生物碱单体镇痛制剂研究进展
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摘要
疼痛是几千年来严重影响人们生活质量的问题之一。疼痛的起因复杂且种类繁多,长期疼痛还会导致抑郁,开发药效显著、毒副作用小的镇痛制剂已成为研究热点。近年研究发现,生物碱单体具有γ-氨基丁酸、大麻素、辣椒碱等镇痛作用靶点,若将其制剂应用于镇痛领域可借此弥补传统阿片及非甾体类镇痛药物存在成瘾性、副作用高等缺陷,但尚未有相关文献对此领域的研究成果进行总括。该文首先介绍了疼痛的产生机制和镇痛的作用靶点,在此基础上对国家食品药品监督管理总局(CFDA)批准上市的生物碱单体镇痛制剂的应用现状(品种数量、剂型种类、用药说明、镇痛作用机制及优点)进行了统计和分析,进而对生物碱单体镇痛制剂的研究动态(制剂新剂型及新技术)进行综述,最后指出了此领域研究中存在已上市制剂的用药信息不完善、研究的科研成果转化不足、已开发生物碱单体镇痛成分种类过少等问题,并针对上述问题指出发展方向,以期为生物碱单体类药物的进一步开发和深入研究提供参考。
Pain is one of the problems that seriously affect people's quality of life for thousands of years. The causes of pain are complex and varied,and long-term pain can also lead to depression. It has become a research hotspot to develop analgesic preparations with significant drug effects and small side effects. Recent studies have shown that certain alkaloid monomers have analgesic targets such as γ-aminobutyric acid,cannabinoids,and capsaicin. If their preparation is applied to the analgesic field,they can make up for the defects such as strong addiction and side effects of traditional opioid and non-steroidal analgesic drugs,but there is no relevant literature to summarize the research results in this field. This article first introduces the mechanism of pain production and the target of analgesia. Based on this,the application status of alkaloid monomer analgesic preparations approved by China Food and Drug Administration( CFDA)( number varieties,type of dosage form,drug description,analgesic mechanism and advantages) was analyzed,and the research dynamics of alkaloid monomer analgesic preparations( new formulation and new technology) were reviewed. Finally,some problems in this field were pointed out,such as imperfect medication information,inadequate transformation of research results,and too few kinds of analgesic components in developed alkaloids. The development direction was also pointed out for the above problems,with a view to provide reference for further development and in-depth research.
Pain is one of the problems that seriously affect people's quality of life for thousands of years. The causes of pain are complex and varied,and long-term pain can also lead to depression. It has become a research hotspot to develop analgesic preparations with significant drug effects and small side effects. Recent studies have shown that certain alkaloid monomers have analgesic targets such as γ-aminobutyric acid,cannabinoids,and capsaicin. If their preparation is applied to the analgesic field,they can make up for the defects such as strong addiction and side effects of traditional opioid and non-steroidal analgesic drugs,but there is no relevant literature to summarize the research results in this field. This article first introduces the mechanism of pain production and the target of analgesia. Based on this,the application status of alkaloid monomer analgesic preparations approved by China Food and Drug Administration( CFDA)( number varieties,type of dosage form,drug description,analgesic mechanism and advantages) was analyzed,and the research dynamics of alkaloid monomer analgesic preparations( new formulation and new technology) were reviewed. Finally,some problems in this field were pointed out,such as imperfect medication information,inadequate transformation of research results,and too few kinds of analgesic components in developed alkaloids. The development direction was also pointed out for the above problems,with a view to provide reference for further development and in-depth research.
引文
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[36] Lee J Y,Yoon S Y,Won J,et al. Sinomenine produces peripheral analgesic effects via inhibition of voltage-gated sodium currents[J]. Neuroscience,2017,358:28.
[37] Li S,Han J,Wang D S,et al. Sinomenine attenuates chronic inflammatory pain in mice[J]. Metab Brain Dis,2017,32(1):211.
[38] Zhu Q,Sun Y H,Zhu J,et al.Antinociceptive effects of sinomenine in a rat model of neuropathic pain[J]. Sci Rep UK,2014,4:7270.
[39]黄先涛,贾本良.盐酸青藤碱治疗各种风湿痛的疗效[J].湖南医学,1986,3:321.
[40] Tung N T,Tran C S,Pham T M,et al. Development of solidified self-microemulsifying drug delivery systems containing l-tetrahydropalmatine:design of experiment approach and bioavailability comparison[J]. Int J Pharm,2018,537(1/2):9.
[41] Geng S,Zheng Y,Meng M,et al. Gingerol reverses the cancerpromoting effect of capsaicin by increased TRPV1 level in a urethane-induced lung carcinogenic model[J]. J Agric Food Chem,2016,64(31):6203.
[42] Suresh D,Srinivasan K. Tissue distribution&elimination of capsaicin,piperine&curcumin following oral intake in rats[J]. Indian J Med Res,2010,131(5):682.
[43] De Freitas GBL,De Almeida D J,Carraro,et al. Formulation,characterization,and in vitro/in vivo,studies of capsaicin-loaded albumin nanoparticles[J]. Mater Sci Eng C Mater Biol Appl,2018,93:70.
[44]王雪娇,董同力嘎,张师,等.高乌甲素-β-环糊精聚合物微球的制备和释放性能及动力学模拟[J].中国新药杂志,2015,24(4):470.
[45]张壮丽,王陆巡,赵宁,等.喷雾干燥法制备盐酸千金藤碱微囊[J].中成药,2014(8):1648.
[46]黄瑜,付聪,薛冰,等.延胡索乙素单层渗透泵片的制备及体外评价[J].海南大学学报:自然科学版,2017,35(4):337.
[47] Sun Y L,Zhu S S,Lu W J,et al. A novel enteric positioning osmotic pump capsule-based controlled release system of sinomenine hydrochloride:in vitro and in vivo evaluation[J]. J Drug Deliv Sci Tec,2019,49:188.
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[49] Cao Y,Tao Y,Zhou Y,et al. Development of sinomenine hydrochloride-loaded polyvinylalcohol/maltose microneedle for transdermal delivery[J]. J Drug Deliv Sci Tec,2016,35:1.
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[2] Szigethy E,Knisely M,Drossman D.Opioid misuse in gastroenterology and non-opioid management of abdominal pain[J]. Nat Rev Gastro Hepat,2018,15(3):168.
[3] Farmer A D,Holt C B,Downes T J,et al. Pathophysiology,diagnosis,and management of opioid-induced constipation[J].Lancet Gastroenterol Hepatol,2018,3(3):203.
[4] Macêdo P J O M,Oliveira P S,Foldvary-Schaefer N,et al. Insomnia in people with epilepsy:a review of insomnia prevalence,risk factors and associations with epilepsy-related factors[J]. Epilepsy Res,2017,135(9):158.
[5]苏漫,朱清,李俊旭.镇痛药物作用靶点的研究现状[J].中国药理学通报,2018,34(2):161.
[6]陶炳,张奥,蓝蓉.生物碱类镇痛活性成分及其镇痛机制研究进展[J].时珍国医国药,2011,22(4):957.
[7] Yekkirala A S,Roberson D P,Bean B P,et al. Breaking barriers to novel analgesic drug development[J]. Nat Rev Drug Discov,2017,16(8):545.
[8]李秋月,许海玉,杨洪军.促炎因子TNF-α,IL-1β,IL-6在神经病理性疼痛中的研究进展[J].中国中药杂志,2017,42(19):3709.
[9]李先林,王静,王雪颖.阿片成瘾的神经生物学机制研究进展[J].临床医药文献电子杂志,2017(33):196.
[10]苏漫,朱清,李俊旭.镇痛药物作用靶点的研究现状[J].中国药理学通报,2018,34(2):161.
[11] Kuboyama K,Tsuda M,Tsutsui M,et al. Reduced spinal microglial activation and neuropathic pain after nerve injury in mice lacking all three nitric oxide synthases[J]. Mol Pain,2011,7(1):50.
[12] Bankar G,Goodchild S J,Howard S,et al. Selective Na V1. 7 antagonists with long residence time show improved efficacy against inflammatory and neuropathic pain[J]. Cell Rep,2018,24(12):3133.
[13] Wolkerstorfer A,Handler N,Buschmann H. New approaches to treating pain[J]. Bioorg Med Chem Lett,2016,26(4):1103.
[14]刘晓丽,吕翠,张文生.TRPV1与中药止痛作用研究进展[J].中国中药杂志,2014,39(10):1757.
[15] De la Pena E,Gomis A,Ferrer-Montiel A,et al. TRPV1 channelmodulation by hyaluronan reduces pain[J]. Channels(Austin),2016,10(2):81.
[16] Zhou H H,Wu D L,Gao L Y,et al.L-tetrahydropalmatine alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice[J]. Neuroreport,2016,27(7):476.
[17] Evangelista S.Novel therapeutics in the field of capsaicin and pain[J].Expert Rev Clin Phar,2015,8(4):373.
[18] Gao T,Hao J,Wiesenfeld-Hallin Z,et al. Analgesic effect of sinomenine in rodents after inflammation and nerve injury[J]. Eur J Pharmacol,2013,721(1/3):5.
[19]杜廷海,吕久省,吕靖中.头痛一嗅宁治疗血管神经性头痛的临床和实验研究[J].中国医药学报,1997,12(1):6.
[20]陆刚.针刺联合山莨菪碱治疗肾绞痛30例临床疗效观察[J].内蒙古中医药,2018,37(8):54.
[21]王丽丽,李卫华,岳华.辣椒碱软膏临床应用72例观察[J].中国现代药物应用,2012,6(12):97.
[22]吴明光.新型长效镇痛药辣椒碱研究进展[J].中国新药杂志,1994(4):10.
