癌痛平胶囊治疗癌痛的临床研究及机制探讨
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摘要
目的：在中医理论指导下,结合导师临床经验,对癌痛的中医理论进行探讨,阐明癌痛的病因病机、病理性质及治疗大法,为癌痛平胶囊的研制提供中医理论依据。通过对癌痛平胶囊的临床观察及疼痛机制的实验研究,探讨中医治疗癌痛的优势。
方法：1、理论研究：检索历代文献,通过整理分析,阐述中医学、现代医学对癌性疼痛的认识,根据中医理论和导师临床经验,对癌性疼痛的中医理论进行探讨。
2、临床研究：将符合入组标准的病例随机分为癌痛平胶囊治疗组和单用阿片类药物组进行治疗,观察两组病人的肿瘤客观疗效、疾病进展时间、生活质量评分、强阿片类药物使用剂量及副反应。
3、实验研究：观察癌痛平胶囊对福尔马林致痛大鼠下丘脑、垂体、腰髓NO、β-EP的影响及对H22移植瘤小鼠的体重、瘤重、肿瘤细胞凋亡、肿瘤VEGF的测定及CXCL12-CXCR4生物轴的影响,探讨癌痛平胶囊治疗癌痛的机制。
结果：1、理论研究：癌性疼痛的病因主要包括六淫邪毒、七情内伤、正气亏虚、痰浊为患、瘀血内停、癌毒流串,病因病机的关键是癌毒弥散,阻滞气血经络,病理因素有寒、痰、瘀、毒,其中以癌毒为关键因素,病理性质总属于本虚标实,以标实为主。病变部位不定,牵涉脏腑以肺、肝、肾三脏为主,癌痛早期主要以肺、肝为主,晚期涉及于肾。治疗癌痛的方法是消癌解毒、化痰祛瘀、通络止痛。
2、临床研究：在原发肿瘤病灶的控制上,治疗组的稳定率为82.5%,而对照组为50%,治疗组的稳定率高于对照组,经统计学处理,两组差别具有显著性(P<0.01),显示了癌痛平胶囊能够控制肿瘤的生长速度,具有抗肿瘤作用。治疗组的TTP为55.80±21.38天,对照组为45.38±23.07天,治疗组长于对照组,两组比较有统计学意义(P<0.05)。两组病人同时使用强阿片类药物控制癌痛时,联合癌痛平胶囊治疗的疼痛患者的强阿片类药物使用量明显低于单独使用强阿片类药物患者的使用量,相关的副反应也出现的较少,患者的生活质量也较高。通过相应的癌痛治疗后,无论治疗组还是对照组,患者的生活质量均有较大幅度的提高,与治疗前相比有统计学意义。但是相对于对照组,治疗组提高的更为明显,有显著差异(P<0.01)。同时,患者在口服弱阿片类止痛药物时,出现便秘症状的发生率较高,而在治疗组的发生率很低,两者相比有显著差异(P<0.01)。
3、实验研究：实验结果显示,癌痛平胶囊能明显降低福尔马林致痛大鼠下丘脑、垂体、腰髓N0的含量；明显提高福尔马林致痛大鼠下丘脑、垂体、腰髓β-内啡肽的含量；癌痛平胶囊18g/kg和36g/kg剂量能够显著的抑制荷瘤小鼠的生长,抑制率分别为31.3%和55.3%,具有很好的抗肿瘤效果。癌痛平18g/kg和36g/kg能够明显诱导H22肝癌细胞的凋亡,且36g/kg癌痛平能够显著抑制VEGF的表达,降低肿瘤的血管生成。并且36g/kg癌痛平显著降低CXCR4的表达,降低肿瘤细胞的转移能力。
结论：癌痛平胶囊是在中医理论指导下研制的治疗癌性疼痛的中药复方新制剂,与对照相比,治疗组在控制癌痛的同时,还能够稳定瘤体；延长患者的疾病进展时间；和强阿片类药物联合应用时,能减少患者的强阿片类类药物使用量及其副反应,这些均可使晚期癌痛患者获得较好的生活质量和较长的生存期。癌痛平胶囊的中枢镇痛作用机理可能主要是通过影响中枢系统的神经递质,抑制伤害性信息的传导和痛觉产生；癌痛平胶囊抗肿瘤机制是多途径、多靶点的,癌痛平胶囊临床良好的的疼痛控制与癌痛平的抗肿瘤机制有关。
[Objective]:Under the guidance of traditional Chinese medical (TCM) theory combined with instructor's clinical experience, this article not only explores deeply TCM theory of cancerous pain, clarifies its etiology and pathogenesis, pathological nature and main therapeutic method, but also provides reliable TCM theoretical basis for development of Aitongping (ATP) Capsule. According to clinical observation of ATP capsule and experimental study of its anti-tumor mechanism, the advantages of Chinese medicine in treating cancerous pain will be explored.
