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Qishe Pill (Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China), composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus, has been developed and spread in use into clinical settings in 2009. As individualization has become the trend of modern medicine, a personalized medicine of Qishe Pill should be documented and practiced with various patients according to the ancient TCM system, a classification of personalized constitution type, which has been established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of Qishe Pill and compare its extent of metabolism in the 3 major Constitution Type (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges of individualized and standardized Traditional Chinese Medicine into clinical practice.
With the greatly increased morbidity of neck pain, it brought a large challenge to some optimal therapies for various situations in population at a given time based on their demographic, physiological and pathological characteristics. Chinese proprietary herbal medicines, as a kind of Complementary and Alternative Medicine (CAM), are usually developed from some well-established and long-standing recipes and formulated as tablets or capsules for commerce, convenience or palatability. Although these advantage mentioned, a good quantification and a strict standardization in detail are still need to be improved for individualized implementation in therapeutic strategies. Based on the YQHY decoction (Yi-Qi Hua-Yu Decoction, tonify Qi and promoting circulation and removing stasis), Qishe Pill (Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China) has been developed and spread in use into clinical settings in 2009. As individualization has become the trend of modern medicine, a personalized medicine of Qishe Pill should be documented and practiced with various patients according to the ancient TCM system, a classification of personalized constitution type, which has been established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of Qishe Pill and compare its extent of metabolism in the 3 major Constitution Type (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges of individualized and standardized Traditional Chinese Medicine into clinical practice.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| cohort 1 | Experimental | Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China） in low dosage(3.75mg) |
|
| cohort 2 | Experimental | Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China) in medial dosage(7.5mg) |
|
| cohort 3 | Experimental | Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China）in high dosage(15mg) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Qishe Pill | Drug | Qishe Pill is a thin 0.15 g film-coated pill, composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus, which should be taken orally with water (240mL) after a minimum 10-hour fast |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | Dosing(0 hour) |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 15 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 30 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 45 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 60 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 90 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 120 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 150 min after dosing |
| Measure | Description | Time Frame |
|---|---|---|
| Deep phenotyping with genomics and functional genomics approaches | 3 ml blood samples for genomic variants analysis. The cytochrome P450 gene family, such as CYP1A1, CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP3A4 and CYP3A5 , etc, will be chosen as the target objective. | Dosing(0 hour) |
| Deep phenotyping with genomics and functional genomics approaches |
| Measure | Description | Time Frame |
|---|---|---|
| The Constitution in Chinese Medicine Questionnaire (CCMQ) | Two qualified traditional Chinese medical doctors licensed by the Chinese government determine the constitution according to CCMQ | During screening in the recuitment |
| The Constitution in Chinese Medicine Questionnaire (CCMQ) |
Inclusion
Exclusion
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xue-Jun Cui, Dr. | Contact | 13917715524@139.com | ||
| Yue-li Sun, Dr | Contact | edisonlike2008@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Yong-jun Wang, Dr. | Longhua Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Longhua Hospital, Shanghai University of TCM | Recruiting | Shanghai | Shanghai Municipality | 200032 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8942688 | Background | Aker PD, Gross AR, Goldsmith CH, Peloso P. Conservative management of mechanical neck pain: systematic overview and meta-analysis. BMJ. 1996 Nov 23;313(7068):1291-6. | |
| 20091597 | Background | Cui X, Trinh K, Wang YJ. Chinese herbal medicine for chronic neck pain due to cervical degenerative disc disease. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD006556. doi: 10.1002/14651858.CD006556.pub2. |
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| ID | Term |
|---|---|
| D000073935 | Narrative Medicine |
