介入治疗2次以上，介入治疗2次后判断疗效。所有病例均应用Seldinger技术穿刺股动脉，经原发性肝癌患者腹腔干动脉按要求选择维拉帕米、ADM、DDP和或5-Fu，腹腔干动脉灌注后选择性将导管进入肝右或肝左动脉用MMC+碘化油乳化栓塞。原发性肝癌术后复发患者常规行肠系膜上动脉造影了解复发灶血供是否来源于肠系膜上动脉。
灌注步骤：维拉帕米15mg，生理盐水(NS)30ml，阿霉素(ADM)40～50mg/m2，顺铂(DDP)30～50mg/m2和或氟尿嘧啶(5-Fu)500～600mg/m2，15min后维拉帕米10mg，每组原发性肝癌血供较好的患者按照病灶最大直径每厘米给予40％碘化油1ml与丝裂霉素(MMC)10～12mg乳化栓塞，阿托品使用剂量：皮下、肌内或静脉注射成人常用量：一次0.3～0.5mg，一日0.5～3mg；极量：一次2mg。
2.3观察内容
2.3.1一般项目
血常规、肝肾功能、AFP、心电图于治疗前、治疗后第30天各查一次，并做记录。治疗前、治疗后第30天查B超或CT，治疗60天后B超或CT检查。记录药物不良反应，症状体征变化和KPS评分。2周期后评估患者治疗临床受益判断，有无新病灶出现或原有病灶变化、Karnofsky评分、体重变化、AFP指标变化。维拉帕米灌注前、灌注中、灌注后5min监测心率、血压变化。术前、术后、术中全程监测动态心电图，术前、术后评价有无心功能变化。随访1年生存期。毒副反应按NCI-CTC抗癌药物毒副反应分级(0～IV)标准评价。心功能分级按照美国纽约心脏病学会(NYHA)标准[20]。肝功能评价按照Child-Pugh分级标准。
2.3.2病灶变化
2周期后评价：临床治愈或明显好转：肿块消失或缩小75％以上，碘油均匀聚积，肿瘤血管完全闭塞或肿瘤边缘仅残留少许肿瘤血管或肿瘤染色。好转：肿块缩小30％～75％左右，碘油不均匀聚积，碘油充填面积达肿块面积的1/2以上，肿瘤血管明显减少。稳定：肿块缩小不足肿块的30％，碘油呈斑片絮状聚积，碘油充填面积不足肿块的1/2，肿瘤血管无明显减少。进展或恶化：肿块增大，碘油呈散在斑点状聚积或无明显碘油聚积，碘油聚积面积不足肿块面积的1/3，肿瘤血管明显增多，形成新的肝动脉门静脉瘘或肝动脉肝静脉瘘。
2.3.3疗效判断
第2个疗程后的1个月根据CT或B超检查，AFP定量测定等结果判断疗效。记录AFP指标变化、Karnofsky评分、体重变化和1年生存期。
2.3.4治疗效果测试：
针对心率低于正常的原发性肝癌患者，使用阿托品联合维拉帕米及化疗药物，治疗前心率50.75±4.349*，治疗后心率84.75±6.801，两者比较有明显差异(*p﹤0.05)。如表1所示：
表1，心率低于正常的原发性肝癌患者，阿托品使用前后HCC患者心率变化情况
| 心率 | |
| 阿托品使用前 | 50.75±4.349<sup>*</sup> |
| 阿托品使用后 | 84.75±6.801 |
*p﹤0.05有显著性差异
针对心率正常的原发性肝癌患者，在阿托品使用前提下，提高维拉帕米使用剂量，使用前后，心率无明显变化(p＞0.05)。如表2所示：
表2，不同维拉帕米使用剂量，阿托品使用前后HCC患者心率变化情况
p＞0.05无显著性差异
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。
Claims (1)
1.一种硫酸阿托品在制备通过缓解维拉帕米导致的心律失常从而提高维拉帕米联合化疗药物治疗原发性肝癌的疗效的药物中的用途。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001010405A1 (en) * | 1999-08-04 | 2001-02-15 | Ranbaxy Laboratories Limited | Hydrodynamically balanced oral drug delivery system |
| CN1418621A (zh) * | 2002-12-19 | 2003-05-21 | 王登之 | 治疗心律失常的维拉帕米口腔崩解片及其制备方法 |
| CN1630513A (zh) * | 2002-02-04 | 2005-06-22 | 兰贝克赛实验室有限公司 | 流体动力平衡的以两相释放的口服药物输递系统 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001010405A1 (en) * | 1999-08-04 | 2001-02-15 | Ranbaxy Laboratories Limited | Hydrodynamically balanced oral drug delivery system |
| CN1630513A (zh) * | 2002-02-04 | 2005-06-22 | 兰贝克赛实验室有限公司 | 流体动力平衡的以两相释放的口服药物输递系统 |
| CN1418621A (zh) * | 2002-12-19 | 2003-05-21 | 王登之 | 治疗心律失常的维拉帕米口腔崩解片及其制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| 经动脉灌注碳酸氢钠和维拉帕米提高抗肿瘤药物疗效的初步观察;范平生等;《中国肿瘤临床与康复》;20021231;第9卷(第4期);第18-20页 * |
| 维拉帕米致心律失常30例临床分析;柯军等;《中国综合临床》;20040630;第20卷(第6期);第496-497页 * |
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