[Methods]:1.Theoretical Study:By retrieval of medical literature of past ages and collating and analyzing large data-sets, deeply understanding of cancerous pain in TCM and modern medicine will be illustrated in this article, and TCM theory of cancerous pain will also be explored according to TCM theory and mentor's clinical experience.
2.Clinical Research:Eighty cancer patients were randomly divided into two groups,40patients in the treatedgroup took ATP capsule and40patients in the control group。The relevant clinical conditions of cancerous pain, tumor lesions,TTP, QOL,Daily morphine consumption and adverse reactions.
3.The Experimental Study:The mechanism of analgesic effect of ATP capsule. the effect of ATP capsule on β-EP and NO in hypothalamus;Determine the weight of H22xenografted mice and also the tumor weight, observe tumor cell apoptosis, VEGF expression and the impact of CXCL12-of CXCR4biological axis by electron microscope, and explore the possible anti-tumor mechanism of ATP capsule.
[Results]:1.Theoretical Study:The chief cause of cancerous pain included the six climate exopathogens, internal damage by excess of seven emotions, deficiency of vital Qi, turbid phlegm stagnation, inner blood stasis and spread of cancer toxin, the key point of etiology and pathogenesis is the blockage of Qi and blood and channels by dispersion of cancer toxin, pathological factors include cold, phlegm, blood stasis and cancer toxin, in which the cancer toxin is the key one, the pathological nature attributes to deficiency of Ben and repletion of Biao, and the excessiveness in Biao is more important. Indeterminate lesion location involves Fu organs like lung, liver and kidney, cancerous pain occurs early in lung and liver, and kidney in the late stage. The method of treatment of cancerous pain involves eliminating cancer toxin, removing phlegm and blood stasis, and dredging collaterals and relieving pain.
2.Clinical Research:In the control of the primary tumor lesion, the stability ratio of treatment group was82.5%, but control group50%,which was lower than the treatment group, and the difference was significant (P<0.01). TTP of treatment group was55.80±21.38days (control group45.38±23.07days), which was longer than control group, the difference was statistically significant (P<0.05). The two groups of patients used morphine hydrochloride sustained release tablets meanwhile, the group used morphine combined with ATP capsule had less morphine dosage, fewer morphine-related side effects and higher quality of life than the group used morphine alone to control pain. Through appropriate treatment of cancerous pain, the quality of life of both treatment group and control group dramatically increased compared with before with significant statistically difference. But compared with control group, treatment group improved more significantly (P<0.01). simultaneously, patients with oral administration of weak opioid analgesics had higher incidence of constipation symptoms, but lower in the treatment group, the difference was also significant (P <0.01).
3.Experimental Research:ATP capsule exerts central analgesic effect by inhibiting the release of NO in central nervous system and increasing the content of β-endorphin in central nervous system. ATP capsule at the dosage of18g/kg and36g/kg can significantly inhibit the growth of the tumor-bearing mice, the inhibition ratio were31.3%and55.3%respectively, which showed good anti-tumor effect. ATP capsule at the dosage of18g/kg and36g/kg could obviously induce the apoptosis of hepatocarcinoma H22tumor cells, the dosage of36g/kg can significantly inhibit the expression of VEGF, reduce tumor angiogenesis and the expression of CXCR4, and lessen the metastatic ability of tumor cells.
[Conclusion]:ATP capsule was a new formulation of traditional Chinese medicine in treating cancerous pain developed with the guidance of TCM theory. Compared with control group, the treatment group could control cancerous pain, stabilize the tumor, and also prolong TTP of patients. ATP capsule in combination with morphine therapy can reduce the usage and the side effects of morphine, which insured the advanced stage patients better quality of life and longer survival period. The study shows that Ai Tong Ping capsule may treat cancerous pain by affecting the transmission of nociceptive stimulation and pain sensation in central nervous system. Anti-tumor mechanism of Aitongping capsule is a multi-channel, multi-target, the anti-tumor mechanism of ATP capsule was multi-way and multi-target, whose good pain control ability was associated with its anti-tumor mechanism.
