复方慢呼抗抗鸡毒支原体药效物质基础及质量控制的研究
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摘要
鸡毒支原体(Mycoplasma gallisepticum, MG)是一种可引起鸡慢性呼吸道病(Chronic respiratory disease, CRD)的病原菌,感染此病原菌可增加雏鸡的弱雏率,降低蛋鸡的产蛋率,减少肉鸡体重并延长其上市期,降低饲料的转化率等,使养鸡业遭受巨大的经济损失。复方中兽药复方慢呼抗由黄芩、金银花、百部、紫菀和甘草五味中药组成,现已被证实对治疗鸡毒支原体病有良好的疗效,并且毒副作用小、不易产生耐药性,具有很好的开发潜力。但由于复方慢呼抗药效物质基础尚不明确,无法进一步开展其作用机制、体内生物转化及代谢过程的研究,不仅导致复方慢呼抗缺乏可靠的药理学、毒理学研究数据,而且难以建立可控可评的质量标准,大大限制了复方慢呼抗在临床中的应用。因此,阐明复方慢呼抗药效物质基础,不仅可揭示其应用的利学内涵,而且在此基础上可建立全面的质量控制体系,从而有利的保证复方慢呼抗质量的均一、稳定,进一步保证了临床疗效的可重现性,亦为复方慢呼抗作用机制的研究及其“二次开发”打下基础。
本文首先构建了复方慢呼抗的体外指纹图谱,从宏观的角度来评价复方慢呼抗整体的质量,并用同样的色谱条件建立了血清指纹图谱,通过体外指纹图谱与血清指纹图谱的比对,确定了复力慢呼抗体内直接作用的物质基础；同时进行了体外抗鸡毒支原体的药效学试验,将指纹图谱特征峰的峰面积和药效学数据进行灰色关联度分析,确定了复方慢呼抗抗鸡毒支原体的关键药效组分；建立了关键药效组分的定量方法,用微观的定量分析弥补指纹图谱质量控制的不足,从而建立了宏观指纹图谱与药效组分定量分析相结合的复方慢呼抗质量控制的新方法。本研究取得如下几方而的成果：
1.复方慢呼抗指纹图谱的构建及模式分类研究
采用HPLC法对不同批次的复方慢呼抗样品进行分析,对色谱条件(如色谱柱、检测波长、流动相系统、洗脱梯度等)进行了优化,完成了系统的方法学考察,构建了复方慢呼抗HPLC指纹图谱。应用“中药色谱指纹图谱相似性评价系统2004A版”对复方慢呼抗HPLC指纹图谱进行了相似度评价,并借助于SPSS11.5软件对量化的指纹特征(色谱峰峰面积)进行了聚类分析及主成分分析,结果证明三种分析方法具有很好的一致性,可有效地对复方慢呼抗指纹图谱进行评价。此外,还应用建立的色谱条件对复方慢呼抗与各组成药的相关性进行了分析,通过与指纹图谱进行比对,确定了指纹图谱共有峰的来源。在实际应用时,只需将待测样品按本研究所述的色谱条件进行分析,将量化指纹特征数据输入计算机进行运算,就能快速得出评价结果,这对于复方慢呼抗质量控制的研究具有重要的理论意义和实用价值。
2.复方慢呼抗血浆指纹图谱的建立及血中移行成分分析
在已建立的复方慢呼抗指纹图谱基础上,通过优化含药血浆的前处理条件,建立了复方慢呼抗血.浆指纹图谱。针对不同时间点的移行成分。运用HPLC-DAD方法对复方慢呼抗提取液、给药血浆和空白血浆进行对比分析。结果显示：在给药后15min入血成分较少,仅有11号峰较明显；30min出现入血原形成分最多；60min时,一些入血成分减弱或消失,同时有6个代谢产物产生；在120min第2号峰被检出并且有较高的响应值,其他峰减弱或消失。通过血清药物化学的研究,可以确定指纹图谱中的共有峰绝大部分均可被吸收入血,是复方慢呼抗体内直接作用的物质基础。
3.复方慢呼抗指纹图谱特征与药效关系的研究
由于甘草对复方慢呼抗指纹图谱共有峰无贡献,故舍去甘草,将其他4味药重新组方研究其谱效关系。以原处方量的0.5,1,1.5倍量作为3个考察水平,以方中4味药为考察因素,以L9(34)正交表进行药量的加减试验。将各组样品分别进行指纹图谱分析和体外抗鸡毒支原体的药效学试验,在获得复方慢呼抗指纹图谱与药效学量化数据的基础上,采用灰关联度分析技术,寻找指纹图谱特征峰所代表的化学成分对药效贡献的大小。结果表明复方慢呼抗抗鸡毒支原体的作用是其“化学成分群”共同作用的结果。并且根据关联度的大小,绿原酸、4号峰(未鉴定)、黄芩苷、汉黄芩苷对“抗鸡毒支原体”活性的贡献最大。
4.复万慢呼抗指纹图谱中绿原酸、黄芩营、汉黄岑苷的含量测定