[23] Masclee G. Anti-inflammatory and antipyretic analgesics and drugs used in gout[J]. Side Effects of Drugs Annual,1999,26(10):111.
[24] Wang C F,Peter Gerner,Birgitta Schmidt,et al. Use of bulleyaconitine A as an adjuvant for prolonged cutaneous analgesia in the rat[J]. Anesth Analg,2008,107(4):1397.
[25] Li T F,Fan H,Wang Y X. Aconitum-derived bulleyaconitine a exhibits antihypersensitivity through direct stimulating dynorphin a expression in spinal microglia[J]. J Pain,2016,17(5):530.
[26] Tang X C,Liu X J,Lu W H,et al. Studies on the analgesic action and physical dependence of bulleyaconitine A[J]. Acta Pharm Sin B,1986,21(12):886.
[27]徐宁,刘蕊,臧嘉捷,等.草乌甲素片治疗骨关节炎效果和安全性评价[J].中国医药,2014,9(8):1170.
[28]张轩,周斌,路慧丽.草乌甲素的药理作用机制及临床应用研究进展[J].慢性病学杂志,2016,17(11):1210.
[29] Wright S N. Irreversible block of human heart(hH1)sodium channels by the plant alkaloid lappaconitine[J]. Mol Pharmacol,2001,59(2):183.
[30] Ou S,Zhao Y D,Xiao Z,et al. Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion[J].Neurochem Int,2011,58(5):564.
[31] Yang S,Zhang H,Beier R C,et al. Comparative metabolism of lappaconitine in rat and human liver microsomes and in vivo of rat using ultra high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry[J]. J Pharmaceut Biomed,2015,110:1.
[32]杨琴.高乌甲素用于术后静脉自控镇痛的临床观察[J].医学美学美容:中旬刊,2014(4):26.
[33] Zhao H,Luo F,Li H,et al.Antinociceptive effect of tetrandrine on LPS-induced hyperalgesia via the inhibition of IKKβphosphorylation and the CoX-2/PGE2pathway in mice[J]. PLoS ONE,2014,9(4):e94586.
[34]阮林,黄焕森,金文香,等.汉防己甲素对急性切口痛大鼠的镇痛作用研究[J].中国当代医药,2014,21(36):11.
[35] Whitehouse M W,Fairlie D P,Thong Y H. Anti-inflammatory activity of the isoquinoline alkaloid,tetrandrine,against established adjuvant arthritis in rats[J]. Agent Action,1994,42(3):123.
[36] Lee J Y,Yoon S Y,Won J,et al. Sinomenine produces peripheral analgesic effects via inhibition of voltage-gated sodium currents[J]. Neuroscience,2017,358:28.
[37] Li S,Han J,Wang D S,et al. Sinomenine attenuates chronic inflammatory pain in mice[J]. Metab Brain Dis,2017,32(1):211.
[38] Zhu Q,Sun Y H,Zhu J,et al.Antinociceptive effects of sinomenine in a rat model of neuropathic pain[J]. Sci Rep UK,2014,4:7270.
[39]黄先涛,贾本良.盐酸青藤碱治疗各种风湿痛的疗效[J].湖南医学,1986,3:321.
[40] Tung N T,Tran C S,Pham T M,et al. Development of solidified self-microemulsifying drug delivery systems containing l-tetrahydropalmatine:design of experiment approach and bioavailability comparison[J]. Int J Pharm,2018,537(1/2):9.
[41] Geng S,Zheng Y,Meng M,et al. Gingerol reverses the cancerpromoting effect of capsaicin by increased TRPV1 level in a urethane-induced lung carcinogenic model[J]. J Agric Food Chem,2016,64(31):6203.
[42] Suresh D,Srinivasan K. Tissue distribution&elimination of capsaicin,piperine&curcumin following oral intake in rats[J]. Indian J Med Res,2010,131(5):682.
[43] De Freitas GBL,De Almeida D J,Carraro,et al. Formulation,characterization,and in vitro/in vivo,studies of capsaicin-loaded albumin nanoparticles[J]. Mater Sci Eng C Mater Biol Appl,2018,93:70.
[44]王雪娇,董同力嘎,张师,等.高乌甲素-β-环糊精聚合物微球的制备和释放性能及动力学模拟[J].中国新药杂志,2015,24(4):470.
[45]张壮丽,王陆巡,赵宁,等.喷雾干燥法制备盐酸千金藤碱微囊[J].中成药,2014(8):1648.
[46]黄瑜,付聪,薛冰,等.延胡索乙素单层渗透泵片的制备及体外评价[J].海南大学学报:自然科学版,2017,35(4):337.
[47] Sun Y L,Zhu S S,Lu W J,et al. A novel enteric positioning osmotic pump capsule-based controlled release system of sinomenine hydrochloride:in vitro and in vivo evaluation[J]. J Drug Deliv Sci Tec,2019,49:188.
[48]果秋婷,张小飞.汉防己甲素滴丸的制备工艺优化及溶出度考察[J].中草药,2018,49(5):1056.
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