方法：1、理论研究：检索历代文献,通过整理分析,阐述中医学、现代医学对癌性疼痛的认识,根据中医理论和导师临床经验,对癌性疼痛的中医理论进行探讨。
2、临床研究：将符合入组标准的病例随机分为癌痛平胶囊治疗组和单用阿片类药物组进行治疗,观察两组病人的肿瘤客观疗效、疾病进展时间、生活质量评分、强阿片类药物使用剂量及副反应。
3、实验研究：观察癌痛平胶囊对福尔马林致痛大鼠下丘脑、垂体、腰髓NO、β-EP的影响及对H22移植瘤小鼠的体重、瘤重、肿瘤细胞凋亡、肿瘤VEGF的测定及CXCL12-CXCR4生物轴的影响,探讨癌痛平胶囊治疗癌痛的机制。
结果：1、理论研究：癌性疼痛的病因主要包括六淫邪毒、七情内伤、正气亏虚、痰浊为患、瘀血内停、癌毒流串,病因病机的关键是癌毒弥散,阻滞气血经络,病理因素有寒、痰、瘀、毒,其中以癌毒为关键因素,病理性质总属于本虚标实,以标实为主。病变部位不定,牵涉脏腑以肺、肝、肾三脏为主,癌痛早期主要以肺、肝为主,晚期涉及于肾。治疗癌痛的方法是消癌解毒、化痰祛瘀、通络止痛。
2、临床研究：在原发肿瘤病灶的控制上,治疗组的稳定率为82.5%,而对照组为50%,治疗组的稳定率高于对照组,经统计学处理,两组差别具有显著性(P<0.01),显示了癌痛平胶囊能够控制肿瘤的生长速度,具有抗肿瘤作用。治疗组的TTP为55.80±21.38天,对照组为45.38±23.07天,治疗组长于对照组,两组比较有统计学意义(P<0.05)。两组病人同时使用强阿片类药物控制癌痛时,联合癌痛平胶囊治疗的疼痛患者的强阿片类药物使用量明显低于单独使用强阿片类药物患者的使用量,相关的副反应也出现的较少,患者的生活质量也较高。通过相应的癌痛治疗后,无论治疗组还是对照组,患者的生活质量均有较大幅度的提高,与治疗前相比有统计学意义。但是相对于对照组,治疗组提高的更为明显,有显著差异(P<0.01)。同时,患者在口服弱阿片类止痛药物时,出现便秘症状的发生率较高,而在治疗组的发生率很低,两者相比有显著差异(P<0.01)。
3、实验研究：实验结果显示,癌痛平胶囊能明显降低福尔马林致痛大鼠下丘脑、垂体、腰髓N0的含量；明显提高福尔马林致痛大鼠下丘脑、垂体、腰髓β-内啡肽的含量；癌痛平胶囊18g/kg和36g/kg剂量能够显著的抑制荷瘤小鼠的生长,抑制率分别为31.3%和55.3%,具有很好的抗肿瘤效果。癌痛平18g/kg和36g/kg能够明显诱导H22肝癌细胞的凋亡,且36g/kg癌痛平能够显著抑制VEGF的表达,降低肿瘤的血管生成。并且36g/kg癌痛平显著降低CXCR4的表达,降低肿瘤细胞的转移能力。
结论：癌痛平胶囊是在中医理论指导下研制的治疗癌性疼痛的中药复方新制剂,与对照相比,治疗组在控制癌痛的同时,还能够稳定瘤体；延长患者的疾病进展时间；和强阿片类药物联合应用时,能减少患者的强阿片类类药物使用量及其副反应,这些均可使晚期癌痛患者获得较好的生活质量和较长的生存期。癌痛平胶囊的中枢镇痛作用机理可能主要是通过影响中枢系统的神经递质,抑制伤害性信息的传导和痛觉产生；癌痛平胶囊抗肿瘤机制是多途径、多靶点的,癌痛平胶囊临床良好的的疼痛控制与癌痛平的抗肿瘤机制有关。
[Objective]:Under the guidance of traditional Chinese medical (TCM) theory combined with instructor's clinical experience, this article not only explores deeply TCM theory of cancerous pain, clarifies its etiology and pathogenesis, pathological nature and main therapeutic method, but also provides reliable TCM theoretical basis for development of Aitongping (ATP) Capsule. According to clinical observation of ATP capsule and experimental study of its anti-tumor mechanism, the advantages of Chinese medicine in treating cancerous pain will be explored.