由于复方慢呼抗中的绿原酸、黄芩苷、汉黄芩苷与抗鸡毒支原体活性的关联度较大,他们的含量在一定程度上可反应复力慢呼抗的质量优劣。因此,本试验采用指纹图谱的色谱条件,以三种成分最大吸收波长作为检测波长,对三种活性成分进行了方法学考察并同时测定各成分的含量。结果表明方法学考察中各项试验结果的RSD均小于3%,表明仪器精密度高、方法的重复性好,并具有良好的回收率和稳定性。复方慢呼抗提取物中三种成分的含量为别为(1.53±0.03)%、(10.93±0.27)%、(4.476±0.11)%。建立的三种成分同时测定方法,不仅使定量分析更加简便、快捷,并且可以弥补指纹图谱在定量控制方面的不足,二者结合可以更有效、全面的控制复方慢呼抗的质量。
5.复方慢呼抗提取工艺的研究
黄芩苷、汉黄芩苷、绿原酸已被确定为复方慢呼抗抗鸡毒支原体的关键组分,引入总评“归一值”将三个指标综合为一个指标,在对提取温度、提取时间、液料比进行单因素考察基础上,采用Box-Behnken响应面法进行了工艺的优化。通过Design-expert软件7.0对此模型的最佳结果进行预测,当提取温度为92.58℃,液料比为25.23：1,提取时间为2.42h时,预测最佳OD值为0.741,经试验验证,获得的OD值为0.7591,偏差仅为2.44%。最后进行了提取次数的考察,结果显示第二次提取可明显的改善提取效果,但再增加提取次数对成分的溶出率影响不大,因此选择提取次数为2次。考虑到实际操作的可行性,将最终提取工艺确定为提取温度93℃,液料比25：1,提取时间2.4h,提取次数2次。通过建立以药效组分为指标的提取工艺,可实现在同样药量下,保证有效成分的最大溶出,使得复方慢呼抗的作用得到进一步保障。
本研究为中兽药抗鸡毒支原体药效物质基础及质量控制的研究提供了一条新途径,即首先采用血清药物化学的方法确定中兽药体内直接作用的物质基础,再用谱效结合的方法辨识出关键药效组分。同时,提出以指纹图谱结合关键药效组分定量分析的方法,来全面的控制复方中兽药的质量。本研究具有理论意义和实用价值,同时对指纹图谱技术、血清药物化学及谱效关系在中兽药中的应用起到了示范作用。
Mycoplasma gallisepticum (MG) was a primary pathogen causing chronic respiratory disease (CRD) in chicken, and MG infection could lead to high unhealthy chicken rates, dropping egg production, lower weight, prolonged period of onset to market. So it may result in economic losses in the poultry industry. Compound Manhukang was a pharmaceutical preparation used for the treatment of upper respiratory infection disease caused by MG infection. The compound medicine was composed of five Chinese medicinal herbs i.e. Scutellariae Radix, Lonicerae japonicae Flos, Stemonae Radix. Asleris radix et rhizome and Glycyrrhiza Radix. The medicine had sufficient commercial potential because it had a definitely curative effect, without poison and side effect. As the complex chemical constituents in Manhukang and the unknown active substance in vivo, studying on the action mechanism, the process of biotransformation and metabolism would be aimLess, which also had severely constrainted the modern research of Manhukang, and resulted in the low export rate.
