含海藻与甘草反药组合的海藻玉壶汤应用于甲状腺肿大大鼠模型配伍宜忌条件研究
摘要
背景：中药“十八反”是中药药性理论的重要组成部分,属中药配伍禁忌的核心内容,长期以来一直在临床实践中发挥着重要指导作用。对于反药能否同用,历来争议颇多,这也成为中医药学界的难题之一。广大的中医药工作者从文献、化学、药理学、毒理学等方面进行了大量研究,但仍无法全面地揭示配伍禁忌的科学本质内涵。目前研究主要集中在单纯反药组合在生理状态下进行的研究,而针对反药组合在复方下应用的研究相对较少。因此,为了更贴近临床应用的特点,本课题选择含反药组合的经典方剂海藻玉壶汤为切入点,甲状腺肿大病理模型为载体,从方证结合的角度,考察复方中不同比例、不同剂量及不同炮制品种配伍的海藻与甘草在不同条件下的生物学效应。
目的：从临床应用角度,通过动物实验研究,揭示海藻与甘草这对反药组合的不同条件下配伍应用的宜忌条件,探索其更贴近临床使用的增毒(减效)的禁忌条件及致毒特征,或增效(减毒)的适宜条件及起效特征,为指导临床医生安全合理使用海藻与甘草反药组合提供科学支撑,为丰富和完善中药配伍禁忌理论提供可靠的依据。
方法：首先通过探讨海藻、甘草单味药,单纯反药组合及含有反药组合的复方的急性毒性比较实验,考察含反药组合的复方较单味给药组有无毒性增加。根据急性毒性试验结果,确定不同比例配伍实验中海藻与甘草的最大用药剂量范围。其次,根据“973”课题组SOP均匀设计法,低限为药典剂量中的最小剂量,高限为急性毒性试验确定的剂量,按二因素七水平的原则,分别设置海藻与甘草配伍的七个配比组,即甘草与海藻配比一组(14.52：6.24)、配比二组(9.68：12.49)、配比三组(19.36：0.54)、配比四组(4.84：2.08)、配比五组(0.14：8.32)、配比六组(29.04：4.16)、配比七组(24.20：10.40),以正常组、模型组及优甲乐作为对照,观察含海藻甘草不同配比的海藻玉壶汤对甲状腺肿大大鼠模型生物学效应。通过检测大鼠血清中甲状腺激素,尿中碘含量,甲状腺病理形态及甲状腺中相关基因的表达来评价药效学作用,通过心、肝、肾功能性指标,血液系统,生殖系统等指标检测以及相应脏器组织病理形态学观察其是否具有毒性,采用中药组方优化软件及SPSS软件进行数据分析,拟得出海藻与甘草不同配伍比例宜忌条件。
然后,选择生物效应显著的配比进行海藻与甘草不同剂量配伍及炮制品种配伍对甲状腺肿大大鼠模型生物学效应的研究。其中在甘草海藻不同剂量配伍实验研究中,在甘草海藻相同比例(9：5.5)的情况下,分别设置剂量一组(生甘草：海藻=27g：16.5g)、剂量二组(生甘草：海藻=9g：5.5g)、剂量三组(生甘草：海藻=3g：1.83g)、剂量四组(生甘草：海藻=1g：0.61g)；在甘草海藻不同炮制品种配伍的实验中,分别设置相同配伍比例、相同剂量的生甘草配海藻组(生甘草：海藻=9g：5.5g)、炙甘草配海藻组(炙甘草：海藻=9g：5.5g),均以正常组、模型组及阳性药组作为对照,通过检测大鼠血清中甲状腺激素,尿中碘含量,甲状腺病理形态及甲状腺中相关基因的表达来评价药效学作用,通过心、肝、肾功能性指标,血液系统,生殖系统等指标检测及相应脏器组织病理形态学观察评价其是否具有毒性,并采用SPSS软件进行分析,得出二者剂量配伍宜忌条件及炮制品种宜忌条件。
结果：
1.急性毒性实验
(1)根据预实验结果,海藻组、海藻+生甘草组、海藻+炙甘草组死亡率大于80%,需进行LD50实验,其余各组需进行LD50(n)实验。结果表明海藻组、海藻与炙甘草合煎液属小毒范畴,LD50值分别为35.67g·kg-1·d-1,44.29g·kg-1·d-1,海藻与生甘草合煎组LD50值为50.98g·kg-1·d-1,分别相当于临床70kg人每公斤体重日用量的145.2倍,182.6倍和211.5倍。在LD50(n)实验中,炙甘草组连续给药第8天死亡数量达到半数,LD50(8)为70.69g·kg-1·d-1,生甘草组LD50(19)为82.98g·kg-1·d-1,海藻玉壶汤(生甘草)组LD50(7)为79.24g·kg-1·d-1,海藻玉壶汤(炙甘草)组LD50(6)为77.49g·kg1·d-1
(2)单味海藻LD50数值最小,属小毒范畴,其中毒原因可能与海藻中含有大量的碘和钠有关。碘服用过量,中毒可表现腹痛、恶心呕吐、惊厥乃至昏迷、休克等症状,此外,海藻中含有丰富的钠盐,一次性大量服用可能会导致高钠血症。其高渗状态会导致脑细胞失水,造成烦躁、肌张力增高、抽搐、惊厥等神经系统症状。炙甘草组小鼠死亡原因可能不属于毒性表现,推测是由于药液粘腻,影响吸收,导致胃肠胀气所引起,具体原因有待进一步验证。
(3)海藻与生(炙)甘草两种反药配伍使用具有一定的毒性,但含反药组合的复方未表现出明显的毒性。
2.基于均匀设计的海藻与甘草不同比例配伍实验研究
(1)药效：海藻玉壶汤中海藻与甘草不同配比在某种程度上均有抑制丙硫氧嘧啶所导致的甲状腺肿大,以配比一组(14.52：6.24)、三组(19.36：0.54)、六组(29.04：4.16)表现最为明显,配比一组与配比五组(0.14：8.32)还能够回调丙硫氧嘧啶造成的促甲状腺激素升高,配比五组、六组、七组可使大鼠尿中碘的含量升高。
毒性：配比二组(9.68：12.49)心脏系数显著降低,病理变化显示心肌细胞排列紊乱,心肌纤维萎缩、有少量炎性细胞浸润等病理改变；一组、二组(9.68：12.49)大鼠血清中AST/ALT比值显著升高,且一组、六组、七组(24.20：10.40)肝细胞组织结构损伤较其他组稍重；配比一组、三组、六组、七组的肾脏系数明显增大,配比三组、四组、五组、六组、七组血中K+浓度显著降低,病理结果显示配比一组、三组病变较重；七个配比组雌性大鼠卵巢重量均较模型组显著降低,病理结果卵泡数量减少,皮质萎缩。七个配比组对于血液系统无明显影响。海藻甘草不同配伍比例的海藻玉壶汤总体毒性反应并不严重,且与海藻、甘草的比例无明显线性关系,有些毒性指标还需结合进一步病理及分子生物学指标进行分析。
(2)机制探讨：海藻甘草配比一至七组均能增强甲状腺中TPO mRNA的表达,以配比一组与五组作用最强。Tg的转录水平未受到PTU的抑制,配比一组、五组、六组具有促进Tg转录的作用,在某种程度上具有恢复甲状腺激素达到正常水平的作用。
可能导致肝脏毒性的原因：配比一组、二组、三组、七组大鼠肝脏中基因CYP3A1mRNA含量有升高的趋势,以配比七组(24.20：10.40)的表达最高,有一定的随甘草剂量增加而升高的趋势。配比三组、五组、七组有极个别大鼠肝脏CYP3A2的1nRNA有表达,组间无差异。
(3)根据海藻与甘草配伍的七个配比组实验结果,并结合中药组方优化软件进行分析。得出甘草与海藻配伍的适宜条件为甘草：海藻在9：10-24：11之间,即具有降低大鼠甲状腺重量,回调大鼠体内甲状腺激素水平异常,改变甲减大鼠认知能力低下等作用,且肝、肾毒性较小等特点。按上述比例配伍使用可能不显示相反作用,但此结果仅为软件分析结果,有待通过实验进行验证。
当海藻剂量为5.5g,甘草剂量>15g；或甘草剂量为9g,海藻剂量>24g,对大鼠肝、肾系统可能会造成一定的毒性影响。该结果与不同比例配伍实验中肝损伤较重的配比组肝、肾病理组织结构变化情况相吻合。
3.以生甘草与海藻9g：5.5g的比例进行不同剂量配伍的实验研究
(1)药效及其机制：经中药组方优化软件分析计算,海藻玉壶汤中生甘草与海藻配伍比例在9：5.5时应用效果最佳。因此,按此比例不同剂量设置了剂量一组(生甘草：海藻=27g：16.5g)、剂量二组(生甘草：海藻=9g：5.5g)、剂量三组(生甘草：海藻=3g：1.83g)、剂量四组(生甘草：海藻=1g：0.61g)。结果表明四个剂量组均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常。尤以剂量4组(甘草：海藻为1g：0.61g)作用最为明显,其对甲减大鼠体重、饮水量、下丘脑-垂体-甲状腺轴、大鼠血清中T3、T4、FT3、FT4、TBG含量及行为学的异常均显示出较好的效果。其作用机制可能与调节甲状腺中TPO与Tg mRNA的表达有关。该剂量分别约相当于人的等效剂量为11g：7g,属2010版《中国药典》规定剂量范围内。
(2)毒性及其机制：海藻玉壶汤剂量1组(27g：16.5g)及2组(9g：5.5g)大鼠肝细胞出现明显病变其机制可能与剂量1组升高大鼠肝脏中CYP3A1mRNA的表达有关；剂量1组大鼠肾脏出现轻微器质性病变；海藻玉壶汤四个剂量组对雌性大鼠均在一定程度上降低大鼠卵巢系数,病理显示其卵泡数量减少,皮质萎缩,表现出一定的生殖毒性；除剂量3组(3g：1.83g)外,其余各组大鼠睾丸系数均降低。表现出相反作用。综合以上检测指标,大剂量应用的剂量1组(27g：16.5g)肝肾的损伤较为明显,该剂量相当于人的等效剂量为302g：185g,剂量过大,因此不宜配伍使用。
4.以生甘草与海藻9g：5.5g的比例进行不同炮制品种配伍的实验研究
(1)药效及机制：海藻玉壶汤中海藻与甘草不同炮制品种应用时,均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常。生、炙甘草组间无明显差异,其作用机制可能与调节甲状腺中TPO与Tg mRNA的表达有关。
(2)毒性及机制：炙甘草与海藻9g：5.5g配伍使用时,增加大鼠肝脏中CYP2E1mRNA的表达,病理结果表现出一定的肝脏损伤,呈现出相反作用；病理结果显示炙甘草与海藻配伍时对肾脏的损伤作用较生甘草组稍重；从血液系统来看,使甲减大鼠红细胞及血红蛋白含量显著减少,白细胞与血小板数量显著增加,表现出相反作用。但对心脏系统未表现出明显的相反作用。因此,海藻玉壶汤原方中采用的生甘草与海藻配伍使用可能为适宜使用的配伍条件。
结论：由以上结果可知,含有甘草与海藻反药组合的复方并非在所有配伍情况下都出现相反情况,在适宜的配伍条件下,亦可表现出较好的药效。在海藻甘草不同配伍比例的研究中,当生甘草与海藻(9g：5.5g)配伍时有较好的药效,且肝、肾毒性较小。甘草与海藻配伍的适宜条件为甘草：海藻在9：10-24：11之间,即具有降低大鼠甲状腺重量,回调大鼠体内甲状腺激素水平,且肝、肾毒性较小等特点。当海藻剂量为5.5g,甘草剂量>15g；或甘草剂量为9g,海藻剂量>24g,可能会对肝、肾系统造成一定的毒性影响。该结果与不同比例配伍实验中肝损伤较重的配比组肝、肾组织病理结构变化情况基本吻合。
在海藻甘草不同剂量配伍的研究中,当配伍比例相同(生甘草：海藻为9：5.5)时,四个剂量组均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常。以小剂量1g：0.61g(药典范围内剂量)配伍应用时药效较好,肝、肾损伤较轻,该剂量分别约相当于人的等效剂量为11g：7g,属2010版《中国药典》规定计量范围内。大剂量应用的剂量1组(甘草：海藻为27g：16.5g)肝肾的损伤较为明显,该剂量分别约相当于人的等效剂量为302g：185g,剂量过大,因此不宜配伍使用。
在海藻甘草不同炮制品种的研究中,甘草海藻相同配比、相同剂量,不同炮制品种均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常,且组间无明显差异。炙甘草与海藻配伍后对大鼠肝脏、肾脏及血液系统对肝肾脏功能影响较重。二者配伍相反主要的毒性靶器官为肝脏与肾脏,具体机制尚有待进一步实验研究。
Background:"Eighteen antagonisms" has been through a history of thousand years until now which is the controversial prohibited combinations in traditional Chinese medicine.should they be used in clinic or not has been a historical matters that people have been argued about it. Recently, the researches indicate that the Eighteen antagonisms are conditional prohibited combinations. These scientific research were mainly focus on single medicinal combinations. However, instead of single combination, the compound which have the drug combination was often used in clinic. Therefore, in order to close to clinical application, we selected Haizao Yuhu decoction which contains a prohibited combination, namely Haizao(Sargassum)and Gancao (glycyrrhizae radix et rhizoma) in this study. Change the compatibility proportion,, dosage and prepared varieties, we attempts to reveal the the relation between Haizao and Gancao, and its suitable/contraindicant conditions of this prohibited combination.
Object:From a clinical perspective, through animal experiments, reveals the application compatibility Haizao and Gancao the anti drug combinations under different conditions and conditions, to explore the more close to clinical use increase toxicity (reduction) of the taboo conditions and toxic characteristics, or synergistic (attenuated) of the appropriate conditions and work characteristics, in order to provide scientific support for the safe use of reasonable guide clinicians in algae and licorice anti drug combination, provide a reliable basis for enriching and perfecting the incompatibility of Chinese medicine theory.
Method:First of all, we performed acute toxicity test to find out the lethal median dose of Gancao and Haizao.Secondly,based on the results of acute toxicity,we set up seven matched groups according to the principle uniform design(two factors seven level) compared with normal, model, positive group.Using ANOVA (analysis of variance) in combination with optimized formula soft, we analysed the dose range whether Gancao was used concomitantly with Haizao or not.Third, we chose a ratio of marked effect to conduct the expeiment of different dose and preparata compatibility of Gancao and Haizao. Finally, we made a comprehensive analysis to reveal the compatibility and the taboo conditions of Gancao and Gansui.
Result:
1. Acute Toxicity
①The acute toxicity of different groups on mice is:Sargassum>Sargassum with prepared Radix Glycyrrhizae>Sargassum with Radix Glycyrrhizae>prepared Radix Glycyrrhizae>Haizao Yuhu decoction Radix Glycyrrhizae)>Haizao Yuhu decoction(Radix Glycyrrhizae)>Radix Glycyrrhizae.
②Application of Sargassum alone has toxicity strongest, the reason of poison maybe related that the seaweed contains large amounts of iodine and sodium. Iodine overdose, abdominal pain, nausea and vomiting, can behave convulsions and coma, shock and other symptoms of poisoning, in addition, seaweed is rich in sodium, one-time large doses can cause hypernatremia. The hypertonic condition can cause brain cell loss, cause irritability, muscle tension, convulsions, seizures and other symptoms of nervous system. The causes of death of Zhigancao (prepared Radix Glycyrrhizae) mice may be liquid sticky, affect the absorption, causing the cause flatulence, may not belong to the toxicity, need further verification.
③A large number of long-term use has certain toxicity of Sargassum and Radix Glycyrrhizae/Radix Glycyrrhizae, but the compound containing anti drug combinations showed no obvious toxicity.
2The effect and toxicity of Haizao Yuhu decoction with different proportions of Sargassum and Radix Glycyrrhizae in goiter rats
①Effect:Haizao Yuhu decoction with different proportions of Sargassum and Radix Glycyrrhizae can inhibit thyroid enlargement induce by PTU in some degree. the proportion of group one, group three,group six was the most obvious, group one and the five also can callback the thyroid stimulating hormone increased, five, group five, six, seven can make the content of iodine in urine increased obviously.
Toxicity:The cardiac coefficient of group twoobviously reduces, pathological changes showed that the myocardial cells arranged in disorder, cardiac muscle fiber atrophy, change a small amount of inflammatory cell infiltration in pathology; AST/ALT of group one and group two increased significantly, and the liver cell and tissue of group one,six and seven damage than other group slightly heavier; kidney coefficient ratio in group one, group three, group six, group seven increased obviously, ratio of the group three, group four, group five, group six, groups seven of blood K+concentration significantly reduced, pathology results showed group one, three of lesions were heavier; these seven groups of female rats ovary weight was significantly lower than the model group, the pathological results were reduced, cortical atrophy. Seven different groups had no significant effect for blood system. The Haizao Yuhu decoction overall toxicity algae licorice in different compatibility proportion is not serious, no obvious linear relationship between Sargassum and Radix Glycyrrhizae.
②The effect mechanism:The one to seven groups of Sargassum and Radix Glycyrrhizae can enhanced the expression of TPO mRNA in the thyroid, ratio of group one and the five had the strongest effect. The transcript level of Tg was not inhibited by PTU, group one, five and six groups can promote Tg transcription, with recovery of thyroid hormone to reach the normal level to some extent.
Possible causes of liver toxicity:increased CYP3A1mRNA content in group one, group two, group three, group seven of rat liver, with ratio of the seven group expression is highest, with licorice dose increasing trend. Ratio of the three group, five group, seven group have the extremely individual rat liver CYP3A2mRNA expression, no differences between groups.
③According to the compatibility of Sargassum and Radix Glycyrrhizae seven different set of experimental results, combined with Chinese medicine prescription optimization software analysis. The results, suitable condition of Sargassum and Radix Glycyrrhizae: Sargassum:Radix Glycyrrhizae between9:10-24:11, which can reduce the weight of thyroid of rats, abnormal callback rats thyroid hormone levels, changes in hypothyroid rats cognitive ability is low, and the liver, kidney toxicity is low etc. According to the proportions of use may not show the opposite effect, but the result is only the result of software analysis, to be verified by experiment.When the dosage of Sargassum is5.5g>15g or Radix Glycyrrhizae dose; dose was9g, seaweed dose>24g, may cause some toxic effects on the liver, kidney system. The results are consistent with the pathological changes in renal tissue of liver, and the proportion of different proportions of experimental liver injury heavier.
3. Experimental study on the proportion of different dosage of Radix Glycyrrhizae: Sargassum (9:5.5)
①The Chinese medicine prescription optimization software of analysis and calculation, the Haizao Yuhu decoction with Radix Glycyrrhizae:Sargassum compatibility proportion in9:5.5application,the effect is best. Therefore, according to the proportion of different doses of set dose group (Radix Glycyrrhizae:Sargassum=27g:16.5g), dose group two (Radix Glycyrrhizae:Sargassum=9g:5.5g), dose group three (Radix Glycyrrhizae: Sargassum=3g:1.83g), dose group four (Radix Glycyrrhizae:Sargassum=1g:0.61g). The results show that the four dose groups were improved in varying degrees by propylthiouracil caused by hypothyroidism rats body weight, food consumption, body temperature and abnormal expression of thyroid hormone. The dose of4groups (Radix Glycyrrhizae: Sargassum as1g:0.61g) for the most obvious role, the serum hypothyroid rats weight, the amount of water, the hypothalamus pituitary thyroid axis, rats in T3, T4, FT3, FT4, TBG content and behavioral abnormalities showed good effect. The mechanism may be related with the expression of TPO and Tg mRNA of thyroid. The equivalent of the11g:7g, is the2010version of Regulations of measurement range
②the mechanism may be related with the dose of group1increased CYP3A1mRNA in rat liver expression of rat liver cells; renal dose group1rats appeared slight pathological changes; the Haizao Yuhu decoction four dose groups of female rats are in a certain extent, reduce ovarian coefficient of rats, pathological display the follicle number reduce, atrophy of cortex, showed some reproductive toxicity; in addition to dose group3, testis coefficient of all rats were decreased. Show the opposite effect. Based on the above indexes, using large dose dose group1(27g:16.5g) in liver and kidney damage is more obvious, the equivalent dose and the dose equivalent of302g:185g, dosage is too large, so it should not be compatible for use.
4. Experimental study on the proportion of different processing varieties of Radix Glycyrrhizae:Sargassum
Haizao Yuhu decoction with a ratio of Radix Glycyrrhizae:Sargassum is9:5.5application compatibility, different processing varieties at different levels can improve the body weight, caused by propylthiouracil abnormal hormone levels in hypothyroid rats feed temperature and related thyroid content, expression, and no significant difference between groups. But the licorice and seaweed compatibility on rat liver, kidney and blood system showed certain toxicity, raw licorice compatibility is serious, has the opposite effect, so not compatible for use.
Conclusion:From the above result, Radix Glycyrrhizae:Sargassum in the compound containing the drug combination is not in all circumstances "reverse", select the compatibility conditions suitable, also showed better efficacy. When the raw licorice and seaweed (9g:5.5g) and has better efficacy, and liver, kidney toxicity is small; when the compatibility proportion of the same, with small dose of1g:0.61g (Pharmacopoeia range dose) effective application compatibility, liver, kidney injury is light; the same proportion, the same dose of different processed varieties, application compatibility, the compatibility of Radix Glycyrrhizae and seaweed on liver kidney function was not affected. The two combined opposite the main toxicity target organ is the liver and kidney, the specific mechanism needs further experimental research.
目的：从临床应用角度,通过动物实验研究,揭示海藻与甘草这对反药组合的不同条件下配伍应用的宜忌条件,探索其更贴近临床使用的增毒(减效)的禁忌条件及致毒特征,或增效(减毒)的适宜条件及起效特征,为指导临床医生安全合理使用海藻与甘草反药组合提供科学支撑,为丰富和完善中药配伍禁忌理论提供可靠的依据。
方法：首先通过探讨海藻、甘草单味药,单纯反药组合及含有反药组合的复方的急性毒性比较实验,考察含反药组合的复方较单味给药组有无毒性增加。根据急性毒性试验结果,确定不同比例配伍实验中海藻与甘草的最大用药剂量范围。其次,根据“973”课题组SOP均匀设计法,低限为药典剂量中的最小剂量,高限为急性毒性试验确定的剂量,按二因素七水平的原则,分别设置海藻与甘草配伍的七个配比组,即甘草与海藻配比一组(14.52：6.24)、配比二组(9.68：12.49)、配比三组(19.36：0.54)、配比四组(4.84：2.08)、配比五组(0.14：8.32)、配比六组(29.04：4.16)、配比七组(24.20：10.40),以正常组、模型组及优甲乐作为对照,观察含海藻甘草不同配比的海藻玉壶汤对甲状腺肿大大鼠模型生物学效应。通过检测大鼠血清中甲状腺激素,尿中碘含量,甲状腺病理形态及甲状腺中相关基因的表达来评价药效学作用,通过心、肝、肾功能性指标,血液系统,生殖系统等指标检测以及相应脏器组织病理形态学观察其是否具有毒性,采用中药组方优化软件及SPSS软件进行数据分析,拟得出海藻与甘草不同配伍比例宜忌条件。
然后,选择生物效应显著的配比进行海藻与甘草不同剂量配伍及炮制品种配伍对甲状腺肿大大鼠模型生物学效应的研究。其中在甘草海藻不同剂量配伍实验研究中,在甘草海藻相同比例(9：5.5)的情况下,分别设置剂量一组(生甘草：海藻=27g：16.5g)、剂量二组(生甘草：海藻=9g：5.5g)、剂量三组(生甘草：海藻=3g：1.83g)、剂量四组(生甘草：海藻=1g：0.61g)；在甘草海藻不同炮制品种配伍的实验中,分别设置相同配伍比例、相同剂量的生甘草配海藻组(生甘草：海藻=9g：5.5g)、炙甘草配海藻组(炙甘草：海藻=9g：5.5g),均以正常组、模型组及阳性药组作为对照,通过检测大鼠血清中甲状腺激素,尿中碘含量,甲状腺病理形态及甲状腺中相关基因的表达来评价药效学作用,通过心、肝、肾功能性指标,血液系统,生殖系统等指标检测及相应脏器组织病理形态学观察评价其是否具有毒性,并采用SPSS软件进行分析,得出二者剂量配伍宜忌条件及炮制品种宜忌条件。
结果：
1.急性毒性实验
(1)根据预实验结果,海藻组、海藻+生甘草组、海藻+炙甘草组死亡率大于80%,需进行LD50实验,其余各组需进行LD50(n)实验。结果表明海藻组、海藻与炙甘草合煎液属小毒范畴,LD50值分别为35.67g·kg-1·d-1,44.29g·kg-1·d-1,海藻与生甘草合煎组LD50值为50.98g·kg-1·d-1,分别相当于临床70kg人每公斤体重日用量的145.2倍,182.6倍和211.5倍。在LD50(n)实验中,炙甘草组连续给药第8天死亡数量达到半数,LD50(8)为70.69g·kg-1·d-1,生甘草组LD50(19)为82.98g·kg-1·d-1,海藻玉壶汤(生甘草)组LD50(7)为79.24g·kg-1·d-1,海藻玉壶汤(炙甘草)组LD50(6)为77.49g·kg1·d-1
(2)单味海藻LD50数值最小,属小毒范畴,其中毒原因可能与海藻中含有大量的碘和钠有关。碘服用过量,中毒可表现腹痛、恶心呕吐、惊厥乃至昏迷、休克等症状,此外,海藻中含有丰富的钠盐,一次性大量服用可能会导致高钠血症。其高渗状态会导致脑细胞失水,造成烦躁、肌张力增高、抽搐、惊厥等神经系统症状。炙甘草组小鼠死亡原因可能不属于毒性表现,推测是由于药液粘腻,影响吸收,导致胃肠胀气所引起,具体原因有待进一步验证。
(3)海藻与生(炙)甘草两种反药配伍使用具有一定的毒性,但含反药组合的复方未表现出明显的毒性。
2.基于均匀设计的海藻与甘草不同比例配伍实验研究
(1)药效：海藻玉壶汤中海藻与甘草不同配比在某种程度上均有抑制丙硫氧嘧啶所导致的甲状腺肿大,以配比一组(14.52：6.24)、三组(19.36：0.54)、六组(29.04：4.16)表现最为明显,配比一组与配比五组(0.14：8.32)还能够回调丙硫氧嘧啶造成的促甲状腺激素升高,配比五组、六组、七组可使大鼠尿中碘的含量升高。
毒性：配比二组(9.68：12.49)心脏系数显著降低,病理变化显示心肌细胞排列紊乱,心肌纤维萎缩、有少量炎性细胞浸润等病理改变；一组、二组(9.68：12.49)大鼠血清中AST/ALT比值显著升高,且一组、六组、七组(24.20：10.40)肝细胞组织结构损伤较其他组稍重；配比一组、三组、六组、七组的肾脏系数明显增大,配比三组、四组、五组、六组、七组血中K+浓度显著降低,病理结果显示配比一组、三组病变较重；七个配比组雌性大鼠卵巢重量均较模型组显著降低,病理结果卵泡数量减少,皮质萎缩。七个配比组对于血液系统无明显影响。海藻甘草不同配伍比例的海藻玉壶汤总体毒性反应并不严重,且与海藻、甘草的比例无明显线性关系,有些毒性指标还需结合进一步病理及分子生物学指标进行分析。
(2)机制探讨：海藻甘草配比一至七组均能增强甲状腺中TPO mRNA的表达,以配比一组与五组作用最强。Tg的转录水平未受到PTU的抑制,配比一组、五组、六组具有促进Tg转录的作用,在某种程度上具有恢复甲状腺激素达到正常水平的作用。
可能导致肝脏毒性的原因：配比一组、二组、三组、七组大鼠肝脏中基因CYP3A1mRNA含量有升高的趋势,以配比七组(24.20：10.40)的表达最高,有一定的随甘草剂量增加而升高的趋势。配比三组、五组、七组有极个别大鼠肝脏CYP3A2的1nRNA有表达,组间无差异。
(3)根据海藻与甘草配伍的七个配比组实验结果,并结合中药组方优化软件进行分析。得出甘草与海藻配伍的适宜条件为甘草：海藻在9：10-24：11之间,即具有降低大鼠甲状腺重量,回调大鼠体内甲状腺激素水平异常,改变甲减大鼠认知能力低下等作用,且肝、肾毒性较小等特点。按上述比例配伍使用可能不显示相反作用,但此结果仅为软件分析结果,有待通过实验进行验证。
当海藻剂量为5.5g,甘草剂量>15g；或甘草剂量为9g,海藻剂量>24g,对大鼠肝、肾系统可能会造成一定的毒性影响。该结果与不同比例配伍实验中肝损伤较重的配比组肝、肾病理组织结构变化情况相吻合。
3.以生甘草与海藻9g：5.5g的比例进行不同剂量配伍的实验研究
(1)药效及其机制：经中药组方优化软件分析计算,海藻玉壶汤中生甘草与海藻配伍比例在9：5.5时应用效果最佳。因此,按此比例不同剂量设置了剂量一组(生甘草：海藻=27g：16.5g)、剂量二组(生甘草：海藻=9g：5.5g)、剂量三组(生甘草：海藻=3g：1.83g)、剂量四组(生甘草：海藻=1g：0.61g)。结果表明四个剂量组均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常。尤以剂量4组(甘草：海藻为1g：0.61g)作用最为明显,其对甲减大鼠体重、饮水量、下丘脑-垂体-甲状腺轴、大鼠血清中T3、T4、FT3、FT4、TBG含量及行为学的异常均显示出较好的效果。其作用机制可能与调节甲状腺中TPO与Tg mRNA的表达有关。该剂量分别约相当于人的等效剂量为11g：7g,属2010版《中国药典》规定剂量范围内。
(2)毒性及其机制：海藻玉壶汤剂量1组(27g：16.5g)及2组(9g：5.5g)大鼠肝细胞出现明显病变其机制可能与剂量1组升高大鼠肝脏中CYP3A1mRNA的表达有关；剂量1组大鼠肾脏出现轻微器质性病变；海藻玉壶汤四个剂量组对雌性大鼠均在一定程度上降低大鼠卵巢系数,病理显示其卵泡数量减少,皮质萎缩,表现出一定的生殖毒性；除剂量3组(3g：1.83g)外,其余各组大鼠睾丸系数均降低。表现出相反作用。综合以上检测指标,大剂量应用的剂量1组(27g：16.5g)肝肾的损伤较为明显,该剂量相当于人的等效剂量为302g：185g,剂量过大,因此不宜配伍使用。
4.以生甘草与海藻9g：5.5g的比例进行不同炮制品种配伍的实验研究
(1)药效及机制：海藻玉壶汤中海藻与甘草不同炮制品种应用时,均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常。生、炙甘草组间无明显差异,其作用机制可能与调节甲状腺中TPO与Tg mRNA的表达有关。
(2)毒性及机制：炙甘草与海藻9g：5.5g配伍使用时,增加大鼠肝脏中CYP2E1mRNA的表达,病理结果表现出一定的肝脏损伤,呈现出相反作用；病理结果显示炙甘草与海藻配伍时对肾脏的损伤作用较生甘草组稍重；从血液系统来看,使甲减大鼠红细胞及血红蛋白含量显著减少,白细胞与血小板数量显著增加,表现出相反作用。但对心脏系统未表现出明显的相反作用。因此,海藻玉壶汤原方中采用的生甘草与海藻配伍使用可能为适宜使用的配伍条件。
结论：由以上结果可知,含有甘草与海藻反药组合的复方并非在所有配伍情况下都出现相反情况,在适宜的配伍条件下,亦可表现出较好的药效。在海藻甘草不同配伍比例的研究中,当生甘草与海藻(9g：5.5g)配伍时有较好的药效,且肝、肾毒性较小。甘草与海藻配伍的适宜条件为甘草：海藻在9：10-24：11之间,即具有降低大鼠甲状腺重量,回调大鼠体内甲状腺激素水平,且肝、肾毒性较小等特点。当海藻剂量为5.5g,甘草剂量>15g；或甘草剂量为9g,海藻剂量>24g,可能会对肝、肾系统造成一定的毒性影响。该结果与不同比例配伍实验中肝损伤较重的配比组肝、肾组织病理结构变化情况基本吻合。
在海藻甘草不同剂量配伍的研究中,当配伍比例相同(生甘草：海藻为9：5.5)时,四个剂量组均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常。以小剂量1g：0.61g(药典范围内剂量)配伍应用时药效较好,肝、肾损伤较轻,该剂量分别约相当于人的等效剂量为11g：7g,属2010版《中国药典》规定计量范围内。大剂量应用的剂量1组(甘草：海藻为27g：16.5g)肝肾的损伤较为明显,该剂量分别约相当于人的等效剂量为302g：185g,剂量过大,因此不宜配伍使用。
在海藻甘草不同炮制品种的研究中,甘草海藻相同配比、相同剂量,不同炮制品种均能在不同程度上改善由丙硫氧嘧啶造成的甲减大鼠体重、食水量、体温及相关甲状腺激素表达异常,且组间无明显差异。炙甘草与海藻配伍后对大鼠肝脏、肾脏及血液系统对肝肾脏功能影响较重。二者配伍相反主要的毒性靶器官为肝脏与肾脏,具体机制尚有待进一步实验研究。
Background:"Eighteen antagonisms" has been through a history of thousand years until now which is the controversial prohibited combinations in traditional Chinese medicine.should they be used in clinic or not has been a historical matters that people have been argued about it. Recently, the researches indicate that the Eighteen antagonisms are conditional prohibited combinations. These scientific research were mainly focus on single medicinal combinations. However, instead of single combination, the compound which have the drug combination was often used in clinic. Therefore, in order to close to clinical application, we selected Haizao Yuhu decoction which contains a prohibited combination, namely Haizao(Sargassum)and Gancao (glycyrrhizae radix et rhizoma) in this study. Change the compatibility proportion,, dosage and prepared varieties, we attempts to reveal the the relation between Haizao and Gancao, and its suitable/contraindicant conditions of this prohibited combination.
Object:From a clinical perspective, through animal experiments, reveals the application compatibility Haizao and Gancao the anti drug combinations under different conditions and conditions, to explore the more close to clinical use increase toxicity (reduction) of the taboo conditions and toxic characteristics, or synergistic (attenuated) of the appropriate conditions and work characteristics, in order to provide scientific support for the safe use of reasonable guide clinicians in algae and licorice anti drug combination, provide a reliable basis for enriching and perfecting the incompatibility of Chinese medicine theory.
Method:First of all, we performed acute toxicity test to find out the lethal median dose of Gancao and Haizao.Secondly,based on the results of acute toxicity,we set up seven matched groups according to the principle uniform design(two factors seven level) compared with normal, model, positive group.Using ANOVA (analysis of variance) in combination with optimized formula soft, we analysed the dose range whether Gancao was used concomitantly with Haizao or not.Third, we chose a ratio of marked effect to conduct the expeiment of different dose and preparata compatibility of Gancao and Haizao. Finally, we made a comprehensive analysis to reveal the compatibility and the taboo conditions of Gancao and Gansui.
Result:
1. Acute Toxicity
①The acute toxicity of different groups on mice is:Sargassum>Sargassum with prepared Radix Glycyrrhizae>Sargassum with Radix Glycyrrhizae>prepared Radix Glycyrrhizae>Haizao Yuhu decoction Radix Glycyrrhizae)>Haizao Yuhu decoction(Radix Glycyrrhizae)>Radix Glycyrrhizae.
②Application of Sargassum alone has toxicity strongest, the reason of poison maybe related that the seaweed contains large amounts of iodine and sodium. Iodine overdose, abdominal pain, nausea and vomiting, can behave convulsions and coma, shock and other symptoms of poisoning, in addition, seaweed is rich in sodium, one-time large doses can cause hypernatremia. The hypertonic condition can cause brain cell loss, cause irritability, muscle tension, convulsions, seizures and other symptoms of nervous system. The causes of death of Zhigancao (prepared Radix Glycyrrhizae) mice may be liquid sticky, affect the absorption, causing the cause flatulence, may not belong to the toxicity, need further verification.
③A large number of long-term use has certain toxicity of Sargassum and Radix Glycyrrhizae/Radix Glycyrrhizae, but the compound containing anti drug combinations showed no obvious toxicity.
2The effect and toxicity of Haizao Yuhu decoction with different proportions of Sargassum and Radix Glycyrrhizae in goiter rats
①Effect:Haizao Yuhu decoction with different proportions of Sargassum and Radix Glycyrrhizae can inhibit thyroid enlargement induce by PTU in some degree. the proportion of group one, group three,group six was the most obvious, group one and the five also can callback the thyroid stimulating hormone increased, five, group five, six, seven can make the content of iodine in urine increased obviously.
Toxicity:The cardiac coefficient of group twoobviously reduces, pathological changes showed that the myocardial cells arranged in disorder, cardiac muscle fiber atrophy, change a small amount of inflammatory cell infiltration in pathology; AST/ALT of group one and group two increased significantly, and the liver cell and tissue of group one,six and seven damage than other group slightly heavier; kidney coefficient ratio in group one, group three, group six, group seven increased obviously, ratio of the group three, group four, group five, group six, groups seven of blood K+concentration significantly reduced, pathology results showed group one, three of lesions were heavier; these seven groups of female rats ovary weight was significantly lower than the model group, the pathological results were reduced, cortical atrophy. Seven different groups had no significant effect for blood system. The Haizao Yuhu decoction overall toxicity algae licorice in different compatibility proportion is not serious, no obvious linear relationship between Sargassum and Radix Glycyrrhizae.
②The effect mechanism:The one to seven groups of Sargassum and Radix Glycyrrhizae can enhanced the expression of TPO mRNA in the thyroid, ratio of group one and the five had the strongest effect. The transcript level of Tg was not inhibited by PTU, group one, five and six groups can promote Tg transcription, with recovery of thyroid hormone to reach the normal level to some extent.
Possible causes of liver toxicity:increased CYP3A1mRNA content in group one, group two, group three, group seven of rat liver, with ratio of the seven group expression is highest, with licorice dose increasing trend. Ratio of the three group, five group, seven group have the extremely individual rat liver CYP3A2mRNA expression, no differences between groups.
③According to the compatibility of Sargassum and Radix Glycyrrhizae seven different set of experimental results, combined with Chinese medicine prescription optimization software analysis. The results, suitable condition of Sargassum and Radix Glycyrrhizae: Sargassum:Radix Glycyrrhizae between9:10-24:11, which can reduce the weight of thyroid of rats, abnormal callback rats thyroid hormone levels, changes in hypothyroid rats cognitive ability is low, and the liver, kidney toxicity is low etc. According to the proportions of use may not show the opposite effect, but the result is only the result of software analysis, to be verified by experiment.When the dosage of Sargassum is5.5g>15g or Radix Glycyrrhizae dose; dose was9g, seaweed dose>24g, may cause some toxic effects on the liver, kidney system. The results are consistent with the pathological changes in renal tissue of liver, and the proportion of different proportions of experimental liver injury heavier.
3. Experimental study on the proportion of different dosage of Radix Glycyrrhizae: Sargassum (9:5.5)
①The Chinese medicine prescription optimization software of analysis and calculation, the Haizao Yuhu decoction with Radix Glycyrrhizae:Sargassum compatibility proportion in9:5.5application,the effect is best. Therefore, according to the proportion of different doses of set dose group (Radix Glycyrrhizae:Sargassum=27g:16.5g), dose group two (Radix Glycyrrhizae:Sargassum=9g:5.5g), dose group three (Radix Glycyrrhizae: Sargassum=3g:1.83g), dose group four (Radix Glycyrrhizae:Sargassum=1g:0.61g). The results show that the four dose groups were improved in varying degrees by propylthiouracil caused by hypothyroidism rats body weight, food consumption, body temperature and abnormal expression of thyroid hormone. The dose of4groups (Radix Glycyrrhizae: Sargassum as1g:0.61g) for the most obvious role, the serum hypothyroid rats weight, the amount of water, the hypothalamus pituitary thyroid axis, rats in T3, T4, FT3, FT4, TBG content and behavioral abnormalities showed good effect. The mechanism may be related with the expression of TPO and Tg mRNA of thyroid. The equivalent of the11g:7g, is the2010version of
②the mechanism may be related with the dose of group1increased CYP3A1mRNA in rat liver expression of rat liver cells; renal dose group1rats appeared slight pathological changes; the Haizao Yuhu decoction four dose groups of female rats are in a certain extent, reduce ovarian coefficient of rats, pathological display the follicle number reduce, atrophy of cortex, showed some reproductive toxicity; in addition to dose group3, testis coefficient of all rats were decreased. Show the opposite effect. Based on the above indexes, using large dose dose group1(27g:16.5g) in liver and kidney damage is more obvious, the equivalent dose and the dose equivalent of302g:185g, dosage is too large, so it should not be compatible for use.
4. Experimental study on the proportion of different processing varieties of Radix Glycyrrhizae:Sargassum
Haizao Yuhu decoction with a ratio of Radix Glycyrrhizae:Sargassum is9:5.5application compatibility, different processing varieties at different levels can improve the body weight, caused by propylthiouracil abnormal hormone levels in hypothyroid rats feed temperature and related thyroid content, expression, and no significant difference between groups. But the licorice and seaweed compatibility on rat liver, kidney and blood system showed certain toxicity, raw licorice compatibility is serious, has the opposite effect, so not compatible for use.
Conclusion:From the above result, Radix Glycyrrhizae:Sargassum in the compound containing the drug combination is not in all circumstances "reverse", select the compatibility conditions suitable, also showed better efficacy. When the raw licorice and seaweed (9g:5.5g) and has better efficacy, and liver, kidney toxicity is small; when the compatibility proportion of the same, with small dose of1g:0.61g (Pharmacopoeia range dose) effective application compatibility, liver, kidney injury is light; the same proportion, the same dose of different processed varieties, application compatibility, the compatibility of Radix Glycyrrhizae and seaweed on liver kidney function was not affected. The two combined opposite the main toxicity target organ is the liver and kidney, the specific mechanism needs further experimental research.
引文
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