[Methods]:1.Theoretical Study:By retrieval of medical literature of past ages and collating and analyzing large data-sets, deeply understanding of cancerous pain in TCM and modern medicine will be illustrated in this article, and TCM theory of cancerous pain will also be explored according to TCM theory and mentor's clinical experience.
2.Clinical Research:Eighty cancer patients were randomly divided into two groups,40patients in the treatedgroup took ATP capsule and40patients in the control group。The relevant clinical conditions of cancerous pain, tumor lesions,TTP, QOL,Daily morphine consumption and adverse reactions.
3.The Experimental Study:The mechanism of analgesic effect of ATP capsule. the effect of ATP capsule on β-EP and NO in hypothalamus;Determine the weight of H22xenografted mice and also the tumor weight, observe tumor cell apoptosis, VEGF expression and the impact of CXCL12-of CXCR4biological axis by electron microscope, and explore the possible anti-tumor mechanism of ATP capsule.
[Results]:1.Theoretical Study:The chief cause of cancerous pain included the six climate exopathogens, internal damage by excess of seven emotions, deficiency of vital Qi, turbid phlegm stagnation, inner blood stasis and spread of cancer toxin, the key point of etiology and pathogenesis is the blockage of Qi and blood and channels by dispersion of cancer toxin, pathological factors include cold, phlegm, blood stasis and cancer toxin, in which the cancer toxin is the key one, the pathological nature attributes to deficiency of Ben and repletion of Biao, and the excessiveness in Biao is more important. Indeterminate lesion location involves Fu organs like lung, liver and kidney, cancerous pain occurs early in lung and liver, and kidney in the late stage. The method of treatment of cancerous pain involves eliminating cancer toxin, removing phlegm and blood stasis, and dredging collaterals and relieving pain.
2.Clinical Research:In the control of the primary tumor lesion, the stability ratio of treatment group was82.5%, but control group50%,which was lower than the treatment group, and the difference was significant (P<0.01). TTP of treatment group was55.80±21.38days (control group45.38±23.07days), which was longer than control group, the difference was statistically significant (P<0.05). The two groups of patients used morphine hydrochloride sustained release tablets meanwhile, the group used morphine combined with ATP capsule had less morphine dosage, fewer morphine-related side effects and higher quality of life than the group used morphine alone to control pain. Through appropriate treatment of cancerous pain, the quality of life of both treatment group and control group dramatically increased compared with before with significant statistically difference. But compared with control group, treatment group improved more significantly (P<0.01). simultaneously, patients with oral administration of weak opioid analgesics had higher incidence of constipation symptoms, but lower in the treatment group, the difference was also significant (P <0.01).
3.Experimental Research:ATP capsule exerts central analgesic effect by inhibiting the release of NO in central nervous system and increasing the content of β-endorphin in central nervous system. ATP capsule at the dosage of18g/kg and36g/kg can significantly inhibit the growth of the tumor-bearing mice, the inhibition ratio were31.3%and55.3%respectively, which showed good anti-tumor effect. ATP capsule at the dosage of18g/kg and36g/kg could obviously induce the apoptosis of hepatocarcinoma H22tumor cells, the dosage of36g/kg can significantly inhibit the expression of VEGF, reduce tumor angiogenesis and the expression of CXCR4, and lessen the metastatic ability of tumor cells.
[Conclusion]:ATP capsule was a new formulation of traditional Chinese medicine in treating cancerous pain developed with the guidance of TCM theory. Compared with control group, the treatment group could control cancerous pain, stabilize the tumor, and also prolong TTP of patients. ATP capsule in combination with morphine therapy can reduce the usage and the side effects of morphine, which insured the advanced stage patients better quality of life and longer survival period. The study shows that Ai Tong Ping capsule may treat cancerous pain by affecting the transmission of nociceptive stimulation and pain sensation in central nervous system. Anti-tumor mechanism of Aitongping capsule is a multi-channel, multi-target, the anti-tumor mechanism of ATP capsule was multi-way and multi-target, whose good pain control ability was associated with its anti-tumor mechanism.
引文
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