The effective substances of Manhukang should be revealed by using the method of Serum pharmaco-chemistry and spectrum-effect combination. On this basis, a quality consistency assessment was developed based on quantitative determination of the effective substances and qualitative fingerprinting analysis. It has an actual sense of not only spreading the culture of traditional medicine, but also promoting the investigation and development, serving the human beings and transforming it into commodity's advantages, which consequently advance economy development rapidly in local region.
By using the method of Serum pharmaco-chemistry of Chinese Medicine, the analysis of constituents in blood was been carried out after oral administration of Manhukang extract. According to HPLC fingerprint and anti-mycoplasma activity test, grey relational analysis was applied to find the active compositions. On this basis, quantitative determination of active compositions was carried out with HPLC method as a supplement for quality control of Manhukang. And we have already achieved such achievement as follows:
1. The establishment of Manhukang fingerprint and studies on pattern classification
HPLC was introduced to analyze Manhukang samples from different batches. Mobile phase, chromatographic column and detected wavelength etc. were optimized to complete the systemic methodology and establish the HPLC fingerprint of Manhukang. Moreover, the similarity evaluation of chromatograms was processed by systematically comparing chromatograms with a professional analytical software recommended by State Food and Drug Administration. The quantitative fingerprint characteristic was treated with cluster analysis and principal component analysis with the help of SPSS11.5software, which proved to be consistent with the similarity evaluation. In order to identify the origins of these characteristic peaks from each herb, a comparative study was carried out between Manhukang and individual herbs. So the correlation between fingerprint of the preparations and that of their raw herbs was also examined in this study. Actually, the determined samples just need to be analyzed with the chromatographic conditions described above, and input the quantitative fingerprint characteristic of the samples into computer to calculate, then the classified results would be quickly acquired, which has both academic significance and applied value.
2. Study on Serum pharmaco-chemistry of Manhukang
By using the established analysis method of HPLC-DAD, the analysis method of serum pharmaco-chemistry was established after optimizing the pretreatment condition of plasma. From a comprehensive analysis of the HPLC-DAD chromatography of Manhukang, controlled plasma and dosed plasma, the constituents in blood were analyzed at different time point. It can be seen that only No.11peak was more obvious at15min after oral administration. Then30min after oral administration, major essential components were detected. After an hour, six new components were detected and some components disappeared. The No.2peak appeared at120min after oral administration. By using the method of Serum pharmaco-chemistry of Chinese Medicine, the majority of common peaks in the fingerprint were absorbed into serum. They were the main material basis for the treatment of upper respiratory infection disease.
3. Study on the correlation between characteristic of Manhukang fingerprint and pharmacodynamics
Glycyrrhiza Radix had no contribution to the common peaks of the fingerprint, so rounding it, the other herbs had been combined into nine groups of samples. At the premise of the acquired characteristic of fingerprint and pharmacodynamic data, grey relational analysis was selected to show what the constituents represented by fingerprint contributed to pharmaeodynamies. It could be concluded that effects were the total results of chemical constituents group in Manhukang. According to the relational grade, chlorogenic acid, baicalin, wogonoside and an unknown component had great contribution to anti-mycoplasma activity.
4. Simultaneous determination of chlorogenic acid, baicalin and wogonoside in Manhukang by high performance liquid chromatography-DAD method
A high performance liquid chromatographic method was developed to simultaneously determine chlorogenic acid, baicalin and wogonoside based on the chromatographic conditions of fingerprinting. The results show that RSD of the test results in the methodological study were less than3%, indicating that the instrument precision, reproducible, recovery and stability of the method were credible. The content of the three components were0.463±0.009,2.42±0.06,0.97±0.02, respectively. The establishment of content determination method could supply the deficiency of fingerprint in quantitative control. The efficient quality control method would be established combinative method using HPLC quantitative and qualitative analyses.
5. Optimization of extraction of Manhukang by response surface methodology
The extraction process of Manhukang was optimized with extraction temperature, extraction time and ratio of water to material as independent variables, and the overall desirability value of the yield of chlorogenic acid, baicalin and wogonoside as evaluation indexes; Quadratic polynomial fitting and depicting of3D-response surface were performed and from which the optimal extraction process was selected. The optimal extraction process was as follows:extraction temperature92.58℃, ratio of water to material25.23and extraction time2.42h. Under the optimized condition, the experimental value of0.738±0.015was well in close agreement with the value predicted by the model. Moreover, the overall desirability value in the condition was higher than that of the non-optimized condition. These results help in designing the process of optimal chlorogenic acid, baicalin and wogonoside from compound Manhukang.
