银杏类制剂安全性研究进展
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摘要
银杏已有600多年的药用历史。历代中医药文献大多认为银杏有毒或有小毒。大量的临床试验均表明银杏类制剂具有较好的耐受性。多数不良反应如过敏反应、自发性出血、癫痫发作等多散见于个案报道。虽然动物毒理学试验发现银杏类制剂具有致癌性,细胞毒理学试验发现某些黄酮苷类如槲皮素、山柰酚具有基因毒性,但大量的临床和流行病学研究尚未发现银杏类制剂或其中的成分与癌症具有相关性。与抗血小板、抗凝药物、精神神经类药物、钙离子拮抗剂等联用时,要注意药物之间的相互作用引发的不良反应。企业应发挥不良反应监测的主体作用,积极构建药物上市后安全性证据体。本文对银杏类制剂的安全性研究进行综述,以期为临床应用和进一步开发此类制剂提供参考。
Ginkgo Biloba has a medical history of more than 600 years. Most of the Chinese medicine literatures of the past dynasties indicated that ginkgo was poisonous or slightly poisonous. A large number of clinical trials have shown that Ginkgo Biloba preparations have good tolerance. Most of adverse reactions, such as allergic reactions, spontaneous hemorrhages, seizures, etc. were sporadic in case reports. Although toxicological experiment in animals have found the carcinogenicity of Ginkgo Biloba preparations and cell toxicology tests have found the genotoxicity of some flavonoid glycosides such as quercetin and kaempferol, a large number of clinical and epidemiological studies have not found the correlation between Ginkgo Biloba preparations or their components and cancer. When combined with antiplatelet agents,anticoagulants, psychotropic drugs and calcium ion antagonist, attentions should be paid to the adverse reactions caused by the interactions between drugs. Enterprises should play a major role in adverse reaction monitoring, and actively establish the body of safety evidence of post-marketing drug. This paper reviewed the safety literatures of Ginkgo Biloba preparations to provide references for clinical application and further development of Ginkgo Biloba preparations.
Ginkgo Biloba has a medical history of more than 600 years. Most of the Chinese medicine literatures of the past dynasties indicated that ginkgo was poisonous or slightly poisonous. A large number of clinical trials have shown that Ginkgo Biloba preparations have good tolerance. Most of adverse reactions, such as allergic reactions, spontaneous hemorrhages, seizures, etc. were sporadic in case reports. Although toxicological experiment in animals have found the carcinogenicity of Ginkgo Biloba preparations and cell toxicology tests have found the genotoxicity of some flavonoid glycosides such as quercetin and kaempferol, a large number of clinical and epidemiological studies have not found the correlation between Ginkgo Biloba preparations or their components and cancer. When combined with antiplatelet agents,anticoagulants, psychotropic drugs and calcium ion antagonist, attentions should be paid to the adverse reactions caused by the interactions between drugs. Enterprises should play a major role in adverse reaction monitoring, and actively establish the body of safety evidence of post-marketing drug. This paper reviewed the safety literatures of Ginkgo Biloba preparations to provide references for clinical application and further development of Ginkgo Biloba preparations.
引文
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5 Hausen B M. The sensitizing capacity of ginkgolic acids in guinea pigs.American Journal of Contact Dermatitis Official Journal of the American Contact Dermatitis Society, 1998, 9(3):146.
6 Gaus W, Westendorf J, Diebow R, et al. Identification of adverse drug reactions by evaluation of a prescription database, demonstrated for"risk of bleeding", Methods of Information in Medicine, 2005, 44(5):697-703.
7 Koch E, Jaggy H, Chatterjee S S. Evidence for immunotoxic effects of crude Ginkgo biloba, L. leaf extracts using the popliteal lymph node assay in the mouse. International Journal of Immunopharmacology,2000, 22(3):229.
8 P Assalian, H C Margolese. Treatment of antidepressant-induced sexual side effects. Journal of Sex&Marital Therapy, 1996, 22(3):218-24.
9 Koch E, Jaggy H, Chatterjee S S. Evidence for immunotoxic effects of crude Ginkgo biloba L. leaf extracts using the popliteal lymph node assay in the mouse. International Journal of Immunopharmacology,2000, 22(3):229-236.
10 Hecker H, Johannisson R, Koch E, et al. In vitro evaluation of the cytotoxic potential of alkylphenols from Ginkgo biloba L. Toxicology,2002, 177(2):167-177.
11 Luepke N P. Evidence for toxic effects of alkylphenols from Ginkgo biloba in the hen's egg test(HET). Phytomedicine Baronruppert G, 2001,8(2):133-138.
12 Regan J. Induction of DNA strand-breaks in primary rat hepatocytes by ginkgolic acids. Die Pharmazie Westendorf J, 2000, 55(11):864.
13 谢培山.银杏叶标准提取物EGb761^R及银杏叶制剂的质量评价(待续).中国中药杂志, 1999, 24(2):3-5.
14 国家药典委员会.中华人民共和国药典(一部).北京:中国医药科技出版社, 2015:416.
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16 European Pharmacopoeia Monograph. Ginkgo dry extract, refined and quantified, Monograph, 2008:3461-3463.
17 Lin H, Guo X, Zhang S, et al. Mechanistic evaluation of Ginkgo biloba leaf extract-induced genotoxicity in L5178Y cells. Toxicological Sciences An Official Journal of the Society of Toxicology, 2014, 139(2):338.
18 Zhang Z, Chen S, Mei H, et al. Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.Scientific Reports, 2015, 5:14633.
19 Dajas F. Life or death:neuroprotective and anticancer effects of quercetin.Journal of Ethnopharmacology, 2012, 143(2):383-396.
20 Calderónmonta?o J M, Burgosmorón E, Pérezguerrero C, et al. A review on the dietary flavonoid kaempferol. Mini Reviews in Medicinal Chemistry, 2011, 11(4):298-344.
21 Boots A W, Haenen G R, Bast A. Health effects of quercetin:from antioxidant to nutraceutical. European Journal of Pharmacology, 2008,585(2-3):325-337.
22 Nishiumi S, Miyamoto S, Kawabata K, et al. Dietary flavonoids as cancerpreventive and therapeutic biofactors. Frontiers in Bioscience, 2011, 3(3):1332.
23 Kuo S M. Dietary flavonoid and cancer prevention:evidence and potential mechanism. Critical Reviews in Oncogenesis, 1997, 8(1):47.
24 Yao H, Xu W, Shi X, et al. Dietary flavonoids as cancer prevention agents.Journal of Environmental Science&Health Part C, 2011, 29(1):1-31.
25 Kiefer M. Review about Ginkgo biloba special extract EGb 761(Ginkgo).Current Pharmaceutical Design Gertz H J, 2004, 10(3):261.
26 Gaus W. Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract. Toxicology Heinonen T, 2015, 327(1):95.
27 Mei N, Guo X, Ren Z, et al. Review of Ginkgo biloba-induced toxicity,from experimental studies to human case reports. Journal of Environmental Science&Health Part C Environmental Carcinogenesis&Ecotoxicology Reviews, 2017, 35(1):1.
28 Knipschild P. Ginkgo biloba for cerebral insufficiency. British Journal of Clinical Pharmacology Kleijnen J, 1992, 34(4):352-358.
29 Dekosky S T, Williamson J D, Fitzpatrick A L, et al. Ginkgo biloba for prevention of dementia:a randomized controlled trial. Jama, 2008, 300(19):2253.
30 Diamond B J, Shiflett S C, Feiwel N, et al. Ginkgo biloba, extract:Mechanisms and clinical indications. Arch Phys Med Rehabil, 2000, 81(5):668-678.
31 Tomb R R, Foussereau J, Sell Y. Mini-epidemic of contact dermatitis from ginkgo tree fruit(Ginkgo biloba L.). Contact Dermatitis, 1988, 19(4):281-283.
32 Pennisi R S. Acute generalised exanthematous pustulosis induced by the herbal remedy Ginkgo biloba. Medical Journal of Australia, 2006,184(11):583.
33 Metz D, Weston P, Barker D. Case report of vasculitic rash induced by Ginkgo biloba and/or Horny Goat Weed. Bmj Case Reports, 2009, 2009(mar08 1):733-745.
34 Yuste M, Sanchez-Estella J, Santos J C, et al. Stevens-Johnson syndrome/toxic epidermal necrolysis treated with intravenous immunoglobulins.Actas dermo-sifiliograficas, 2005, 96(9):589-592.
35 Sowers W F, Weary P E, Collins O D, et al. Ginkgo-tree dermatitis.Archives of Dermatology, 1965, 91(5):452-456.
36 Hausen B M. The sensitizing capacity of ginkgolic acids in guinea pigs.American Journal of Contact Dermatitis Official Journal of the American Contact Dermatitis Society, 1998, 9(3):146-8.
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38 Bent S, Goldberg H, Padula A, et al. Spontaneous bleeding associated with Ginkgo biloba. Journal of General Internal Medicine, 2005, 20(7):657-661.
39 Schultz S K. Ginkgo biloba extract:review of CNS effects. Annals of Clinical Psychiatry Official Journal of the American Academy of Clinical Psychiatrists Ponto L L, 2003, 15(2):109.
40 Hauser D, Gayowski T, Singh N. Bleeding complications precipitated by unrecognized Gingko biloba, use after liver transplantation. Transplant International, 2002, 15(7):377-379.
41 Singh V, Singh S P, Chan K. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. International Journal of Neuropsychopharmacology, 2010, 13(2):257.
42 Miwa H, Iijima M, Tanaka S, et al. Generalized convulsions after consuming a large amount of gingko nuts. Epilepsia, 2001, 42(2):280-281.
43 Gregory P J. Seizure associated with Ginkgo biloba? Annals of Internal Medicine, 2001, 134(4):344.
44 Wada K, Ishigaki S, Ueda K, et al. Studies on the constitution of edible and medicinal plants. I. Isolation and identification of 4-O-methylpyridoxine,toxic principle from the seed of Ginkgo biloba L. Chemical&Pharmaceutical Bulletin, 1988, 36(5):1779-1782.
45 Wada K, Ishigaki S, Ueda K, et al. An antivitamin B6, 4'-methoxypyridoxine,from the seed of Ginkgo biloba L. Chemical&Pharmaceutical Bulletin,1985, 33(8):3555.
46 Drewke C. Ginkgo biloba and ginkgotoxin. Journal of Natural Products Leistner E, 2010, 73(1):86-92.
47 Kajiyama Y, Fujii K, Takeuchi H, et al. Ginkgo seed poisoning.Pediatrics, 2002, 109(109):325-327.
48 Lorenzo C D, Ceschi A, Colombo F, et al. Identification and quantification of biomarkers to confirm the poisoning by Ginkgo biloba seeds in a 2-year-old boy. Toxicology Research, 2015, 4(4):922-930.
49 Kobayashi D, Yoshimura T, Johno A, et al. Toxicity of 4′-Omethylpyridoxine-5′-glucoside in Ginkgo biloba seeds. Food Chemistry, 2011, 126(3):1198-1202.
50 Liu Y, Chen S N, Mcalpine J B, et al. Quantification of a Botanical Negative Marker without an Identical Standard:Ginkgotoxin in Ginkgo biloba. Journal of Natural Products, 2014, 77(3):611-617.
51 Evans J R. Ginkgo biloba extract for age-related macular degeneration.Cochrane Database of Systematic Reviews, 2013, 1(1):CD001775.
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2 Uemura K. Cenozoic history of ginkgo in east asia. ginkgo biloba a global treasure. Springer Japan, 1997:207-221.
3 Tredici P D. Ginkgos and people-a thousand years of interaction.Arnoldia, 1991, 51(2):2-15.
4 梁立兴.中国银杏药用史.中国现代中药, 1999(3):44-45.
5 Hausen B M. The sensitizing capacity of ginkgolic acids in guinea pigs.American Journal of Contact Dermatitis Official Journal of the American Contact Dermatitis Society, 1998, 9(3):146.
6 Gaus W, Westendorf J, Diebow R, et al. Identification of adverse drug reactions by evaluation of a prescription database, demonstrated for"risk of bleeding", Methods of Information in Medicine, 2005, 44(5):697-703.
7 Koch E, Jaggy H, Chatterjee S S. Evidence for immunotoxic effects of crude Ginkgo biloba, L. leaf extracts using the popliteal lymph node assay in the mouse. International Journal of Immunopharmacology,2000, 22(3):229.
8 P Assalian, H C Margolese. Treatment of antidepressant-induced sexual side effects. Journal of Sex&Marital Therapy, 1996, 22(3):218-24.
9 Koch E, Jaggy H, Chatterjee S S. Evidence for immunotoxic effects of crude Ginkgo biloba L. leaf extracts using the popliteal lymph node assay in the mouse. International Journal of Immunopharmacology,2000, 22(3):229-236.
10 Hecker H, Johannisson R, Koch E, et al. In vitro evaluation of the cytotoxic potential of alkylphenols from Ginkgo biloba L. Toxicology,2002, 177(2):167-177.
11 Luepke N P. Evidence for toxic effects of alkylphenols from Ginkgo biloba in the hen's egg test(HET). Phytomedicine Baronruppert G, 2001,8(2):133-138.
12 Regan J. Induction of DNA strand-breaks in primary rat hepatocytes by ginkgolic acids. Die Pharmazie Westendorf J, 2000, 55(11):864.
13 谢培山.银杏叶标准提取物EGb761^R及银杏叶制剂的质量评价(待续).中国中药杂志, 1999, 24(2):3-5.
14 国家药典委员会.中华人民共和国药典(一部).北京:中国医药科技出版社, 2015:416.
15 Grollino M G, RaschellàG, Cordelli E, et al. Cytotoxicity, genotoxicity and gene expression changes elicited by exposure of human hepatic cells to Ginkgo biloba leaf extract. Food&Chemical Toxicology, 2017,109 (Pt 1):S0278691517305598.
16 European Pharmacopoeia Monograph. Ginkgo dry extract, refined and quantified, Monograph, 2008:3461-3463.
17 Lin H, Guo X, Zhang S, et al. Mechanistic evaluation of Ginkgo biloba leaf extract-induced genotoxicity in L5178Y cells. Toxicological Sciences An Official Journal of the Society of Toxicology, 2014, 139(2):338.
18 Zhang Z, Chen S, Mei H, et al. Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.Scientific Reports, 2015, 5:14633.
19 Dajas F. Life or death:neuroprotective and anticancer effects of quercetin.Journal of Ethnopharmacology, 2012, 143(2):383-396.
20 Calderónmonta?o J M, Burgosmorón E, Pérezguerrero C, et al. A review on the dietary flavonoid kaempferol. Mini Reviews in Medicinal Chemistry, 2011, 11(4):298-344.
21 Boots A W, Haenen G R, Bast A. Health effects of quercetin:from antioxidant to nutraceutical. European Journal of Pharmacology, 2008,585(2-3):325-337.
22 Nishiumi S, Miyamoto S, Kawabata K, et al. Dietary flavonoids as cancerpreventive and therapeutic biofactors. Frontiers in Bioscience, 2011, 3(3):1332.
23 Kuo S M. Dietary flavonoid and cancer prevention:evidence and potential mechanism. Critical Reviews in Oncogenesis, 1997, 8(1):47.
24 Yao H, Xu W, Shi X, et al. Dietary flavonoids as cancer prevention agents.Journal of Environmental Science&Health Part C, 2011, 29(1):1-31.
25 Kiefer M. Review about Ginkgo biloba special extract EGb 761(Ginkgo).Current Pharmaceutical Design Gertz H J, 2004, 10(3):261.
26 Gaus W. Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract. Toxicology Heinonen T, 2015, 327(1):95.
27 Mei N, Guo X, Ren Z, et al. Review of Ginkgo biloba-induced toxicity,from experimental studies to human case reports. Journal of Environmental Science&Health Part C Environmental Carcinogenesis&Ecotoxicology Reviews, 2017, 35(1):1.
28 Knipschild P. Ginkgo biloba for cerebral insufficiency. British Journal of Clinical Pharmacology Kleijnen J, 1992, 34(4):352-358.
29 Dekosky S T, Williamson J D, Fitzpatrick A L, et al. Ginkgo biloba for prevention of dementia:a randomized controlled trial. Jama, 2008, 300(19):2253.
30 Diamond B J, Shiflett S C, Feiwel N, et al. Ginkgo biloba, extract:Mechanisms and clinical indications. Arch Phys Med Rehabil, 2000, 81(5):668-678.
31 Tomb R R, Foussereau J, Sell Y. Mini-epidemic of contact dermatitis from ginkgo tree fruit(Ginkgo biloba L.). Contact Dermatitis, 1988, 19(4):281-283.
32 Pennisi R S. Acute generalised exanthematous pustulosis induced by the herbal remedy Ginkgo biloba. Medical Journal of Australia, 2006,184(11):583.
33 Metz D, Weston P, Barker D. Case report of vasculitic rash induced by Ginkgo biloba and/or Horny Goat Weed. Bmj Case Reports, 2009, 2009(mar08 1):733-745.
34 Yuste M, Sanchez-Estella J, Santos J C, et al. Stevens-Johnson syndrome/toxic epidermal necrolysis treated with intravenous immunoglobulins.Actas dermo-sifiliograficas, 2005, 96(9):589-592.
35 Sowers W F, Weary P E, Collins O D, et al. Ginkgo-tree dermatitis.Archives of Dermatology, 1965, 91(5):452-456.
36 Hausen B M. The sensitizing capacity of ginkgolic acids in guinea pigs.American Journal of Contact Dermatitis Official Journal of the American Contact Dermatitis Society, 1998, 9(3):146-8.
37 Charlotte K P D. Is There a Risk of Bleeding Associated with Standardized Ginkgo bilobaExtract Therapy? A Systematic Review and Meta?analysis. Pharmacotherapy the Journal of Human Pharmacology&Drug Therapy, 2011, 31(5):490.
38 Bent S, Goldberg H, Padula A, et al. Spontaneous bleeding associated with Ginkgo biloba. Journal of General Internal Medicine, 2005, 20(7):657-661.
39 Schultz S K. Ginkgo biloba extract:review of CNS effects. Annals of Clinical Psychiatry Official Journal of the American Academy of Clinical Psychiatrists Ponto L L, 2003, 15(2):109.
40 Hauser D, Gayowski T, Singh N. Bleeding complications precipitated by unrecognized Gingko biloba, use after liver transplantation. Transplant International, 2002, 15(7):377-379.
41 Singh V, Singh S P, Chan K. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. International Journal of Neuropsychopharmacology, 2010, 13(2):257.
42 Miwa H, Iijima M, Tanaka S, et al. Generalized convulsions after consuming a large amount of gingko nuts. Epilepsia, 2001, 42(2):280-281.
43 Gregory P J. Seizure associated with Ginkgo biloba? Annals of Internal Medicine, 2001, 134(4):344.
44 Wada K, Ishigaki S, Ueda K, et al. Studies on the constitution of edible and medicinal plants. I. Isolation and identification of 4-O-methylpyridoxine,toxic principle from the seed of Ginkgo biloba L. Chemical&Pharmaceutical Bulletin, 1988, 36(5):1779-1782.
45 Wada K, Ishigaki S, Ueda K, et al. An antivitamin B6, 4'-methoxypyridoxine,from the seed of Ginkgo biloba L. Chemical&Pharmaceutical Bulletin,1985, 33(8):3555.
46 Drewke C. Ginkgo biloba and ginkgotoxin. Journal of Natural Products Leistner E, 2010, 73(1):86-92.
47 Kajiyama Y, Fujii K, Takeuchi H, et al. Ginkgo seed poisoning.Pediatrics, 2002, 109(109):325-327.
48 Lorenzo C D, Ceschi A, Colombo F, et al. Identification and quantification of biomarkers to confirm the poisoning by Ginkgo biloba seeds in a 2-year-old boy. Toxicology Research, 2015, 4(4):922-930.
49 Kobayashi D, Yoshimura T, Johno A, et al. Toxicity of 4′-Omethylpyridoxine-5′-glucoside in Ginkgo biloba seeds. Food Chemistry, 2011, 126(3):1198-1202.
50 Liu Y, Chen S N, Mcalpine J B, et al. Quantification of a Botanical Negative Marker without an Identical Standard:Ginkgotoxin in Ginkgo biloba. Journal of Natural Products, 2014, 77(3):611-617.
51 Evans J R. Ginkgo biloba extract for age-related macular degeneration.Cochrane Database of Systematic Reviews, 2013, 1(1):CD001775.
52 Resende F A, Vilegas W, Santos L C D, et al. Mutagenicity of Flavonoids Assayed by Bacterial Reverse Mutation(Ames)Test.Molecules, 2012, 17(5):5255-5268.
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