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Research Status and Methods of Rationality of Daily Oral Administration Times of Traditional Chinese Medicine Preparations
WORLD SCIENCE AND TECHNOLOGY MODERNIZATION OF TRADITIONAL CHINESE MEDICINE AND MATERIA MEDICA
Volume 13, Issue 6, December 2011 Online English edition of the Chinese language journal Cite this article as: Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
RESEARCH
Research Status and Methods of Rationality of Daily Oral Administration Times of Traditional Chinese Medicine Preparations Yuan Hailong, Xiao Xiaohe* Institute of Chinese Materia Medica, 302 Military Hospital, Beijing 100039, China
Abstract: The rationality of daily oral administration times of traditional Chinese medicine (TCM) is a key scientific problem on its safety and efficacy in clinical application. In this article, the current research situation and essentiality of daily oral administration times of TCM were stated. One evaluation pattern was put forward on the basis of pharmacodynamic/pharmacokinetic (PD-PK) and mainly on the basis of pharmacodynamic biomarkers (PD-Markers). Key Words: Rationality of daily oral administration times, methodology, PD-PK, PD-Markers
The rationality of daily oral administration times of traditional Chinese medicine (TCM) preparations is a crucial scientific problem for the clinical safety and efficacy of TCM treatment. Oral administration times of TCM preparations were mostly decided by subjective experience of clinicians. But the rationality is due to lack of scientific evidences. There were almost no scientific studies on the daily oral administration times of TCM [1]. Researches on TCM include its resource research in field, its processing and production research in factory, and its clinical research on usage rationality. Because of the high concern and large investment from related government departments and enterprises, the modernization of TCM industry has achieved great stage progress in its resource and production research in recent years [2]. The work consideration should be retroposited adequately, which means to enhance the study on clinical safety and efficacy of TCM for improving its clinical effects. The rational oral administration times of TCM preparations were one of the most important factors for clinical rational use of drugs [3].
1 Research status of the rationality of daily oral administration times of TCM preparations Studies on the daily oral administration times of TCM preparations were almost blank. In the study of new drugs, researchers always paid more attention to the exploration of dosage, but paid little attention to the study of daily administration times. Administration times often worked empirically, with a certain arbitrariness and subjective nature. For example, when the prescriptive dosage of a medicine was 4 tablets a day, the possible administration was twice a day, and if a
medicine was taken 9 tablets a day, it was possibly suggested to take it 3 times a day. The internationalization of TCM preparations is the long-term goal of internationalization of TCM industry. Therefore, the study on daily oral administration times of TCM preparation will be a critical content in the future. Studies on the rational daily oral administration times of TCM decoction were rarely covered. The current daily administration times of decoction were confused just like a mess. The oral administration times of TCM decoction can be once, twice, or three times a day. Over the years, administration of TCM preparations was based on experiences. In the traditional anthology Wen Bing Tiao Bian, it was recorded that most prescriptions were taken three times a day. In our investigation, currently, the hospital pharmacy prepared the decoction and distributed the liquid in bags. Basically, the oral administration times of the decoction was one bag per time, twice a day, or follow the doctor’s order. All these administration methods did not take the characteristic of the prescription itself into consideration. It lacked the scientific basis. With the accelerated pace of modern life, the administration time of once a day has become more common. Yi Xue Yuan Liu Lun recorded that “Both correct prescription and correct administration method were necessary for curing a disease. If the administration method was wrong, even if the prescription was correct, not only the disease would not be cured, but also the patient would be harmed by the drug. This could not be unknown.” Hence, the question is that how many administration times in a day is more rational and what is the basis. Therefore, clarifying the time-effect relationship and determining TCM decoction administration time will improve the clinical
Received date: 18 November 2011 *Corresponding author. Tel.: 86-10-66933322, E-mail: [email protected] Foundation item: Supported by the National Natural Science Foundation (81073069), and the Key National Science & Technology Specific Projects – “Significant new drugs creation” (2009ZX09502-022). Copyright © 2011, World Science and Technology Press. Published by Elsevier BV. All rights reserved.
Yuan Hailong / Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
efficacy of TCM, which may even become one of the fundamental measures in TCM practice [4].
2 Research idea for the rationality of daily oral administration times of TCM preparations 2.1 PD-PK research on the rationality of daily oral administration times of TCM preparations is in accordance with Chinese medicine characteristics Pharmacodynamic/pharmacokinetic (PK-PD) has been successfully applied in the research of chemical drugs. PK-PD provides a scientific basis for developing clinical administration plan [5-6]. Chemical drug is often of single composition, and the administration plans of most drugs can be developed on the basis of the combination of PK-PD of their compositions. However, the composition of TCM preparation is too complex to support its administration plan by simple composition pharmacokinetics [7-11]. According to the characteristics of TCM preparations, in the research on the rationality of daily oral administration times of TCM preparation, the clinical efficacy is core and PD-PK of the composition is evidence. It is PD-PK that emphasizes on the clinical efficacy and shows the holism concept of TCM rather than PK-PD. 2.2 Application of PD-Markers made PD research more process-orientated and operative. The bottleneck problem of PD research is that the PD indexes of most TCM preparations are difficult to be quantified. The PD research methods of biologics drug should be referred to PD-Markers as pharmacokinetics index. The PD-Markers showed dynamic process of change and measured by ELISA kit. The administration times are determined on the basis of plasma pharmacokinetics of PD-Markers. The application of PD-Markers will greatly expand the application scope of pharmaco-effect method. Along with in-depth metabolomics study in the post-genomic era, PD-Markers of many syndromes will be revealed [12]. 2.3 Establishment of research method on the rationality of daily oral administration times of TCM preparations based on PD-PK Following the research idea of translational medicine, under the guidance of syndrome-prescription-method of TCM and the precondition that syndrome, prescription and usage corresponds to each other, the syndrome features, and curing rules have been analyzed. Then, according to the nature of herbs, the administration times are clarified scientifically by using PD-PK research model. The model establishment was combined with clinical validation with TCM characteristics. The main contents were as follows. 2.3.1 Syndrome characteristics and application method research on model drug Based on TCM theory and combined with syndrome cha-
racteristics, initial treatment principle and method were determined. 2.3.2
Animal model establishment
According to the Drug Registration Guideline and relevant literatures, animal models were established in combination with TCM theories and syndrome characteristics. 2.3.3 Research on the migrating constituents in blood of normal and pathological models Different drug delivery methods were given to animal models, and significant PK-Markers were dynamically determined. The time-amount curve was processed mathematically and a series of parameters were calculated. All these provided scientific basis for drug administration frequency. 2.3.4 PD-PK research on normal and pathological models Different administration methods were used for animal models. The real-time monitoring of pharmacological effects of subjects and performance indicators was recorded to achieve mathematical fitting time-effect curve. 2.3.5
Selection and confirmation of PD-Markers
With major syndromes and the role of the nature of the model drug, the associated PD-Markers of major syndrome were screened as pharmacokinetic markers. 2.3.6 Research on plasma pharmacokinetic parameters of PD-Markers in normal and pathological models The PD-Markers concentration in the plasma was measured by ELISA. And the time-concentration curve was achieved to calculate the pharmacokinetic parameters of plasma. 2.3.7
Clinical validation
On the basis of experimental study, significant changes in daily oral administration times were selected. The main indication of the model drug was taken as the observation direction. The stratified randomized controlled trial contained 24 samples. The PD-PK clinical research of patients and clinical therapeutic study were conducted. The clinical meaning and scientific meaning of the daily oral administration time model were validated clinically to further prove the objectivity, scientificity, and rationality of the model. 2.3.8 Research on the rationality of daily administration times of model drug on the basis of PD-PK Comparison between the normal and the pathological animal models of different delivery methods reveals the consistency and difference of “time–effect/time–amount.” Combined with syndrome characteristics and clinical validation, the experimental data mining analysis was conducted to establish a series of effective, objective, scientific, and rational daily administration time of both tradition decoction and modern solid dosage.
