细辛散剂急性毒性的实验研究
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摘要
目的
细辛是一味常用中药，临床应用已有两千多年的历史。因其有毒，《中国药典》(2000年版)明确规定细辛用量为1～3g。然而《中国药典》规定的剂量并不为临床所遵循，大剂量使用细辛治疗多种病症者不乏其例，不但没有引起毒副反应，还获得了满意的临床效果。
究其原因，在于细辛的毒性及其机制不甚明了。有鉴于斯，本课题从文献研究和实验研究着手，希冀在此方面作一初步探讨，为临床安全有效地使用细辛提供参考。
方法
1．文献研究：查阅近30年来国内外期刊杂志所报道的细辛用量及毒性方面的文献，对影响细辛毒性的相关因素诸如细辛的品种、采制、用法、用量、毒性等进行系统分析研究。
2．实验研究：①急性毒性实验，主要观察小鼠大剂量灌服细辛散剂(包括细辛根散剂和细辛全草散剂)后所出现的毒性反应和死亡情况，并分别测定其半数致死量(LD_(50))。②组织病理学观察，对给药后死亡(未死动物14天后断头处死)的小鼠即时取其心、肝、肺、肾，甲醛固定，石蜡包埋切片，HE染色，观察细辛散剂对小鼠重要脏器的影响。③家兔呼吸运动及神经电生理研究，利用BL-410生物机能实验系统对给药前后家兔膈神经电活动及呼吸变化等进行记录，分析细辛毒性对膈神经电活动的影响。
结果
1．文献研究表明，细辛所含挥发油中的黄樟醚为其主要毒性成分，因此其毒性的大小与其挥发油的含量多少密切相关。细辛的应用，古今存在着很大的差异。如古代用根、单用、研末服；而现代用带根全草，多入复方、煎服。由于药用部位不同，故采集季节、炮制方法等均不一样。这些都直接影响着细辛挥发油的含量，毒性也因之而异，也是细辛古今用量悬殊的主要原因。
2．急性毒性实验表明，细辛根散剂及全草散剂对小鼠灌胃的LD_(50)分别为6.5229g／kg，11.7052g／kg，提示细辛根散剂的毒性大于全草散剂的毒性。
3．组织病理学观察显示，大剂量细辛对小鼠肺、肝、肾等重要脏器均有程度不同的病理损害，其中以肺病损较为突出。肺脏病变主要表现为有轻重不等的出血、瘀血、水肿；肺泡壁毛细血管可见程度不一的白细胞粘附滞留阻塞血管，严重者，肺内出现白细胞灶性聚集或肺泡壁因毛细血管浸润而增厚。
4．家兔呼吸运动及膈神经电生理研究表明，给药后，家兔的呼吸出现了先兴奋后抑制的过程。其呼吸幅度、频率及膈神经电活动振幅、频率也随之发生相应的改变。
结论
湖北中医学院
硕士研究生毕业论文
1.细辛有毒，能造成肺、肝、肾等多器官程度不一的损害，表现为组织充
血、出血、水肿、炎症等病变，其中以急性肺损伤(刀cut。了如君初ju琪ALI)
最为严重，其病变主要在肺毛细血管和肺泡.
2.细辛急性毒性造成的急性肺损伤，可导致低张性缺氧，造成低氧血症和
呼吸窘迫，最后致呼吸衰竭，类似于急性呼吸窘迫综合症(左cu把，。sPlot口理
dlst厂己55 sy刀办口刃己，ARDS人
3.细辛对呼吸系统的影响主要表现为呼吸先兴奋后抑制，可能是通过传感
器(化学感受器和J感受器)先兴奋呼吸中枢，随着PacoZ的降低或缺氧的急
性加重，进而抑制呼吸中枢所致。
Objective
Asarurn is a kind of Chinese herbs in common use, and its clinical application contains more than 2000 years. Because it is poisonous, there is a popular saying "No Asarum can be used over one qian" (qian, a measure unit of weight). The Pharmacopeia (abbr.Ph) of the People's Republic of China (1st part, published in 2000) (to call for short below: China abbr.Ph) demonstrably prescript Asarum' dosage is 1 ~ 3g. However, the dosage China abbr.Ph prescripted cannot be always abided by clinicians. There are always many cases of curing types of disease with heavy dosage of Asarum, with not any noxious or side effects but with the satisfactory results.