In this study, a new approach was provided for the research of Chinese medicine effective substance. The main material basis was identified, which were absorbed into serum by the method of Serum pharmaco-chemistry, then applying the combination of fingerprint and pharmacodynamics to identify the efficacy components. Meantime, advancing the quantitative analysis method of fingerprint combined with key efficacy component to fully control the quality of veterinary pharmaceutical in Chinese veterinary medicine. This study has theoretical significance and practical value as well as the modeling effect of the application of fingerprint, serum pharmaceutical chemistry and "spectrum-effect" relationships in Veterinary pharmaceutical.
本文首先构建了复方慢呼抗的体外指纹图谱,从宏观的角度来评价复方慢呼抗整体的质量,并用同样的色谱条件建立了血清指纹图谱,通过体外指纹图谱与血清指纹图谱的比对,确定了复力慢呼抗体内直接作用的物质基础；同时进行了体外抗鸡毒支原体的药效学试验,将指纹图谱特征峰的峰面积和药效学数据进行灰色关联度分析,确定了复方慢呼抗抗鸡毒支原体的关键药效组分；建立了关键药效组分的定量方法,用微观的定量分析弥补指纹图谱质量控制的不足,从而建立了宏观指纹图谱与药效组分定量分析相结合的复方慢呼抗质量控制的新方法。本研究取得如下几方而的成果：
1.复方慢呼抗指纹图谱的构建及模式分类研究
采用HPLC法对不同批次的复方慢呼抗样品进行分析,对色谱条件(如色谱柱、检测波长、流动相系统、洗脱梯度等)进行了优化,完成了系统的方法学考察,构建了复方慢呼抗HPLC指纹图谱。应用“中药色谱指纹图谱相似性评价系统2004A版”对复方慢呼抗HPLC指纹图谱进行了相似度评价,并借助于SPSS11.5软件对量化的指纹特征(色谱峰峰面积)进行了聚类分析及主成分分析,结果证明三种分析方法具有很好的一致性,可有效地对复方慢呼抗指纹图谱进行评价。此外,还应用建立的色谱条件对复方慢呼抗与各组成药的相关性进行了分析,通过与指纹图谱进行比对,确定了指纹图谱共有峰的来源。在实际应用时,只需将待测样品按本研究所述的色谱条件进行分析,将量化指纹特征数据输入计算机进行运算,就能快速得出评价结果,这对于复方慢呼抗质量控制的研究具有重要的理论意义和实用价值。
2.复方慢呼抗血浆指纹图谱的建立及血中移行成分分析
在已建立的复方慢呼抗指纹图谱基础上,通过优化含药血浆的前处理条件,建立了复方慢呼抗血.浆指纹图谱。针对不同时间点的移行成分。运用HPLC-DAD方法对复方慢呼抗提取液、给药血浆和空白血浆进行对比分析。结果显示：在给药后15min入血成分较少,仅有11号峰较明显；30min出现入血原形成分最多；60min时,一些入血成分减弱或消失,同时有6个代谢产物产生；在120min第2号峰被检出并且有较高的响应值,其他峰减弱或消失。通过血清药物化学的研究,可以确定指纹图谱中的共有峰绝大部分均可被吸收入血,是复方慢呼抗体内直接作用的物质基础。
3.复方慢呼抗指纹图谱特征与药效关系的研究
由于甘草对复方慢呼抗指纹图谱共有峰无贡献,故舍去甘草,将其他4味药重新组方研究其谱效关系。以原处方量的0.5,1,1.5倍量作为3个考察水平,以方中4味药为考察因素,以L9(34)正交表进行药量的加减试验。将各组样品分别进行指纹图谱分析和体外抗鸡毒支原体的药效学试验,在获得复方慢呼抗指纹图谱与药效学量化数据的基础上,采用灰关联度分析技术,寻找指纹图谱特征峰所代表的化学成分对药效贡献的大小。结果表明复方慢呼抗抗鸡毒支原体的作用是其“化学成分群”共同作用的结果。并且根据关联度的大小,绿原酸、4号峰(未鉴定)、黄芩苷、汉黄芩苷对“抗鸡毒支原体”活性的贡献最大。
4.复万慢呼抗指纹图谱中绿原酸、黄芩营、汉黄岑苷的含量测定
由于复方慢呼抗中的绿原酸、黄芩苷、汉黄芩苷与抗鸡毒支原体活性的关联度较大,他们的含量在一定程度上可反应复力慢呼抗的质量优劣。因此,本试验采用指纹图谱的色谱条件,以三种成分最大吸收波长作为检测波长,对三种活性成分进行了方法学考察并同时测定各成分的含量。结果表明方法学考察中各项试验结果的RSD均小于3%,表明仪器精密度高、方法的重复性好,并具有良好的回收率和稳定性。复方慢呼抗提取物中三种成分的含量为别为(1.53±0.03)%、(10.93±0.27)%、(4.476±0.11)%。建立的三种成分同时测定方法,不仅使定量分析更加简便、快捷,并且可以弥补指纹图谱在定量控制方面的不足,二者结合可以更有效、全面的控制复方慢呼抗的质量。
5.复方慢呼抗提取工艺的研究
黄芩苷、汉黄芩苷、绿原酸已被确定为复方慢呼抗抗鸡毒支原体的关键组分,引入总评“归一值”将三个指标综合为一个指标,在对提取温度、提取时间、液料比进行单因素考察基础上,采用Box-Behnken响应面法进行了工艺的优化。通过Design-expert软件7.0对此模型的最佳结果进行预测,当提取温度为92.58℃,液料比为25.23：1,提取时间为2.42h时,预测最佳OD值为0.741,经试验验证,获得的OD值为0.7591,偏差仅为2.44%。最后进行了提取次数的考察,结果显示第二次提取可明显的改善提取效果,但再增加提取次数对成分的溶出率影响不大,因此选择提取次数为2次。考虑到实际操作的可行性,将最终提取工艺确定为提取温度93℃,液料比25：1,提取时间2.4h,提取次数2次。通过建立以药效组分为指标的提取工艺,可实现在同样药量下,保证有效成分的最大溶出,使得复方慢呼抗的作用得到进一步保障。
本研究为中兽药抗鸡毒支原体药效物质基础及质量控制的研究提供了一条新途径,即首先采用血清药物化学的方法确定中兽药体内直接作用的物质基础,再用谱效结合的方法辨识出关键药效组分。同时,提出以指纹图谱结合关键药效组分定量分析的方法,来全面的控制复方中兽药的质量。本研究具有理论意义和实用价值,同时对指纹图谱技术、血清药物化学及谱效关系在中兽药中的应用起到了示范作用。
Mycoplasma gallisepticum (MG) was a primary pathogen causing chronic respiratory disease (CRD) in chicken, and MG infection could lead to high unhealthy chicken rates, dropping egg production, lower weight, prolonged period of onset to market. So it may result in economic losses in the poultry industry. Compound Manhukang was a pharmaceutical preparation used for the treatment of upper respiratory infection disease caused by MG infection. The compound medicine was composed of five Chinese medicinal herbs i.e. Scutellariae Radix, Lonicerae japonicae Flos, Stemonae Radix. Asleris radix et rhizome and Glycyrrhiza Radix. The medicine had sufficient commercial potential because it had a definitely curative effect, without poison and side effect. As the complex chemical constituents in Manhukang and the unknown active substance in vivo, studying on the action mechanism, the process of biotransformation and metabolism would be aimLess, which also had severely constrainted the modern research of Manhukang, and resulted in the low export rate.
The effective substances of Manhukang should be revealed by using the method of Serum pharmaco-chemistry and spectrum-effect combination. On this basis, a quality consistency assessment was developed based on quantitative determination of the effective substances and qualitative fingerprinting analysis. It has an actual sense of not only spreading the culture of traditional medicine, but also promoting the investigation and development, serving the human beings and transforming it into commodity's advantages, which consequently advance economy development rapidly in local region.
By using the method of Serum pharmaco-chemistry of Chinese Medicine, the analysis of constituents in blood was been carried out after oral administration of Manhukang extract. According to HPLC fingerprint and anti-mycoplasma activity test, grey relational analysis was applied to find the active compositions. On this basis, quantitative determination of active compositions was carried out with HPLC method as a supplement for quality control of Manhukang. And we have already achieved such achievement as follows:
1. The establishment of Manhukang fingerprint and studies on pattern classification
HPLC was introduced to analyze Manhukang samples from different batches. Mobile phase, chromatographic column and detected wavelength etc. were optimized to complete the systemic methodology and establish the HPLC fingerprint of Manhukang. Moreover, the similarity evaluation of chromatograms was processed by systematically comparing chromatograms with a professional analytical software recommended by State Food and Drug Administration. The quantitative fingerprint characteristic was treated with cluster analysis and principal component analysis with the help of SPSS11.5software, which proved to be consistent with the similarity evaluation. In order to identify the origins of these characteristic peaks from each herb, a comparative study was carried out between Manhukang and individual herbs. So the correlation between fingerprint of the preparations and that of their raw herbs was also examined in this study. Actually, the determined samples just need to be analyzed with the chromatographic conditions described above, and input the quantitative fingerprint characteristic of the samples into computer to calculate, then the classified results would be quickly acquired, which has both academic significance and applied value.
2. Study on Serum pharmaco-chemistry of Manhukang
By using the established analysis method of HPLC-DAD, the analysis method of serum pharmaco-chemistry was established after optimizing the pretreatment condition of plasma. From a comprehensive analysis of the HPLC-DAD chromatography of Manhukang, controlled plasma and dosed plasma, the constituents in blood were analyzed at different time point. It can be seen that only No.11peak was more obvious at15min after oral administration. Then30min after oral administration, major essential components were detected. After an hour, six new components were detected and some components disappeared. The No.2peak appeared at120min after oral administration. By using the method of Serum pharmaco-chemistry of Chinese Medicine, the majority of common peaks in the fingerprint were absorbed into serum. They were the main material basis for the treatment of upper respiratory infection disease.
3. Study on the correlation between characteristic of Manhukang fingerprint and pharmacodynamics
Glycyrrhiza Radix had no contribution to the common peaks of the fingerprint, so rounding it, the other herbs had been combined into nine groups of samples. At the premise of the acquired characteristic of fingerprint and pharmacodynamic data, grey relational analysis was selected to show what the constituents represented by fingerprint contributed to pharmaeodynamies. It could be concluded that effects were the total results of chemical constituents group in Manhukang. According to the relational grade, chlorogenic acid, baicalin, wogonoside and an unknown component had great contribution to anti-mycoplasma activity.
4. Simultaneous determination of chlorogenic acid, baicalin and wogonoside in Manhukang by high performance liquid chromatography-DAD method
A high performance liquid chromatographic method was developed to simultaneously determine chlorogenic acid, baicalin and wogonoside based on the chromatographic conditions of fingerprinting. The results show that RSD of the test results in the methodological study were less than3%, indicating that the instrument precision, reproducible, recovery and stability of the method were credible. The content of the three components were0.463±0.009,2.42±0.06,0.97±0.02, respectively. The establishment of content determination method could supply the deficiency of fingerprint in quantitative control. The efficient quality control method would be established combinative method using HPLC quantitative and qualitative analyses.
5. Optimization of extraction of Manhukang by response surface methodology
The extraction process of Manhukang was optimized with extraction temperature, extraction time and ratio of water to material as independent variables, and the overall desirability value of the yield of chlorogenic acid, baicalin and wogonoside as evaluation indexes; Quadratic polynomial fitting and depicting of3D-response surface were performed and from which the optimal extraction process was selected. The optimal extraction process was as follows:extraction temperature92.58℃, ratio of water to material25.23and extraction time2.42h. Under the optimized condition, the experimental value of0.738±0.015was well in close agreement with the value predicted by the model. Moreover, the overall desirability value in the condition was higher than that of the non-optimized condition. These results help in designing the process of optimal chlorogenic acid, baicalin and wogonoside from compound Manhukang.
In this study, a new approach was provided for the research of Chinese medicine effective substance. The main material basis was identified, which were absorbed into serum by the method of Serum pharmaco-chemistry, then applying the combination of fingerprint and pharmacodynamics to identify the efficacy components. Meantime, advancing the quantitative analysis method of fingerprint combined with key efficacy component to fully control the quality of veterinary pharmaceutical in Chinese veterinary medicine. This study has theoretical significance and practical value as well as the modeling effect of the application of fingerprint, serum pharmaceutical chemistry and "spectrum-effect" relationships in Veterinary pharmaceutical.
引文
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