Yuan Hailong / Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
follows. The drug has obvious efficacy and definite clinical effects. The efficacy of this drug is easy to be quantified with objective indicators or easy to be accessed with PD-Markers. The material basis of the drug efficacy is relatively clear.
Model Drug
Syndrome
Prescriptions
Pharmacodynamics & pharmacokinetics of PD-Markers
Pharmacokinetics of PK-Markers
Usage
Clinic PD-PK Study
Correlation of PD-PK
Comprehensive Analysis Research on the rationality of daily administration times
Build the study method of rational daily administration times of TCMs
Fig. 1
3
Research ideas of the rationality of daily oral administration times of TCM
Key issues require to be solved
To realize the study model of daily oral administration times of Chinese herbal decoction, three key technologies are required as support. The first key point is to take quality control of herbs and preparations as top priority. Chemical and biological evaluation can be jointly used in the quality control of herbal medicine. It includes multi-index determination, fingerprints, and biological activity evaluation. The second key point is the study on PD-Markers. The PD-Markers must be a dynamic process indicator that is able to reflect the main effect of plasma pharmacokinetic parameters in reasonable number of daily dosage. The third key point is the successful establishment of PD-PK model. The model design is a very important influential factor. The key components, which contain the choice of transitional body, blood-drawing time setting, and the efficacy indicator setting of direct related drug, are crucial to the successful establishment of PD-PK model.
4 Main serviceable range of research methods of the rationality of daily oral administration times Theoretically, study model based on PD-PK can be applied to all prescriptions. However, from the practical and operational level, this model is more applicable to conditions as
5 Features and advantages of research methods on the rationality of daily oral administration times 5.1 This study laid a theoretical foundation for the study on rationality of daily oral administration times, which provides valid scientific evidences for TCM administration. It was the first time to address and study the administration issue of TCM and explain the key scientific issues of rationality of clinical daily administration times. This study laid a theoretical foundation and filled vacancy in this research field. 5.2 This study established PD-Markers method in the PD research of Chinese medicine for the first time. This method has paved a new path for the PD study of Chinese medicine. It solves the problem of quantifying effect indicators of Chinese medicine. At the same time, the study method of rationality on daily oral administration times of Chinese medicine was established on the basis of PD-PK characteristics, which also fit the Chinese medicine characteristics. 5.3 This study paid equal attention to the traditional preparation form and modern preparation form. Traditional decoction research can be directly used in the clinic, which is more practical. The modern formulation research can provide technical support for new drug research and development.
6
Conclusion
To improve the effectiveness and scientificity of clinical application of oral medicine, to transfer basic research achievements into clinical applications, our research team put forward the study model based on PD-PK and mainly based on PD-Markers. The study method of rationality on daily oral drug administration times was established according to the Chinese medicine characteristics. Currently, this model has been used in the study of Rhubarb, Yinchenhao Decoction, and ZhengganQinghuang Tablets as demonstration. The study has also been supported by the National Natural Science Foundation of China. Related research results will be reported.
References [1]
Yuan HL, Xiao XH. Evaluation pattern for rationality of daily administration times of Chinese Materia Medica based on pharmacodynamics-pharmacokinetics. Chinese Traditional and
Yuan Hailong / Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
Herbal Drugs 2011, 42(3): 417-419. [2]
[4]
[5] [6] [7]
Shu Y, Li LD. Appliance of PK/PD modeling in traditional Chinese medicine research. Chinese Pharmacological Bulle-
ented standardization of Chinese medicine. World Science
tin 2008, 24(11): 1405-1408.
and Technology (Modernization of Traditional Chinese Medi[3]
[8]
Xiao XH, Wang JB, Dai CM et al. Study on the chinic-ori-
cine and Materia Medica) 2010, 12(4): 617-622. Xiao XH, Xiao PG., WANG YY. Some key Issues about scientific research on traditional Chinese medicine. China Journal of Chinese Materia Medica 2009, 34(2): 119-123. Zhou Y, Lv JL, Yuan HL et al. Primary Research on the Rationality of daily administration frequency of rhubarb for constipation rats. World Science and Technology (Modernization of Traditional Chinese Medicine and Materia Medica) 2011, 13(3): 518-522. Liu CX. Pharmacokinetic study of China’s development review. Chinese Pharmaceutical Journal 2010, 45(2): 81-89. Workman P. Challenge of PK/PD measurements in modern drug development. Eur J cancer 2002, 38(16): 2189-2193. Wang GJ. Component of traditional Chinese medicine complex pharmacokinetic and pharmacodynamic studies to the overall explore. Chinese Pharmaceutical Association 2008 Annual Report and the 8th Week Set Chinese Pharmacist 2008.
[9]
Yue PF, Yuan HL, Xiao XH et al. Preparation and pharmacokinetics of puerarin submicron emulsion in rabbits. Chinese Journal of Pharmaceuticals, 2007, 38(7): 491-495.
[10] Du LJ, Xing DM, Zhao YN et al. Assessment of pharmacodynamics of compound preparations made of two Chinese medicinal herbs and pharmacokinetics of their tested components and a discussion on study method of pharmacokinetics of traditional Chinese medicine. World Science and Technology (Modernization of Traditional Chinese Medicine and Materia Medica) 2005, 7(3): 29-33. [11] Wang X, Sun W, Sun H et al. Analysis of the constituents in the rat plasma after oral administration of Yin Chen Hao Tang by UPLC/Q-TOF-MS/MS. J Pharm Biomed Anal 2008, 46(3): 477-490. [12] Wang XJ. Pharmacometabonomics-based elucidation of the synergetic effects of multi-component TCMs and related medical formula. Chinese Journal of Natural Medicines. 2009, 7 (2): 90-94.
Volume 13, Issue 6, December 2011 Online English edition of the Chinese language journal Cite this article as: Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
RESEARCH
Research Status and Methods of Rationality of Daily Oral Administration Times of Traditional Chinese Medicine Preparations Yuan Hailong, Xiao Xiaohe* Institute of Chinese Materia Medica, 302 Military Hospital, Beijing 100039, China
Abstract: The rationality of daily oral administration times of traditional Chinese medicine (TCM) is a key scientific problem on its safety and efficacy in clinical application. In this article, the current research situation and essentiality of daily oral administration times of TCM were stated. One evaluation pattern was put forward on the basis of pharmacodynamic/pharmacokinetic (PD-PK) and mainly on the basis of pharmacodynamic biomarkers (PD-Markers). Key Words: Rationality of daily oral administration times, methodology, PD-PK, PD-Markers
The rationality of daily oral administration times of traditional Chinese medicine (TCM) preparations is a crucial scientific problem for the clinical safety and efficacy of TCM treatment. Oral administration times of TCM preparations were mostly decided by subjective experience of clinicians. But the rationality is due to lack of scientific evidences. There were almost no scientific studies on the daily oral administration times of TCM [1]. Researches on TCM include its resource research in field, its processing and production research in factory, and its clinical research on usage rationality. Because of the high concern and large investment from related government departments and enterprises, the modernization of TCM industry has achieved great stage progress in its resource and production research in recent years [2]. The work consideration should be retroposited adequately, which means to enhance the study on clinical safety and efficacy of TCM for improving its clinical effects. The rational oral administration times of TCM preparations were one of the most important factors for clinical rational use of drugs [3].
1 Research status of the rationality of daily oral administration times of TCM preparations Studies on the daily oral administration times of TCM preparations were almost blank. In the study of new drugs, researchers always paid more attention to the exploration of dosage, but paid little attention to the study of daily administration times. Administration times often worked empirically, with a certain arbitrariness and subjective nature. For example, when the prescriptive dosage of a medicine was 4 tablets a day, the possible administration was twice a day, and if a
medicine was taken 9 tablets a day, it was possibly suggested to take it 3 times a day. The internationalization of TCM preparations is the long-term goal of internationalization of TCM industry. Therefore, the study on daily oral administration times of TCM preparation will be a critical content in the future. Studies on the rational daily oral administration times of TCM decoction were rarely covered. The current daily administration times of decoction were confused just like a mess. The oral administration times of TCM decoction can be once, twice, or three times a day. Over the years, administration of TCM preparations was based on experiences. In the traditional anthology Wen Bing Tiao Bian, it was recorded that most prescriptions were taken three times a day. In our investigation, currently, the hospital pharmacy prepared the decoction and distributed the liquid in bags. Basically, the oral administration times of the decoction was one bag per time, twice a day, or follow the doctor’s order. All these administration methods did not take the characteristic of the prescription itself into consideration. It lacked the scientific basis. With the accelerated pace of modern life, the administration time of once a day has become more common. Yi Xue Yuan Liu Lun recorded that “Both correct prescription and correct administration method were necessary for curing a disease. If the administration method was wrong, even if the prescription was correct, not only the disease would not be cured, but also the patient would be harmed by the drug. This could not be unknown.” Hence, the question is that how many administration times in a day is more rational and what is the basis. Therefore, clarifying the time-effect relationship and determining TCM decoction administration time will improve the clinical
Received date: 18 November 2011 *Corresponding author. Tel.: 86-10-66933322, E-mail: [email protected] Foundation item: Supported by the National Natural Science Foundation (81073069), and the Key National Science & Technology Specific Projects – “Significant new drugs creation” (2009ZX09502-022). Copyright © 2011, World Science and Technology Press. Published by Elsevier BV. All rights reserved.
Yuan Hailong / Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
efficacy of TCM, which may even become one of the fundamental measures in TCM practice [4].
2 Research idea for the rationality of daily oral administration times of TCM preparations 2.1 PD-PK research on the rationality of daily oral administration times of TCM preparations is in accordance with Chinese medicine characteristics Pharmacodynamic/pharmacokinetic (PK-PD) has been successfully applied in the research of chemical drugs. PK-PD provides a scientific basis for developing clinical administration plan [5-6]. Chemical drug is often of single composition, and the administration plans of most drugs can be developed on the basis of the combination of PK-PD of their compositions. However, the composition of TCM preparation is too complex to support its administration plan by simple composition pharmacokinetics [7-11]. According to the characteristics of TCM preparations, in the research on the rationality of daily oral administration times of TCM preparation, the clinical efficacy is core and PD-PK of the composition is evidence. It is PD-PK that emphasizes on the clinical efficacy and shows the holism concept of TCM rather than PK-PD. 2.2 Application of PD-Markers made PD research more process-orientated and operative. The bottleneck problem of PD research is that the PD indexes of most TCM preparations are difficult to be quantified. The PD research methods of biologics drug should be referred to PD-Markers as pharmacokinetics index. The PD-Markers showed dynamic process of change and measured by ELISA kit. The administration times are determined on the basis of plasma pharmacokinetics of PD-Markers. The application of PD-Markers will greatly expand the application scope of pharmaco-effect method. Along with in-depth metabolomics study in the post-genomic era, PD-Markers of many syndromes will be revealed [12]. 2.3 Establishment of research method on the rationality of daily oral administration times of TCM preparations based on PD-PK Following the research idea of translational medicine, under the guidance of syndrome-prescription-method of TCM and the precondition that syndrome, prescription and usage corresponds to each other, the syndrome features, and curing rules have been analyzed. Then, according to the nature of herbs, the administration times are clarified scientifically by using PD-PK research model. The model establishment was combined with clinical validation with TCM characteristics. The main contents were as follows. 2.3.1 Syndrome characteristics and application method research on model drug Based on TCM theory and combined with syndrome cha-