| D011843 | Radiculopathy |
| D019547 | Neck Pain |
| ID | Term |
|---|---|
| D033262 | Narration |
| D003142 | Communication |
| D001519 | Behavior |
| D010523 | Peripheral Nervous System Diseases |
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| ID | Term |
|---|---|
| C000710647 | qishe |
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| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 180 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 240 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 360 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 480 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 600 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 720 min after dosing |
| Plasma concentrations of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 1440 min after dosing |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 2160 min after dosing |
| Plasma sampling of Qishe Pill for pharmacokinetic analysis | 5 ml blood samples for pharmacokinetic analysis | 2880 min after dosing |
| Vital signs | body temperature, heart rate and blood pressure | Dosing(0 hour) |
| Vital signs | body temperature, heart rate and blood pressure | 180 min after dosing |
| Vital signs | body temperature, heart rate and blood pressure | 720 min after dosing |
| Vital signs | body temperature, heart rate and blood pressure | 1440 min after dosing |
| Vital signs | body temperature, heart rate and blood pressure | 2160 min after dosing |
| Vital signs | body temperature, heart rate and blood pressure | 2880 min after dosing |
| ECG monitoring | Electrocardiograms (ECGs) | Dosing(0 hour) |
| ECG monitoring | Electrocardiograms (ECGs) | 180 min after dosing |
| ECG monitoring | Electrocardiograms (ECGs) | 720 min after dosing |
| ECG monitoring | Electrocardiograms (ECGs) | 1440 min after dosing |
| ECG monitoring | Electrocardiograms (ECGs) | 2160 min after dosing |
| ECG monitoring | Electrocardiograms (ECGs) | 2880 min after dosing |
| Number of Participants with Adverse Events | The investigators will assess all clinical AEs according to the Medical Dictionary for Regular Activities criteria, in terms of intensity (mild, moderate, or severe), duration, outcome and relationship to the study drug. | Day 1 of drug administration and blood sampling |
| Number of Participants with Adverse Events | The investigators will assess all clinical AEs according to the Medical Dictionary for Regular Activities criteria, in terms of intensity (mild, moderate, or severe), duration, outcome and relationship to the study drug. | Day 2 of drug administration and blood sampling |
| Number of Participants with Adverse Events | The investigators will assess all clinical AEs according to the Medical Dictionary for Regular Activities criteria, in terms of intensity (mild, moderate, or severe), duration, outcome and relationship to the study drug. | Day 3 of drug administration and blood sampling |
| Number of Participants with Adverse Events | Subjects will be requested to return to the study unit 4 d after drug administration and blood sampling for a follow-up visit. | 4 days after drug administration and blood sampling |
| Peak Plasma Concentration (Cmax) of Qishe Pill in low dosage | The maximum plasma concentration | 4 days after drug administration and blood sampling |
| Peak Plasma Concentration (Cmax) of Qishe Pill in medial dosage | The maximum plasma concentration | 4 days after drug administration and blood sampling |
| Peak Plasma Concentration (Cmax) of Qishe Pill in high dosage | The maximum plasma concentration | 4 days after drug administration and blood sampling |
| The Time to Peak Plasma Concentration (Tmax) of Qishe Pill in low dosage | The time to maximum concentration | 4 days after drug administration and blood sampling |
| The Time to Peak Plasma Concentration (Tmax) of Qishe Pill in medial dosage | The time to maximum concentration | 4 days after drug administration and blood sampling |
| The Time to Peak Plasma Concentration (Tmax) of Qishe Pill in high dosage | The time to maximum concentration | 4 days after drug administration and blood sampling |
| Area under the Plasma Concentration versus Time Curve (AUC) of Qishe Pill in low dosage | The area under the plasma concentration-time curve (AUC) will be calculated using the linear trapezoidal rule. | 4 days after drug administration and blood sampling |
| Area under the Plasma Concentration versus Time Curve (AUC) of Qishe Pill in medial dosage | The area under the plasma concentration-time curve (AUC) will be calculated using the linear trapezoidal rule. | 4 days after drug administration and blood sampling |
| Area under the Plasma Concentration versus Time Curve (AUC) of Qishe Pill in high dosage | The area under the plasma concentration-time curve (AUC) will be calculated using the linear trapezoidal rule. | 4 days after drug administration and blood sampling |
| The distribution volume (DF) of Qishe Pill in low dosage | The distribution volume (DF) will be calculated by Dose/AUC/ke. ke is the elimination rate constant. | 4 days after drug administration and blood sampling |