Now the reason lies in no more acknowledge with Asarum' virulence mechanisms. Because of this, through literature and experimental research, my scientific research topic aims at working out it. At the same time, the topic provide clinical application reference for the safe and efficient use of Asarum.
Methods
1. Literature investigation: After consulting much literature on it issued in the recent 30 years, and systemicly summing up, analyzing and research on the relative factors of Asarum toxicity such as variety, herborizing, making, usage, dosage, toxicity substance.
2.Experimental researches: (1) Acute virulence experiment: The 200 experimental mices were divided into 2 groups in equality, namely: the Asarum roots powder group and the whole Asarum powder group. The chief aim is to observe medicated mices' toxic reaction and death stat, and to calculate each other' 50% lethal dose (LD50). (2)Histopathology research: We draw forthwith the heart constitution, liver constitution, lung and kidney constitution from the dead mices (including of the decollated mices lived after 14 days), and use formaldehyde fossilize them, make filletings, HE Stain, and then observe by light microscope to research into the Asarum' influence on the importanter viscera. (3) Experimental rabbits' respiratory movement and neuroelectricit research: Taking the research records of comparison and analysis of the Asarum medicated and unmedicated rabbits' phrenic nerve activities and Changes with the BL - 410 organism function experimental syste.
Results
1 .Literature investigation indicates: Safrole, a kind volatile oil of Asarum is the toxicity component. And so its toxicity degree has close relation to the volatile oil content. The application of Asarum now is much different from ancient. For instance, the ancients look on Asarum' roots as officinal locus, but modernist do the whole Asarum; Asarum was grinded powder and used solely in ancient times but is
decocted into soup in compound in modern time. And so, the acquisition season and how to make vary with officinal locus vicissitudes. All these factors are directly bound up with the the volatile oil content. Because of it, its toxicity degree and dosge differ in the two eras.
2.Acute virulence experiment shows: It is determined that tHe LDso of the Asarum roots powder and the whole Asarum powder for mice in stomach administration is 6.5229g/kg and 11.7052g/kg respectively. It's clearly that he Asarum roots powder is more poisonous than the whole Asarum powder.
3.Histopathology and respiratory movement research manifests: Heavy dosage of Asarum has toxic effect on lung, liver and kidney of mices in different degree. Among the three visceras, the lung constitution was damaged to the worst degree. The main lesion of lung constitution are as follows: There are congestion and bleeding in aniso-degree in it. It can be found leucocyte adhesiveness retention, emphraxis blood vessel in aniso-degree on alveolar wall blood capillary. More seriously, leucocyte mass or alveolar wall Increase thickly because of blood capillary infiltration.
4.Experimental rabbits' neuroelectricit research evinces:Under administration, experimental rabbits' respiratory movement experience two stages: Respiration excite initially and get be restrained in anaphase. Correspondingly, breath's range and respiratory frequency and the amplitude of vibrati
细辛是一味常用中药，临床应用已有两千多年的历史。因其有毒，《中国药典》(2000年版)明确规定细辛用量为1～3g。然而《中国药典》规定的剂量并不为临床所遵循，大剂量使用细辛治疗多种病症者不乏其例，不但没有引起毒副反应，还获得了满意的临床效果。
究其原因，在于细辛的毒性及其机制不甚明了。有鉴于斯，本课题从文献研究和实验研究着手，希冀在此方面作一初步探讨，为临床安全有效地使用细辛提供参考。
方法
1．文献研究：查阅近30年来国内外期刊杂志所报道的细辛用量及毒性方面的文献，对影响细辛毒性的相关因素诸如细辛的品种、采制、用法、用量、毒性等进行系统分析研究。
2．实验研究：①急性毒性实验，主要观察小鼠大剂量灌服细辛散剂(包括细辛根散剂和细辛全草散剂)后所出现的毒性反应和死亡情况，并分别测定其半数致死量(LD_(50))。②组织病理学观察，对给药后死亡(未死动物14天后断头处死)的小鼠即时取其心、肝、肺、肾，甲醛固定，石蜡包埋切片，HE染色，观察细辛散剂对小鼠重要脏器的影响。③家兔呼吸运动及神经电生理研究，利用BL-410生物机能实验系统对给药前后家兔膈神经电活动及呼吸变化等进行记录，分析细辛毒性对膈神经电活动的影响。
结果
1．文献研究表明，细辛所含挥发油中的黄樟醚为其主要毒性成分，因此其毒性的大小与其挥发油的含量多少密切相关。细辛的应用，古今存在着很大的差异。如古代用根、单用、研末服；而现代用带根全草，多入复方、煎服。由于药用部位不同，故采集季节、炮制方法等均不一样。这些都直接影响着细辛挥发油的含量，毒性也因之而异，也是细辛古今用量悬殊的主要原因。
2．急性毒性实验表明，细辛根散剂及全草散剂对小鼠灌胃的LD_(50)分别为6.5229g／kg，11.7052g／kg，提示细辛根散剂的毒性大于全草散剂的毒性。
3．组织病理学观察显示，大剂量细辛对小鼠肺、肝、肾等重要脏器均有程度不同的病理损害，其中以肺病损较为突出。肺脏病变主要表现为有轻重不等的出血、瘀血、水肿；肺泡壁毛细血管可见程度不一的白细胞粘附滞留阻塞血管，严重者，肺内出现白细胞灶性聚集或肺泡壁因毛细血管浸润而增厚。
4．家兔呼吸运动及膈神经电生理研究表明，给药后，家兔的呼吸出现了先兴奋后抑制的过程。其呼吸幅度、频率及膈神经电活动振幅、频率也随之发生相应的改变。
结论
湖北中医学院
硕士研究生毕业论文
1.细辛有毒，能造成肺、肝、肾等多器官程度不一的损害，表现为组织充
血、出血、水肿、炎症等病变，其中以急性肺损伤(刀cut。了如君初ju琪ALI)
最为严重，其病变主要在肺毛细血管和肺泡.
2.细辛急性毒性造成的急性肺损伤，可导致低张性缺氧，造成低氧血症和
呼吸窘迫，最后致呼吸衰竭，类似于急性呼吸窘迫综合症(左cu把，。sPlot口理
dlst厂己55 sy刀办口刃己，ARDS人
3.细辛对呼吸系统的影响主要表现为呼吸先兴奋后抑制，可能是通过传感
器(化学感受器和J感受器)先兴奋呼吸中枢，随着PacoZ的降低或缺氧的急
性加重，进而抑制呼吸中枢所致。
Objective
Asarurn is a kind of Chinese herbs in common use, and its clinical application contains more than 2000 years. Because it is poisonous, there is a popular saying "No Asarum can be used over one qian" (qian, a measure unit of weight). The Pharmacopeia (abbr.Ph) of the People's Republic of China (1st part, published in 2000) (to call for short below: China abbr.Ph) demonstrably prescript Asarum' dosage is 1 ~ 3g. However, the dosage China abbr.Ph prescripted cannot be always abided by clinicians. There are always many cases of curing types of disease with heavy dosage of Asarum, with not any noxious or side effects but with the satisfactory results.
Now the reason lies in no more acknowledge with Asarum' virulence mechanisms. Because of this, through literature and experimental research, my scientific research topic aims at working out it. At the same time, the topic provide clinical application reference for the safe and efficient use of Asarum.
Methods
1. Literature investigation: After consulting much literature on it issued in the recent 30 years, and systemicly summing up, analyzing and research on the relative factors of Asarum toxicity such as variety, herborizing, making, usage, dosage, toxicity substance.
2.Experimental researches: (1) Acute virulence experiment: The 200 experimental mices were divided into 2 groups in equality, namely: the Asarum roots powder group and the whole Asarum powder group. The chief aim is to observe medicated mices' toxic reaction and death stat, and to calculate each other' 50% lethal dose (LD50). (2)Histopathology research: We draw forthwith the heart constitution, liver constitution, lung and kidney constitution from the dead mices (including of the decollated mices lived after 14 days), and use formaldehyde fossilize them, make filletings, HE Stain, and then observe by light microscope to research into the Asarum' influence on the importanter viscera. (3) Experimental rabbits' respiratory movement and neuroelectricit research: Taking the research records of comparison and analysis of the Asarum medicated and unmedicated rabbits' phrenic nerve activities and Changes with the BL - 410 organism function experimental syste.
Results
1 .Literature investigation indicates: Safrole, a kind volatile oil of Asarum is the toxicity component. And so its toxicity degree has close relation to the volatile oil content. The application of Asarum now is much different from ancient. For instance, the ancients look on Asarum' roots as officinal locus, but modernist do the whole Asarum; Asarum was grinded powder and used solely in ancient times but is
decocted into soup in compound in modern time. And so, the acquisition season and how to make vary with officinal locus vicissitudes. All these factors are directly bound up with the the volatile oil content. Because of it, its toxicity degree and dosge differ in the two eras.
2.Acute virulence experiment shows: It is determined that tHe LDso of the Asarum roots powder and the whole Asarum powder for mice in stomach administration is 6.5229g/kg and 11.7052g/kg respectively. It's clearly that he Asarum roots powder is more poisonous than the whole Asarum powder.
3.Histopathology and respiratory movement research manifests: Heavy dosage of Asarum has toxic effect on lung, liver and kidney of mices in different degree. Among the three visceras, the lung constitution was damaged to the worst degree. The main lesion of lung constitution are as follows: There are congestion and bleeding in aniso-degree in it. It can be found leucocyte adhesiveness retention, emphraxis blood vessel in aniso-degree on alveolar wall blood capillary. More seriously, leucocyte mass or alveolar wall Increase thickly because of blood capillary infiltration.
4.Experimental rabbits' neuroelectricit research evinces:Under administration, experimental rabbits' respiratory movement experience two stages: Respiration excite initially and get be restrained in anaphase. Correspondingly, breath's range and respiratory frequency and the amplitude of vibrati
引文
1．谢伟、陆满文．细辛挥发油的化学与药理作用．宁夏医学杂志，1995，(2)：121～124
2．何家琅．论文摘要集．中国药学会北京分会，1957：68
3．柯铭清．中草药有效成分理化与药理特性．湖南科学技术出版社，1982：108
4. Frederick F Bockes:Cancer Vol1: 205, 247, P1. enum Press, New York,1975
5. Cameron HM, et al: Liver Cell Cancer, 143 Elsevier Scientific Publishing Company, 1976
6. Hashimoto K, Higuchi M, Makino B, Sakakibara I, Kubo M, Komatsu Y,Maruno M, Okada M. Quantitative analysis of aristolochic acids, toxic compounds, contained in some medicinal plants. J Ethnopharmacol 1999 Feb; 64 (2): 185-9
7. Schaneberg BT, Applequist WL, Khan IA. Determination of aristolochic acid Ⅰand Ⅱ in North American species of Asarum and Aristolochia.Pharmazie 2002 Oct;57(10): 686-9
8．李广勋．中药药理毒理与临床．天津：天津科技翻译出版社，1992：532
9．曲淑岩．细辛对中枢神经系统的抑制作用．中医杂志，1982，(6)：72
10．曲淑岩．细辛油的抗炎作用．药学学报，1982，(1)：12
11. Belova LF, Alibekov SD, Baginskaia AI, Sokolov SIa, Pokrovskaia GV.Asarone and its biological properties. Farmakol Toksikol 1985 Nov-Dec;48(6):17-20
12．周金黄．中药药理学．上海：上海科技出版社，1986：31
13．卢国静．细辛用量初探．浙江中医学院学报，1999，(5)：61
14．刘兴武．张仲景配用细辛方剂说要．四川中医，1997，(8)：12
15．焦树德．用药心得十讲．北京：人民卫生出版社，1980：195
16．周玉朱．重用细辛举隅．安徽中医学院学报，1985，(3)：32
17．冯恒善．重用细辛治疗类风湿性关节炎100例分析．河北中医，1984，(1)：16
18．蔡少青、王璇、朱妹．中药细辛的本草考证．北京医科大学学报，1997，(3)：233
19．高学敏、宋树立．细辛的临床应用和毒性反应．中医杂志，1993，(8)：465
20．郭增军、郑其萍、潘银．毛细辛的生药学研究．西北药学杂志，2000，(5)：201
21．蔡少青、王璇、朱妹，等．中药细辛商品药材的机源研究．中国中药杂志，1996，21(12)：712
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23．周长征、杨春澍、柳树林．中药细辛的质量检测．基层中药杂志，1998，(3)：22
24．王家蕊、闫山林．煎煮时间对细辛疗效及毒性的影响．天津药学，1999，(1)：
31
25．贾传春．细辛剂量古今谈．中医药学报，1989，(6)：30
26．李广勋．中药药理毒理与临床．天津：天津科技翻译出版社，1992：532
27．周祯祥、陈泽斌、李军．细辛的用量之争渊源与沿革考辨．中医药学刊，2002，(4)：422
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31．牛振华．细辛入药之我见．陕西中医，1994，(7)：326
32．杨仓良、程方、高渌汶，等．毒剧中药古今用．北京：中国医药科技出版社，1991：2
33．翁维良．临床中药不良反映．中药新药与临床药理，1996，(2)：4
34．翁维良．中药临床药理学．人民卫生出版社，2002：205
35．罗慰慈．现代呼吸病学．北京：人民军医出版社，1997：1010
36．郑则广、陈荣昌、张秀燕，等．两种测量膈神经传导时间和动作电位幅度方法的比较．中国呼吸与危重监护杂志，2002，(1)：36
37．刑国刚、樊小力、宋新爱．股动脉注射琥珀胆碱诱发肌梭传入对膈神经放电的影响．西安医科大学学报，2000，(5)：411
38．杨光华．病理学．北京：人民卫生出版社，2002：39
39．何加琅．第二届全国充血代表大会论文集(二集)．中国药学会，1956：44
40．金惠铭．病理生理学．北京：人民卫生出版社，2002：27，212
41．姚泰．生理学．北京：人民卫生出版社，2001：137
2．何家琅．论文摘要集．中国药学会北京分会，1957：68
3．柯铭清．中草药有效成分理化与药理特性．湖南科学技术出版社，1982：108
4. Frederick F Bockes:Cancer Vol1: 205, 247, P1. enum Press, New York,1975
5. Cameron HM, et al: Liver Cell Cancer, 143 Elsevier Scientific Publishing Company, 1976
6. Hashimoto K, Higuchi M, Makino B, Sakakibara I, Kubo M, Komatsu Y,Maruno M, Okada M. Quantitative analysis of aristolochic acids, toxic compounds, contained in some medicinal plants. J Ethnopharmacol 1999 Feb; 64 (2): 185-9
7. Schaneberg BT, Applequist WL, Khan IA. Determination of aristolochic acid Ⅰand Ⅱ in North American species of Asarum and Aristolochia.Pharmazie 2002 Oct;57(10): 686-9
8．李广勋．中药药理毒理与临床．天津：天津科技翻译出版社，1992：532
9．曲淑岩．细辛对中枢神经系统的抑制作用．中医杂志，1982，(6)：72
10．曲淑岩．细辛油的抗炎作用．药学学报，1982，(1)：12
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