racteristics, initial treatment principle and method were determined. 2.3.2
Animal model establishment
According to the Drug Registration Guideline and relevant literatures, animal models were established in combination with TCM theories and syndrome characteristics. 2.3.3 Research on the migrating constituents in blood of normal and pathological models Different drug delivery methods were given to animal models, and significant PK-Markers were dynamically determined. The time-amount curve was processed mathematically and a series of parameters were calculated. All these provided scientific basis for drug administration frequency. 2.3.4 PD-PK research on normal and pathological models Different administration methods were used for animal models. The real-time monitoring of pharmacological effects of subjects and performance indicators was recorded to achieve mathematical fitting time-effect curve. 2.3.5
Selection and confirmation of PD-Markers
With major syndromes and the role of the nature of the model drug, the associated PD-Markers of major syndrome were screened as pharmacokinetic markers. 2.3.6 Research on plasma pharmacokinetic parameters of PD-Markers in normal and pathological models The PD-Markers concentration in the plasma was measured by ELISA. And the time-concentration curve was achieved to calculate the pharmacokinetic parameters of plasma. 2.3.7
Clinical validation
On the basis of experimental study, significant changes in daily oral administration times were selected. The main indication of the model drug was taken as the observation direction. The stratified randomized controlled trial contained 24 samples. The PD-PK clinical research of patients and clinical therapeutic study were conducted. The clinical meaning and scientific meaning of the daily oral administration time model were validated clinically to further prove the objectivity, scientificity, and rationality of the model. 2.3.8 Research on the rationality of daily administration times of model drug on the basis of PD-PK Comparison between the normal and the pathological animal models of different delivery methods reveals the consistency and difference of “time–effect/time–amount.” Combined with syndrome characteristics and clinical validation, the experimental data mining analysis was conducted to establish a series of effective, objective, scientific, and rational daily administration time of both tradition decoction and modern solid dosage.
Yuan Hailong / Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
follows. The drug has obvious efficacy and definite clinical effects. The efficacy of this drug is easy to be quantified with objective indicators or easy to be accessed with PD-Markers. The material basis of the drug efficacy is relatively clear.
Model Drug
Syndrome
Prescriptions
Pharmacodynamics & pharmacokinetics of PD-Markers
Pharmacokinetics of PK-Markers
Usage
Clinic PD-PK Study
Correlation of PD-PK
Comprehensive Analysis Research on the rationality of daily administration times
Build the study method of rational daily administration times of TCMs
Fig. 1
3
Research ideas of the rationality of daily oral administration times of TCM
Key issues require to be solved
To realize the study model of daily oral administration times of Chinese herbal decoction, three key technologies are required as support. The first key point is to take quality control of herbs and preparations as top priority. Chemical and biological evaluation can be jointly used in the quality control of herbal medicine. It includes multi-index determination, fingerprints, and biological activity evaluation. The second key point is the study on PD-Markers. The PD-Markers must be a dynamic process indicator that is able to reflect the main effect of plasma pharmacokinetic parameters in reasonable number of daily dosage. The third key point is the successful establishment of PD-PK model. The model design is a very important influential factor. The key components, which contain the choice of transitional body, blood-drawing time setting, and the efficacy indicator setting of direct related drug, are crucial to the successful establishment of PD-PK model.
4 Main serviceable range of research methods of the rationality of daily oral administration times Theoretically, study model based on PD-PK can be applied to all prescriptions. However, from the practical and operational level, this model is more applicable to conditions as
5 Features and advantages of research methods on the rationality of daily oral administration times 5.1 This study laid a theoretical foundation for the study on rationality of daily oral administration times, which provides valid scientific evidences for TCM administration. It was the first time to address and study the administration issue of TCM and explain the key scientific issues of rationality of clinical daily administration times. This study laid a theoretical foundation and filled vacancy in this research field. 5.2 This study established PD-Markers method in the PD research of Chinese medicine for the first time. This method has paved a new path for the PD study of Chinese medicine. It solves the problem of quantifying effect indicators of Chinese medicine. At the same time, the study method of rationality on daily oral administration times of Chinese medicine was established on the basis of PD-PK characteristics, which also fit the Chinese medicine characteristics. 5.3 This study paid equal attention to the traditional preparation form and modern preparation form. Traditional decoction research can be directly used in the clinic, which is more practical. The modern formulation research can provide technical support for new drug research and development.
6
Conclusion
To improve the effectiveness and scientificity of clinical application of oral medicine, to transfer basic research achievements into clinical applications, our research team put forward the study model based on PD-PK and mainly based on PD-Markers. The study method of rationality on daily oral drug administration times was established according to the Chinese medicine characteristics. Currently, this model has been used in the study of Rhubarb, Yinchenhao Decoction, and ZhengganQinghuang Tablets as demonstration. The study has also been supported by the National Natural Science Foundation of China. Related research results will be reported.
References [1]
Yuan HL, Xiao XH. Evaluation pattern for rationality of daily administration times of Chinese Materia Medica based on pharmacodynamics-pharmacokinetics. Chinese Traditional and
Yuan Hailong / Mode Tradit Chin Med Mater Med, 2011, 13(6): 952–955
Herbal Drugs 2011, 42(3): 417-419. [2]
[4]
[5] [6] [7]
Shu Y, Li LD. Appliance of PK/PD modeling in traditional Chinese medicine research. Chinese Pharmacological Bulle-
ented standardization of Chinese medicine. World Science
tin 2008, 24(11): 1405-1408.
and Technology (Modernization of Traditional Chinese Medi[3]
[8]
Xiao XH, Wang JB, Dai CM et al. Study on the chinic-ori-
cine and Materia Medica) 2010, 12(4): 617-622. Xiao XH, Xiao PG., WANG YY. Some key Issues about scientific research on traditional Chinese medicine. China Journal of Chinese Materia Medica 2009, 34(2): 119-123. Zhou Y, Lv JL, Yuan HL et al. Primary Research on the Rationality of daily administration frequency of rhubarb for constipation rats. World Science and Technology (Modernization of Traditional Chinese Medicine and Materia Medica) 2011, 13(3): 518-522. Liu CX. Pharmacokinetic study of China’s development review. Chinese Pharmaceutical Journal 2010, 45(2): 81-89. Workman P. Challenge of PK/PD measurements in modern drug development. Eur J cancer 2002, 38(16): 2189-2193. Wang GJ. Component of traditional Chinese medicine complex pharmacokinetic and pharmacodynamic studies to the overall explore. Chinese Pharmaceutical Association 2008 Annual Report and the 8th Week Set Chinese Pharmacist 2008.
[9]
Yue PF, Yuan HL, Xiao XH et al. Preparation and pharmacokinetics of puerarin submicron emulsion in rabbits. Chinese Journal of Pharmaceuticals, 2007, 38(7): 491-495.
[10] Du LJ, Xing DM, Zhao YN et al. Assessment of pharmacodynamics of compound preparations made of two Chinese medicinal herbs and pharmacokinetics of their tested components and a discussion on study method of pharmacokinetics of traditional Chinese medicine. World Science and Technology (Modernization of Traditional Chinese Medicine and Materia Medica) 2005, 7(3): 29-33. [11] Wang X, Sun W, Sun H et al. Analysis of the constituents in the rat plasma after oral administration of Yin Chen Hao Tang by UPLC/Q-TOF-MS/MS. J Pharm Biomed Anal 2008, 46(3): 477-490. [12] Wang XJ. Pharmacometabonomics-based elucidation of the synergetic effects of multi-component TCMs and related medical formula. Chinese Journal of Natural Medicines. 2009, 7 (2): 90-94.