| The distribution volume (DF) of Qishe Pill in medial dosage | The distribution volume (DF) will be calculated by Dose/AUC/ke. ke is the elimination rate constant. | 4 days after drug administration and blood sampling |
| The distribution volume (DF) of Qishe Pill in high dosage | The distribution volume (DF) will be calculated by Dose/AUC/ke. ke is the elimination rate constant. | 4 days after drug administration and blood sampling |
3 ml blood samples for genomic variants analysis. The cytochrome P450 gene family, such as CYP1A1, CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP3A4 and CYP3A5 , etc, will be chosen as the target objective. |
| 2880 min after dosing |
Two qualified traditional Chinese medical doctors licensed by the Chinese government determine the constitution according to CCMQ |
| 2880 min after dosing |
| Laboratory measures and clinical assessment | These parameters including blood count, electrolytes, renal and liver function parameters, blood lipids, age, gender, history of smoking, blood pressure, weight (kg), and height (meters) will be obtained for all subjects. | During screening in the recuitment |
| Background | Wang Q. Classification of the nine basic TCM constitutional type and based expression and diagnosis. Journal of Beijing University of Traditional Chinese medicine. 2005.1-8 |
| Background | Liu Mei, Zhang N, Wang YJ, Shi Q. Purification process research of major compound in Qishe Pill as Astragalus. Acta Chinese Medicine and Pharmacology. 2006(34):14-16. |
| Background | Zhang YQ, Liu XH, Zhang N, Liu M. Quality standard research of Qishe Pill. Lishizhen Med Mater Med Res. 2008(19): 977-979. |
| Background | Liu M, Zhang N, Wang YJ, Zhang YQ, Zhou CJ. Technology research of Qishe Pill, a new medicine for cervical spondylosis. Lishizhen Med Mater Med Res. 2010(21):176-179. |
| Background | Ge JR, Wang HM, Meng CX, Tong PJ. Effects of Qishe Pill, a compound traditional Chinese herbal medicine, on cervical radiculopathy: a randomized controlled trial for Phase III. Chinese Journal of New Drugs and Clinical. 2014(7):56-58. |
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| 1755449 | Background | Makela M, Heliovaara M, Sievers K, Impivaara O, Knekt P, Aromaa A. Prevalence, determinants, and consequences of chronic neck pain in Finland. Am J Epidemiol. 1991 Dec 1;134(11):1356-67. doi: 10.1093/oxfordjournals.aje.a116038. |
| 8066508 | Background | Bovim G, Schrader H, Sand T. Neck pain in the general population. Spine (Phila Pa 1976). 1994 Jun 15;19(12):1307-9. doi: 10.1097/00007632-199406000-00001. |
| 1795327 | Background | van der Donk J, Schouten JS, Passchier J, van Romunde LK, Valkenburg HA. The associations of neck pain with radiological abnormalities of the cervical spine and personality traits in a general population. J Rheumatol. 1991 Dec;18(12):1884-9. |
| Background | Hsu H-Y: 1986 Oriental MateriaMedica. Long Beach, CA: Oriental Healing Arts Institute; 1986. |
| Background | Zhu YB, Wang Q, Xue HS, Origasa H. Preliminary assessment on performance of constitution in Chinese medicine questionnaire. ZhongGuo Lin Chuang Kang Fu 2006; 10 (3): 15-17. |
| Background | FDA/CDER. Guidance for industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers; 2005, http://www.fda.gov/downloads/drugs/guidance-complianceregulatoryinformation/guidances/ucm078932.pdf. |
| Background | EMEA. Strategies to identify and mitigate risks for first-in-human clinical trialswith investigational medicinal products; 2009, http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500002988.pdf. |
| 12133671 | Background | Choo V. WHO reassesses appropriate body-mass index for Asian populations. Lancet. 2002 Jul 20;360(9328):235. doi: 10.1016/S0140-6736(02)09512-0. No abstract available. |
| 7229908 | Background | Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1980 Dec;8(6):553-71. doi: 10.1007/BF01060053. |
| 7334463 | Background | Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data. J Pharmacokinet Biopharm. 1981 Oct;9(5):635-51. doi: 10.1007/BF01061030. |
| 6644555 | Background | Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters. III. Monoexponential model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1983 Jun;11(3):303-19. doi: 10.1007/BF01061870. |
| 18771484 | Background | Feng Y, Pollock BG, Coley K, Marder S, Miller D, Kirshner M, Aravagiri M, Schneider L, Bies RR. Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study. Br J Clin Pharmacol. 2008 Nov;66(5):629-39. doi: 10.1111/j.1365-2125.2008.03276.x. Epub 2008 Jul 31. |
| 14597987 | Background | Zhang WJ, Hufnagl P, Binder BR, Wojta J. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappaB activation and adhesion molecule expression. Thromb Haemost. 2003 Nov;90(5):904-14. doi: 10.1160/TH03-03-0136. |
| 25885543 | Derived | Sun YL, Hou T, Liu SF, Zhang ZL, Zhang N, Yao M, Yang L, Shi Q, Cui XJ, Wang YJ. Population pharmacokinetic modeling of the Qishe pill in three major traditional Chinese medicine-defined constitutional types of healthy Chinese subjects: study protocol for a randomized controlled trial. Trials. 2015 Feb 26;16:64. doi: 10.1186/s13063-015-0568-6. |
| D009468 |
| Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |