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    The value and general consideration of pharmacometric study in new drug development
    LIU Dongyang,WANG Kun,MA Guangli,XIANG Xiaoqiang,LIU Jiang,ZHAO Ping,CHEN Rui,CHEN Yuancheng,HUANG Xiaohui, LI Li,LI Lujin,NIE Jing,WANG Yuzhu,WEI Chunmin,LU Wei,SHI Jun, ZHENG Qingshan
    Chinese Journal of Clinical Pharmacology and Therapeutics    DOI: 10.12092/j.issn.1009-2501.2018.09.001
    General considerations of population pharmacokinetic/pharmacodynamic study in new drug development
    MA Guangli, XU Ling, CHEN Rui, CHEN Yuancheng, ZHAO Wei, LIU Dongyang, JIAO Zheng, LI Jian, JI Shuangmin, LI Li, LI Liang, WANG Yuzhu, YANG Jinbo, WANG Yaning, SUN He, HU Pei, ZHENG Qingshan, LU Wei
    Chinese Journal of Clinical Pharmacology and Therapeutics    DOI: 10.12092/j.issn.1009-2501.2019.11.001
    Accepted: 25 March 2021

    Erythropoietin's biological function and source
    YANG Huan, SHI Yuhong, RAN Haifeng, CHEN Yijin, XU Xiaoyu
    Chinese Journal of Clinical Pharmacology and Therapeutics    2021, 26 (4): 434-443.   DOI: 10.12092/j.issn.1009-2501.2021.04.011
    Abstract1612)      PDF (973KB)(784)       Save
    Erythropoietin is an endogenous 34 000 glycoprotein hormone composed of 165 amino acids. EPO is mainly derived from the liver of the fetus and synthesized in the kidney after birth, but is secreted by the liver, kidney, brain, reproductive system, bone marrow macrophage and mammary gland. The production of EPO is regulated by hypoxia-inducible factors. EPO can significantly stimulate the proliferation and survival of red blood cells and promote hematopoiesis; it has been used clinically to treat chronic renal anemia, anemia caused by bone marrow tumors and myelodysplasia. EPO has a wide range of physiological functions and it is found in all systems of animal life. Apart from promoting hematopoiesis, EPO also promotes angiogenesis, and shows brain protection, kidney protection, heart protection, regulation of metabolism, regulation of inhalation, protection of the digestive system and reproductive system. Animals without EPO can hardly survive. It illustrates that EPO plays an important role in life.
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    Comparison of the calculation approaches of AUC in non-compartment model pharmacokinetics
    CHEN Chao, ZHENG Qingshan, LI Lujin, LI Xue, XU Ling
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (12): 1381-1387.   DOI: 10.12092/j.issn.1009-2501.2020.12.010
    Abstract1585)      PDF (624KB)(932)       Save
    AIM: To study the ways of calculating area under the plasma concentration-time curve (AUC) in non-compartment model pharmacokinetics by comparing the accuracy & precision of every method.  METHODS: Three methods were used to calculate the area under 0-T curve (AUC0-t) in G drug equivalence test. (1) Linear method (2) Linear/Log method: Data before the maximum blood concentration (Cmax) was calculated by the linear trapezoid rule, and those after Cmax by logarithmic trapezoid rule (3) Linear Up/Log Down: The ascending part of the curve was calculated by the linear trapezoid rule, and the descending part by logarithmic trapezoid. Equivalence criterion of AUC0-t after logarithmic transformation is 80.0%-125.0%, and differences between three methods were compared on simulated data. RESULTS: Both the AUC0-t and equivalence analysis results show difference between three methods, in these 24 subjects took G drug of two preparations. Furthermore, Linear and Linear Up/Log Down method have the equivalent conclusion, while not the Linear/Log method. AUC0-t showed great difference in small sample of simulation data, contrast to slight difference in the large sample data case. CONCLUSION: Linear Up/Log Down method is more appropriate for oral administration and multi-peak curves,and Linear calculation is more effective to get stable results in small sample size test or pre-test,while Linear/log method is not so often used. In addition, bioequivalence research should be included in AUC calculation in the analysis plan.
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    Evaluation and calculation of the accumulation index in clinical pharmacokinetics
    LI Xian-xing, LI Lu-jin, XU Ling, ZHENG Qing-shan
    Chinese Journal of Clinical Pharmacology and Therapeutics    2013, 18 (1): 34-38.  
    Abstract1579)      PDF (608KB)(3615)       Save
    AIM: To analyze and evaluate the accumulation index (Rac) in clinical pharmacokinetics of multiple dosing administrations in order to obtain one reasonable method. METHODS: The plasma concentration-time data of arteether was simulated for 1000 subjects in multiple doses administration. The 20-40 subjects were sampled for 1000 time by the Boostrap method and values of Rac were calculated by the AUC, Cmax, Ctrough and model. The values of Rac were evaluated by their distributions. RESULTS: The AUC and Cmax method were more stable than the Ctrough and model method. If the efficacy or toxicity was related with the concentration, it was appropriate to use the Cmax method, and if the efficacy or toxicity was related with the time, it was appropriate to use the AUC method. CONCLUSION: The drug accumulation is related with effectiveness and safety, and the reasonable choice of Rac calculation method should be based on drug and data characteristics.
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    Correlation between vitamin D and thyroid disease
    SU Shan, ZHANG Di, WANG Qiangmei, ZHEN Donghu
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (1): 94-100.   DOI: 10.12092/j.issn.1009-2501.2020.01.014
    Abstract1538)      PDF (3022KB)(460)       Save
    In addition to the role of vitamin D in regulating calcium and phosphorus homeostasis and bone metabolism, immune regulation and anti-tumor proliferation have been gradually proposed by researchers. At present, a large number of studies have found that patients with thyroid diseases have low vitamin D levels, and it is believed that vitamin D insufficiency/ deficiency may be involved in the pathogenesis of thyroid diseases, but the specific relationship and mechanism between vitamin D and thyroid diseases have not been fully clarified. This article reviewed in the relationship between vitamin D and several common thyroid diseases in recent years, in order to analyze the role of vitamin D in the pathogenesis of thyroid diseases, as well as the influence of vitamin D supplementation on the occurrence and development of thyroid diseases.
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    Pharmacology progress on the main bioactive components of Ligusticum chuanxiong hort
    LI Haigang, HU Shaiping, ZHOU Yi, XU Dandan, MA Ning, TANG Jing, BAO Meihua, ZHENG Xiahui
    Chinese Journal of Clinical Pharmacology and Therapeutics    2018, 23 (11): 1302-1308.   DOI: 10.12092/j.issn.1009-2501.2018.11.018
    Abstract1495)      PDF (3254KB)(1157)       Save

    Ligusticum chuanxiong hort contains more than 100 kinds of pharmacological active ingredients. This study summarized its main bioactive components in pharmacology progress based on pharmacokinetics, and explained the pharmacokinetics and pharmacodynamics of ferulic acid, ligustilide, senkyunolide A, senkyunolide I and tetramethylpyrazine in detail. It will provide some new ideas and methods to the clinical application, deep development and utilization of Ligusticum chuanxiong hort.

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    Research progress in the treatment of depression with monome of Chinese herb, drug pairs, compound prescriptions and Chinese patent drugs
    CHEN Ying, YUAN Yonggui
    Chinese Journal of Clinical Pharmacology and Therapeutics    2021, 26 (5): 586-593.   DOI: 10.12092/j.issn.1009-2501.2021.05.016
    Abstract1360)      PDF (536KB)(2096)       Save
    Depression is a relatively common psychosomatic disease in clinical practice. It is mainly characterized by significant and lasting depression. It generally manifests as depression, loss of interest, impaired cognitive function, etc. Some patients are accompanied by somatization symptoms such as insomnia or lethargy, Loss of appetite, fatigue, loss of libido, etc. In severe cases, self-injury or even suicide may occur. According to research, depression has become the third leading cause of disability and death. At present, the pathogenesis of depression has not been definitively concluded, but a large number of studies have shown that it is related to biochemical, neuroendocrine, and neuroimmunological factors. At present, selective 5-HT reuptake inhibitors are routinely used in clinical treatment, such as sertraline, citalopram, Prozac, etc., but they often have slow onset and obvious side effects, making it difficult to achieve satisfactory therapeutic effects. Traditional Chinese medicine has gradually begun to be accepted by doctors and patients in the treatment of refractory diseases due to its multi-component and multi-target characteristics. This article mainly discusses the research progress of Chinese herbal extracts, Chinese herbal medicine pairs, Chinese herbal compound prescriptions, and Chinese patent medicines in the treatment of depression, and provides references for the clinical application of Chinese medicines in the treatment of depression.
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    Exact method of sample size calculation and statistical inference in single-arm clinical trials with objective performance criteria
    CHENG Qi, LIU Yu-xiu, CHEN Lin, LIU Li-xia
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (5): 517-522.  
    Abstract1323)      PDF (279KB)(557)       Save
    AIM: To explore the exact method of sample size estimation and statistical inference in single-arm clinical trials with Objective Performance Criteria (OPC) based on binomial distribution principle.METHODS: This article will systematically and comprehensively discuss the exact method of sample size calculation, confidence interval estimation and hypothesis testing which the single-arm clinical trial method involves in.RESULTS: With the starting point of OPC at 75% by an interval of 1% increasing and the starting point of expected event rate at 76% by an interval of 1% increasing, corresponding exact sample sizes are calculated. And two sets of results under the condition of β of 0.20 and α of 0.05 (one sided and two sided) are tabulated respectively. The exact calculating formulas of confidence interval estimation and hypothesis testing are provided.CONCLUSION: Systematic methodology support is provided for OPC method in single-arm clinical trials in calculating sample size, estimating confidence interval and hypothesis testing.
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    Chinese Journal of Clinical Pharmacology and Therapeutics    2016, 21 (2): 218-224.  
    Abstract1297)      PDF (3257KB)(2990)       Save
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    Progress in research on hyperuricemia cell model
    WU Dan, DIAO Yong, XU Xianxiang
    Chinese Journal of Clinical Pharmacology and Therapeutics    2021, 26 (2): 236-240.   DOI: 10.12092/j.issn.1009-2501.2021.02.017
    Abstract1185)      PDF (332KB)(1125)       Save
    High uric acid models are divided into animal models and cell models. Model construction is very important for hyperuricemia researching and drug screening. High uric acid animal model is mature, but there is a large gap between animals and humans, and animal models still have shortcomings. The cell model research cycle is short and the operation is simple. Meanwhile it is a model closer to human hyperuricemia, but it is rarely reported. This article briefly lists the cells commonly used in the construction of high uric acid models, outlines the construction methods of high uric acid cell models according to the two modeling principles of increasing uric acid synthesis and reducing uric acid excretion, and provides references for the development of hyperuricemia related research.
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    Chemical constituents and Pharmacology of Eucommia ulmoides Oliv.
    FENG Han, ZHOU Hong-Hao, 欧Yang-Dong-Sheng
    Chinese Journal of Clinical Pharmacology and Therapeutics    2015, 20 (6): 713-720.  
    Abstract1167)      PDF (3364KB)(1619)       Save
    Eucommia ulmoide is an ancient species left in tertiary glacier movement. The active phytochemicals found in E.ulmoides are divided into lignans, iridoids, flavonoids, phenylpropanoids, terpenoids and polysaccharide. Eucommia ulmoide displays extensive pharmacological action, as anti-hypertension, anti-hyperlipidemia, anti-hyperglycemic, anti-tumor, anti-bacterial, anti-virus, anti-inflammatory, anti-oxidative, hepatoprotection, renoprotection and anti-osteoporosis. E.ulmoide has long medical history in China, Korea and Japan. This review summarizes the progress in chemistry and pharmacology of E.ulmoides.
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    Two non-parametric methods and its comparation for calculating median difference and its confidence interval
    LI Yun-fei, WANG Kun, HUANG Ji-han, SHENG Yu-cheng, HE Ying-chun, ZHENG Qing-shan
    Chinese Journal of Clinical Pharmacology and Therapeutics    2012, 17 (7): 761-767.  
    Abstract1132)      PDF (548KB)(1813)       Save
    AIM: To introduce two nonparametric methods (Bootstrap and Hodges-Lehmann) for calculating median difference and its confidence interval; the results of these two methods were compared under three pairs of data from three different distributions, and the reason of the difference was discussed. METHODS: Two groups of data were generated from each normal, lognormal and bimodal distribution by computer simulation. The median difference and its confidence interval of each pair were calculated by the two nonparametric methods. This process was repeated for 500 times. RESULTS: The results of the two methods were nearly when data follow normal distribution and it's also agree with the results of parametric method by using mean instead median. For lognormal distribution, the estimated value of median difference and its confidences interval calculated by Bootstrap was larger than the results of Hodges-Lehmann. The results of the two methods was nearly when data distribution was symmetric while the confidence interval was slightly different. CONCLUSION: The two methods are coincident in symmetric distribution. However, Bootstrap emphasizes the position of median while Hodges-Lehmann cares the variance in the case of asymmetric distribution.
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    Dose conversion among different animals and healthy volunteers in pharmacological study
    HUANG Ji-Han,HUANG Xiao-Hui, CHEN Zhi-Yang, ZHENG Qing-Shan, SUN Rui-Yuan
    Chinese Journal of Clinical Pharmacology and Therapeutics    2004, 9 (9): 1069-1072.  
    Abstract1100)      PDF (152KB)(3775)       Save
    In order to obtain equivalent dose, a dose conversion was important among different animals and healthy volunteers in preclinical pharmacology and I phase clinical trials. Body coefficient and standard weight were introduced into the formula to estimate the equivalent dose in this paper.
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    Progress in the roles of adenosine receptors in sleep-wake regulation
    YU Jie, XU Qi, WANG Yi-qun
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (2): 214-218.  
    Abstract1081)      PDF (194KB)(548)       Save
    Adenosine, the product of ATP, widely presented in the brain is proposed to be an endogenous sleep-promoting substance. Among 4 subtypes of adenosine receptor (R), A1R, A2AR, A2BR and A3R, it has been reported that both adenosine A1R and A2AR mediate the somnogenic effects of adenosine. Activation of A1R in the arousal histaminergic posterior hypothalamus, cholinergic basal forebrain and so on promotes sleep. A2AR is mainly localized in the caudate-putaman, nucleus accumbens, olfactory tubercles. Activation of A2AR significantly promotes sleep. A2AR mediates the somnogenic effects of prostaglandin D2, and acts as the target of caffeine. However, the roles of A1R and A2AR in sleep-wake regulation are in debate. This review summarizes the progress in the roles of adenosine receptors in sleep-wake regulation.
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    A novel model-assisted design in phase I clinical trials: Bayesian optimal interval design
    ZHONG Zihang, CHEN Feng, YUAN Ying, CHENG Jiancheng, YU Xuanxuan, YANG Min, TAN Mingmin, ZHAO Yang, BAI Jianling, YU Hao
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (6): 640-648.   DOI: 10.12092/j.issn.1009-2501.2020.06.006
    Abstract1080)      PDF (998KB)(560)       Save
    AIM: To introduce a novel and flexible model-assisted design for Phase I clinical trials: Bayesian optimal interval (BOIN) design, including the process of implementation, practical implementation, and evaluation of its performance. METHODS: BOIN design decides dose escalation/de-escalation by comparing the observed toxicity rate at the current dose with an escalation boundary and a de-escalation boundary that are optimized to minimize the probability of making incorrect decision of dose assignment. The application of the BOIN design is illustrated using a trial example. RESULTS: BOIN combines the advantages of the algorithm-based methods and model-based methods. It enjoys desirable statistical properties -it is optimal, safe, robust and easy to implement. Simulation study shows that the BOIN substantially outperforms the existing designs with higher accuracy to identify the maximum tolerated dose (MTD). CONCLUSION: BOIN design possesses the similar statistical performance to the much more complicated model-based designs. It is simple to implement, and easy to calibrate to meet the safety requirement mandated by regulatory agents. The BOIN design has been widely used in different types of cancers. It is a novel design that holds great potential to substantially improve phase I trials in China.
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    Research progress of monoclonal antibodies in pharmacokinetic characteristics, analysis methods and method validation
    ZHU Xueya, LI Zeyun, TIAN Xin, ZHANG Xiaojian
    Chinese Journal of Clinical Pharmacology and Therapeutics    2021, 26 (1): 113-120.   DOI: 10.12092/j.issn.1009-2501.2021.01.015
    Abstract1072)      PDF (459KB)(1240)       Save
    In recent years, monoclonal antibodies (mAbs) have been developing rapidly and widely used in fields of tumor, immunity, blood and other systemic diseases. Global share of mAbs in prescription drug market had reached up to $ 140 billion, 15.3% by 2019. As macromolecule proteins, with special structures and physiological properties, mAbs have great differences in absorption, distribution, metabolism and excretion in vivo compared with small molecule drugs, including characteristics of relatively large molecular mass, high specificity and selectivity in target combination, non-linear pharmacokinetics, time dependence, long half-life and so on. Fully understanding of these special pharmacokinetic characteristics shall effectively guide analysis of mAbs. Meanwhile, the particularity and complexity of disposal mechanism in organisms greatly increase the difficulty of biological detection. As a result, it is necessary to establish exclusive, sensitive, accurate and repeatable quantification methods in biological samples. This article focuses on pharmacokinetic characteristics, main analytical methods, and methodology validation of quantification for mAbs in biological samples, expounding with comparisons of small molecular drugs, so as to prompt development of pharmacokinetic study of this kind of drugs.
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    Ferroptosis regulatory signaling pathway and its research progress in related diseases
    ZHANG Liang, LIAO Yongqun, XIA Qinchuan, ZHOU Shitong, LI Xiaoli
    Chinese Journal of Clinical Pharmacology and Therapeutics    2022, 27 (2): 227-234.   DOI: 10.12092/j.issn.1009-2501.2022.02.015
    Abstract1063)      PDF (440KB)(832)       Save
    Ferroptosis is an iron-dependent novel type of programmed cell death. The main features of ferroptosis include lipid reactive oxygen accumulation, iron accumulation and lipid peroxidation. The main mechanisms and signal pathways of ferroptosis are complex and closely related to cystine/glutamate antiporter system, glutathione peroxidase 4, ferroptosis suppressor protein 1, and dihydroorotate dehydrogenase. This review summarizes the current regulatory mechanisms of ferroptosis and discusses the research progress of ferroptosis in tumors, non-alcoholic fatty liver disease, Parkinson's disease, and congestive heart failure.
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    TU Jiao, CHEN Hui, NI Ping, QI Xiao, XIAO Wan, XU Lin-Yong
    Chinese Journal of Clinical Pharmacology and Therapeutics    2015, 20 (9): 1011-1019.  
    Abstract1048)      PDF (3781KB)(2380)       Save
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    Inhibiting URAT1 gene expression and reducing blood uric acid level of Chinese Traditional Medicine such as smilax glabra
    SUN Hong, WANG Shao-ming, ZHUANG Jie, HUANG Xu-hui, YAO Jin-zhou
    Chinese Journal of Clinical Pharmacology and Therapeutics    2012, 17 (4): 403-407.  
    Abstract1037)      PDF (336KB)(443)       Save
    AIM: To explore whether Chinese Traditional Medicine such as alismatales, plantaginaceae and smilax glabra can regulate the hyperuricemia mice uric anionic exchanger 1(URAT1) mRNA expression of rats. METHODS: The 48 Wistar rats were randomly divided into control group, model group, benzbromarone group, alismatales group, plantaginaceae group and smilax glabra group. There were 8 rats every group. Alismatales, plantaginaceae,smilax glabra and benzbromarone were given to rats with hyperuricemia model established with potassium oxonate. The quantitative Real-time PCR method was used for detection of URAT1 mRNA gene expression. RESULTS: The blood uric acid level of benzbromarone group, alismatales group, plantaginaceae group and smilax glabra group were significantly lower than those in the model group (P<0.01). The expression of URAT1 mRNA in benzbromarone group, plantaginaceae group, benzbromarone group were lower than those in model group. CONCLUSION: The mechanism for plantaginaceae and smilax glabra may be relevant in inhibiting URAT1 gene mRNA expression of rats, thus accelerating the excretion of uric acid.
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    Bioequivalence of apixaban tablets in healthy Chinese subjects
    NING Xiaoyi, KUANG Yun, HUANG Jie, LIU Yanan, YANG Xiaoyan, YANG Shuang, GUO Can, YANG Guoping
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (3): 306-311.   DOI: 10.12092/j.issn.1009-2501.2020.03.010
    Abstract1033)      PDF (376KB)(927)       Save
    AIM: To evaluate the bioequivalence of the two preparations of apixaban tablets administered once orally under fasting and fed conditions. METHODS: The study was designed as randomized, open, self-crossover, and twenty four healthy volunteers were recruited respectively in fasting and fed conditions. Subjects were assigned to receive a single oral of the test or reference formulation per period at a dose of 2.5 mg. The plasma apixaban concentration was analyzed by LC-MS/MS. The major pharmacokinetic parameters were calculated by WinNonlin 6.4 and the bioequivalence was evaluated.RESULTS:The main pharmacokinetic parameters of a single oral apixaban under fasting condition for T and R were as follows: Cmax (80±14) and (87±21) ng/mL, AUC0-t (713±136) and (733±142) h·ng·mL-1, AUC0-∞ (722±143) and (741±142) h·ng·mL-1, tmax 2.5 h and 2.5 h, t1/2 (9±8) and (8±6) h. The relative bioavailability was 97.16% for AUC0-t, 97.20% for AUC0-∞. The main pharmacokinetic parameters of a single oral apixaban under fed condition for T and R were as follows: Cmax (70±13), (72±13) ng/mL; AUC0-t (642±130), (690±135) h·ng·mL-1; AUC0-∞ (652±129), (704±138) h·ng·mL-1. tmax 2.5 h and 2.5 h, t1/2 (8±4) and (12±9) h. The relative bioavailability was 93.03% for AUC0-t, 92.62% for AUC0-∞. CONCLUSION: The test preparation of apixaban tablets is bioequivalent to the reference preparation under both fasting and fed conditions.
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    Progress in the development of baicalein and its clinical pharmacology study
    SHAN Hui, DU Yinxiao, BAI Hequn, CHEN Junxia, HE Xiaolin, WANG Qian, HU Zijian, LV Cheng, CHEN Xiaoping
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (6): 701-708.   DOI: 10.12092/j.issn.1009-2501.2020.06.013
    Abstract1029)      PDF (545KB)(754)       Save
    The 2019 new coronavirus pneumonia (COVID-19) caused by the new coronavirus (SARS-Cov-2) infection has become a global pandemic, and currently there is a lack of specific antiviral drugs. Traditional Chinese medicine plays a critical role in the treatment of COVID-19. Scutellaria baicalensis is an important component of the Qingfei Paidu decoction recommended in the Chinese National Health Commission's Treatment Regimen and Wuhan Xiehe No.2 and No.3 prescriptions as well. Baicalein is the main ingredient in Scutellaria baicalensis, and has various pharmacological effects such as antiviral, antibacterial, antiallergic, and immunomodulatory activities, showing a broad prospect in new drug development. This article systemically reviewed the recent progress in the preclinical and clinical studies, potential drug interactions, and other aspects of baicalein, which will help further development and clinical application of the drug.
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    New perspectives on the principle of intention to treat in clinical trials#br#
    HUANG Lihong, WANG Ling, YAN Fangrong, WEI Zhaohui, ZHAO Yang, XIA Jielai, CHEN Feng
    Chinese Journal of Clinical Pharmacology and Therapeutics    2021, 26 (4): 449-453.   DOI: 10.12092/j.issn.1009-2501.2021.04.013
    Abstract1028)      PDF (393KB)(519)       Save
    The intention to treat (ITT) principle is widely applied in the randomized controlled trials (RCTs), which is based on the intention to treat a subject (i.e. the planned treatment regimen) rather than the actual treatment given. With the development and progress of clinical trials, ITT principle needs to be reinterpreted. In the standard definition of ITT principle, the intentional grouping of subjects does not specifically refer to randomization, but rather to planned treatment regimen. In non-randomized clinical trials, that subjects agree to be included in a certain treatment regimen is also a type of intention. ITT principles can be applied to evaluate the effectiveness of treatment regimens under patient/doctor determined intentionality in single-arm clinical trials and non-randomized RWS (real world study, RWS). In the practical application, the grouping strategy based on ITT principle should be considered comprehensively according to the research purpose.
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    Research and development progress of the novel acid suppression drugs potassium-competitive acid blockers
    ZHAO Shifeng, WANG Ronghua
    Chinese Journal of Clinical Pharmacology and Therapeutics    2018, 23 (3): 352-360.   DOI: 10.12092/j.issn.1009-2501.2018.03.019
    Abstract1023)      PDF (3587KB)(900)       Save

    The advent of proton pump inhibitors represents an important milestone in the treatment of acid related diseases. However, these drugs have some deficiencies in pharmacokinetics and pharmacodynamics. Potassium-competitive acid blockers reversibly bind to proton pumps in a competitive manner with potassium ions, thereby inhibiting gastric acid secretion and having multiple advantages. In order to provide a new reference for the treatment of acid related diseases, the research and development experience and pharmacological characteristics and clinical research of these drugs are reviewed, and the focuses are on the already listed revaprazan and vonoprazan.

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    Development and application progress of physiologically based pharmacokinetic modeling and its combined use with other modeling methods
    CHEN Wenjun, RUAN Zourong, XIANG Xiaoqiang
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (3): 299-305.   DOI: 10.12092/j.issn.1009-2501.2020.03.009
    Abstract1022)      PDF (589KB)(978)       Save
    Physiologically based pharmacokinetics (PBPK) is one of the main research fields of pharmacometrics, and it plays an important role at all the stages of drug development and clinical practice. In early drug discovery and development, human pharmacokinetics (PK) could be predicted by PBPK modeling using in silico, in vitro and preclinical in vivo data. During clinical studies, PBPK model could be used to investigate the effects of various physiological and pathological factors on PK, such as age, gender, liver/kidney impairment, and to guide dose adjustment of special population (pregnant women, children, etc.). Furthermore, PBPK modeling is now becoming more appealing with the ability to predict drug-drug interaction (DDI) in the case of co-administration of multiple drugs. In recent years, the application of PBPK modeling in industry has increased widely. Also, regulatory agencies have recognized the potential of PBPK and its impact on labeling recommendations. As the popularity of model-informed drug development, the combination of PBPK modeling with other commonly used modeling methods, such as population pharmacokinetics (PopPK), pharmacokinetic/pharmacodynamic (PK/PD) modeling and model-based meta-analysis (MBMA), has shown attractive advantages. In this paper, the origin and development, as well as the application status of PBPK are introduced briefly, and the application of PBPK modeling merged with PopPK, PK/PD and MBMA is reviewed.
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    Analysis of metabolomic data: principal component analysis
    Jiye Aa
    Chinese Journal of Clinical Pharmacology and Therapeutics    2010, 15 (5): 481-489.  
    Abstract1012)      PDF (913KB)(3082)       Save
    Metabolomics has been widely applied to life science and showing a promising perspective. Conventional statistic analysis is not applicable to the large, multivariate dataset generated by high-throughput metabolomic tool, while it's of crucial importance to analyze and interpret the dataset. This article reviews the basic methods of principal components analysis(PCA) that is popular in metabolomics study, aiming at strengthening the fundamental knowledge of PCA and standardizing the methods and procedures for data analysis.
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    Free radical scavenging mechanism of edaravone and its clinical application
    MA Li-ping, SUN Jian-guo, PENG Ying, WANG Guang-ji
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (3): 341-348.  
    Abstract1003)      PDF (344KB)(522)       Save
    Researches certified that overproduction of free radicals has been implicated in many human diseases , as excessive free radicals damage biomacromole- cules such as lipids ,protein and DNA , leading to deleterious effect of the body. Edaravone, a potent free radical scavenger, has been approved in Japan for the treatment of acute cerebral infarction since April 2001. This review illustrated the hypothetical free radical-scavenging mechanism of edaravone and summarized the research progress of edaravone in treating many human diseases. The protective effect of edaravone in treating ischemic/reperfusion injury in many organs( brain, heart et al), neurodegenerative diseases(Amyotrophic Lateral Sclerosis, Parkinson's disease, Alzheimer's disease et al), epilepsy, atherosclerosis, hepatic fibrosis and pulmonary fibrosis diseases, rheumatoid arthritis and sudden hearing loss are described in this review, which may provide reference for the novel clinical application of edaravone in future.
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    The control research of Bupropion combined with Lithium Carbonate in the treatment of bipolar depression
    SHEN Zhong-xia, QIAN Ming-cai, SHEN Xing-hua, CHEN Hai-zhi, LIN Min
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (9): 1042-1046.  
    Abstract976)      PDF (195KB)(658)       Save
    AIM: To explore the efficacy and safety of Bupropion combined with Lithium Carbonate in the treatment of bipolar depression. METHODS: An open prospective randomized study was applied in this research which lasted 8 weeks. 78 inpatients meet the diagnosis criteria of DSM-IV were divided into two groups, one group(the research group, n=40) were treated with Bupropion combined with Lithium Carbonate, the other group(the control group, n=38) were treated with Lithium Carbonate only, HAMD-17 was applied to evaluate the efficacy on the baseline and the end of 1st, 2nd, 4th, 8th week,the BRMS was applied to evaluate the mania state, while the TESS and laboratory tests were applied to evaluate the side effects. RESULTS: HAMD scores of both group declined significantly at the end of 4th and 8th week respectively (P<0.01), but there were no significant difference between two groups(P>0.05). HAMD scores of research group were lower than those of control group at the end of 1st, 2nd week (P<0.05). There were no significant difference at the end of 8th week of remission rate and response rate between two groups(90% vs 89.5%,62.5% vs 60.5%,P>0.05), while the research group had a greater rate at the end of 2nd week(30% vs 10.5%, 20% vs 2.6%,P<0.05). There were no significant difference in side effects and cases switching to mania between two groups. CONCLUSION: Either Bupropion combined with Lithium Carbonate or Lithium Carbonate only would be effective and safe for bipolar depression, but the former can cut down the initial time to become effective and would not increase the risk of turning to mania.
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    LC-MS/MS determination of flunarizine in human plasma and application in bioequivalence evaluation
    CHEN Yao, TAN Zhi-rong, WANG Yi-cheng, LI Hui, LI Ling, DENG Xiao-lan, ZHANG Wei, ZHOU Hong-hao
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (4): 400-406.  
    Abstract968)      PDF (927KB)(623)       Save
    AIM: To establish a LC-MS/MS method for determination of flunarizine in human plasma, and to study the relative bioequivalence of flunarizine hydrochloride made by Yangtze River Pharmaceutical Group Co., Ltd. METHODS: Thermo Hypurity C18 column (150 mm×2.1 mm, 5 μm) was used in the experiment.Acetonitrile-10 mmol/L ammonium formate (including 0.1% formic acid) (65∶35, V/V) was used as mobile phase and the flow rate was 0.3 mL/min and the injection volume was 10 μL.The column temperature was set at 40 ℃,the sample room temperature was set at 15℃.A single oral dose of 20 mg flunarizine hydrochloride and its contrastive drug were given to 18 healthy volunteers in an open randomized two way crossover design.The plasma concentrations were determined by LC-MS/MS method at the different time points. RESULTS: Flunarizine was linear in the range of 0.38-196 ng/mL, the limitation of detection for flunarizine was 0.1 ng/mL,the method was high sensitivity, stability and specificity. The main pharmacokinetic parameters of flunarizine were as follows: Cmax was (86±36) and (82±34 )ng/mL;tmax was 2.5 h(1-3 h) and 3 h(2-5 h);AUC0-24 was (725±338) and (709±320) ng·mL-1·h;AUC0-∞ was (811±375) and (780±330) ng·mL-1·h.The reference drug and the test drug of flunarizine are bioequivalent. CONCLUSION: The method is simple, accurate and repetitive for the determination of flunarizine in human plasma and successfully applied to the bioequivalence evaluation of flunarizine hydrochloride in human.
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    Clinical application and research progress of remimazolam
    JIN Baowei, JIANG Zongming, GUO Jianrong
    Chinese Journal of Clinical Pharmacology and Therapeutics    2021, 26 (12): 1444-1448.   DOI: 10.12092/j.issn.1009-2501.2021.12.016
    Abstract961)      PDF (1006KB)(540)       Save
    Remimazolam is a new ultra-short-acting sedative, with rapid onset and recovery, metabolism independent of liver and kidney function, light respiratory inhibition, stable hemodynamics, long time application without accumulation. Carboxylic acid metabolites have no pharmacological effects, and can be rapidly reversed by antagonist flumazenil, which is expected to become a new choice of clinical sedative. In this paper, pharmacological characteristics and recent research progress of remimazolam are reviewed, which can provide reference for clinical safe drug use.
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    Effects of aripiprazole combined with duloxetine on the treatment effect and VEGF level in patients with refractory depression
    YANG Shitao, ZHU Yihong, TANG Wenxin
    Chinese Journal of Clinical Pharmacology and Therapeutics    2020, 25 (8): 937-942.   DOI: 10.12092/j.issn.1009-2501.2020.08.013
    Abstract952)      PDF (762KB)(272)       Save
    AIM: To explore the effects of aripiprazole and duloxetine on refractory depression and the change of VEGF concentration during treatment.  METHODS: Ninety patients with refractory depression who were treated at the Fourth People's Hospital of Jiande from February 2017 to February 2019 were selected, and 40 healthy volunteers were recruited as healthy control groups. Random numbers table was used to divide patients into aripiprazole combined with duloxetine treatment group (combined treatment group) and duloxetine treatment group (monotherapy group). After 4 weeks of treatment, the differences in efficacy and adverse reactions between the two groups were evaluated. The difference of VEGF level between each group was compared. RESULTS: The effective rate was 88.8% in the combined treatment group and 80.0% in the monotherapy group. The effective rate between the two groups was not statistically significant (P<0.05). After 4 weeks of treatment, the HAMD score in the combined treatment group was lower than that in the monotherapy group, the difference was statistically significant (P<0.05). The difference in adverse reactions between the two groups was not statistically significant (R=0.641, P=0.624). The level of VEGF before treatment in the two treatment groups was higher than that in the healthy control group, and the difference was statistically significant (P<0.01). After treatment, the VEGF level of the two groups decreased compared with before treatment, and the difference was statistically significant (P<0.01). The level of VEGF in the combined treatment group was lower than that in the monotherapy group, and the difference was statistically significant (P<0.05). Pearson correlation analysis showed that the level of VEGF before treatment was positively correlated with the HAMD score (R=0.403, P<0.01), and VEGF decline level is positively correlated with HAMD score reduction rate (R=0.330, P<0.01). CONCLUSION: Aripiprazole combined with duloxetine has a better effect on refractory depression than duloxetine alone, and can significantly reduce the level of VEGF in peripheral blood.
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    Comparison of two kinds of diabetic model mice
    LIU Qian, WANG Qing, ZHANG Xue-mei
    Chinese Journal of Clinical Pharmacology and Therapeutics    2013, 18 (9): 999-1003.  
    Abstract936)      PDF (1041KB)(1093)       Save
    AIM: To compare the classical diabetic db/db mice and another diabetic mice which were established by high-fat diet along with STZ injection for evaluating the two diabetic mice on the diabetes characteristic and the reaction to three different kinds of hypoglycemic drug.METHODS: After weaning male BALB/c mice fed with high-fat diet for 4 weeks, streptozocin(STZ)45 mg/kg were intraperitoneal injected once a day and consecutive three days.One week after the last injection, the fasting blood glucose and glucose tolerance were measured. The STZ diabetes mice were prepared successfully as their impaired glucose tolerance accompanying with fasting glucose higher than 8.0 mmol/L. The fasting blood glucose and glucose tolerance of the 8 weeks old db/db mice were also measured.The db/db mice and the STZ diabetes mice were divided into four groups randomly, treated with rosiglitazone(12 mg/kg),glibenclamide (45 mg/kg),insulin (1 U/kg) and normal saline once a day respectively.After four weeks,biochemical indexes and hormone level related to glucose and lipid metabolism were measured from the samples of the two diabetes models.RESULTS: Compared with the BALB/c normal mice, the fasting blood glucose,total cholesterol and triglycerides in STZ model mice were significantly increased(P<0.05) as well as the glucose tolerance was badly impaired, the serum insulin and c-peptide decreased significantly (P<0.05).Compared with the C57BL mice, the fasting blood glucose,total cholesterol,triglyc erides,the serum insulin and the c-peptide lever of db/db mice were all increased significantly (P<0.05)along with the impaired glucose tolerance.In the STZ experiment mice, rosiglitazone, glibenclamide and insulin decrease the fasting blood glucose and improve impaired the glucose tolerance significantly.In the db/db mice, only rosiglitazone can decrease their fasting blood glucose and improve impaired the glucose tolerance, but there was no change after treated with common dose of glibenclamide and insulin until tripling dose of insulin.CONCLUSION: The characteristics of the STZ diabetes mice induced by high-fat diet and multiple low-dose STZ injection were higher achievement ratio, the stable and lasting diabetes characters.The STZ diabetes mice were sensitive to a variety of different hypoglycemic drugs. db/db mice show severe insulin resistance blunting with endogenous and exogenous insulin.db/db mice show only the same sensitive to rosiglitazone as that of the STZ diabetes mice.
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    Farnesoid X receptor is an important target in lipid metabolism
    LIU Xiaohong, LI Ling, QI Zhenhua, CHEN Binyao, ZHAO Huijia, HAO Zhuowen, YUE Jiang, YE Qifa,WU Jianguo
    Chinese Journal of Clinical Pharmacology and Therapeutics    2018, 23 (8): 955-960.   DOI: 10.12092/j.issn.1009-2501.2018.08.020
    Abstract916)      PDF (2503KB)(673)       Save

    Farnesoid X receptor (FXR) is a kind of nuclear receptors of bile acid activation. FXR influences lipid in the liver, small intestine, and other important organs of various metabolic processes through regulating the expression of target genes such as CYP7A1. This review focuses on the influence of FXR in lipid metabolism on the basis of the related research reviews in recent years, and hopes to provide a scientific basis for prevention and treatment of clinical diseases as FXR is becoming the expected drug-target for diseases such as fatty liver, high blood triglycerides, etc.

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    Understanding of relation among significance test, interval test and confidence interval test in clinical trial
    WANG Jing, HU Jing-qing
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (3): 281-286.  
    Abstract915)      PDF (212KB)(421)       Save
    The significance test is the most primary statistical hypothesis test, and it's basic principle is the principle of little probability. The interval test in clinical trial is the extension of the significance test, which is used to testify whether the difference between two populations is within a certain interval. In the confidence interval test, firstly, we find the confidence interval of the difference between two treatments' effects, and then we can decide whether it is non-inferior, equivalent or superior or not through comparing the confidence interval with the margin. Through the transformation of equations, it can be revealed that the most essential difference between the significance test and the interval test is the margin, which has the clinical meaning, is included in the interval test. In this paper, the consistency is confirmed between the interval test and the confidence interval test, so we can use the confidence interval test to achieve the result of the interval test.
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    Clinical observation on treating polycystic ovary syndrome with sterility with Guizhifulin capsule and Diane-35 and clomifene citrate
    YE Hui-jun, JIANG Yan-jiao, LI Ai-ping, YU Yuan
    Chinese Journal of Clinical Pharmacology and Therapeutics    2012, 17 (6): 691-695.  
    Abstract914)      PDF (227KB)(780)       Save
    AIM: To observe the clinical effect of Guizhifulin capsule, together with Diane-35 and clomifene citrate on polycystic ovary syndrome (PCOS) with sterility. METHODS: From February 2009 to February 2011, 60 PCOS patients with sterility who visiting the out-patient clinic of Obstetrics and Gynecology Sterility Department, Second Affiliated Hospital, Chinese Medical University,were enrolled to be divided randomly into control group (Diane-35+clomifene citrate) and treatment group (Guizhifulin capsule + Diane-35+clomifene citrate).Before and after 3 months treatment, the changes of the following items were observed: body mass index(BMI),waist-to-hip ratio(WHR), hairness score, acne score, volume of ovary,total testosterone(TT),luteinizing hormone (LH), LH-to-Follicular Stimulating Hormone(FSH) ratio,fasting plasma glucose (FPG),fasting insulin(FINS). Additionally, the ovulation rate and pregnancy rate were detected after 3 treatments. RESULTS: (1)There was no statistical difference in WHR, hairness score,acne score between the treatment group and the control group. The volume of ovary was smaller both in the treatment group and control group. BMI was statistically decreased in the treatment group(P<0.05), and no in control group.(2)After treatment,there were statistically decrease in LH,LH-to-FSH ratio, TT ,and increase in SHBG both in treatment group and control group(P<0.05).There was statically decrease in FINS in treatment group(P<0.05), and no in control group(P>0.05).(3)The rate of ovulation and pregnancy was more in treatment group than that in control group, but there was no statisically difference (P>0.05). CONCLUSION: Guizhifulin capsule and Diane-35 and clomifene citrate are able to improve the status of genito-endocrine, glycolipin metabolism, sensitivity to CC and the rate of ovulation and pregnancy.
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    Regulatory mechanism of LDLR and research progress of its related diseases and drugs
    LI Miao, YU Qinwei, JIANG Zhenzhou, ZHANG Luyong,
    Chinese Journal of Clinical Pharmacology and Therapeutics    2022, 27 (8): 946-954.   DOI: 10.12092/j.issn.1009-2501.2022.08.014
    Abstract913)      PDF (519KB)(585)       Save
    Cholesterol is an important lipid component in the body, which not only participates in the formation of cell membranes, but also is the raw material for the synthesis of bile acids and steroid hormones. Low density lipoprotein receptor (LDLR) is involved in cholesterol metabolism and plays an important role in maintaining the cholesterol homeostasis of organism cells. The expression of LDLR is precisely regulated by transcription, post-transcription and post-translation, and the imbalance of ldlr expression will lead to the occurrence and development of many diseases. In this paper, the molecular regulation mechanism of LDLR, the damage of target organs caused by the imbalance of LDLR expression and the research and development progress of drugs targeting LDLR are reviewed, which provides theoretical basis for further understanding of the progress of diseases related to lipid metabolism disorder and new insights for developing drugs targeting LDLR with more effective and less side effects.
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    Optimization of SAE reconciliation in clinical trail
    ZHOU Bei, YU Hao
    Chinese Journal of Clinical Pharmacology and Therapeutics    2018, 23 (4): 428-433.   DOI: 10.12092/j.issn.1009-2501.2018.04.011
    Abstract911)      PDF (2270KB)(678)       Save

    AIM: To realize the semi-automation of SAE (serious adverse events) reconciliation between clinical database and safety database through SAS (statistic analysis system) program, reduce the manual work and improve the accuracy of reconciliation.  METHODS: A CRO company's SAE reconciliation was taken as example, the SAE of safety database was imported into SAS through Proc Import procedure, which was combined with SAE of clinical database and was sorted by subject, AE number or AE name; the same variable one by one was compared, located and marked the inconsistent data point in EXCEL by SAS DDE language, the consistency check was more targeted and more intuitive.RESULTS:The inconsistent data point was accurately located and the workload of manual check was reduced; meanwhile, screening and matching through SAS program reduced the random errors which manual operation may produce. CONCLUSION: This method can assist traditional manual check to a certain extent; also, it can reduce the human dependence, guarantee the quality of check and process a high value of practical application.

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    Research progress in pharmacological and non-pharmacological treatments of hypertension
    XU Jianfei, LIN Li
    Chinese Journal of Clinical Pharmacology and Therapeutics    2022, 27 (4): 433-441.   DOI: 10.12092/j.issn.1009-2501.2022.04.013
    Abstract906)      PDF (473KB)(504)       Save
    Hypertension is the most common chronic non-communicable disease in the world and the most important risk factor for cardiovascular and cerebrovascular diseases. At present, the control rate of hypertension treatment standard is less than 50%, and it is still not effectively managed to a large extent. Despite numerous clinical studies and trials over the past four decades, the progress of new antihypertensive drugs has not been satisfactory. This review discusses recent advances in pharmacological and non-pharmacological treatments for patients with hypertension, and may provide new options for clinical hypertension treatment in the future.
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    Pharmacology and clinical evaluation of vericiguat in the treatment of heart failure
    LIU Ping, QIU Bo, WU Huizhen
    Chinese Journal of Clinical Pharmacology and Therapeutics    2022, 27 (2): 212-218.   DOI: 10.12092/j.issn.1009-2501.2022.02.013
    Abstract902)      PDF (1896KB)(606)       Save
    Vericiguat is a soluble guanylate cyclase stimulator, acting on nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway. Vericiguat can improve the sensitivity soluble guanylate cyclase sensitivity to nitric oxide, stimulate soluble guanylate cyclase without relying on nitric oxide, leading to increased formation of cyclic guanosine monophosphate , which results in multi-dimensional protection effects for the heart. It provides a new therapeutic approach for patients with heart failure. This review provides an overview of mechanism, preclinical studies, pharmacokinetics, clinical efficacy, drug-drug interactions and limitations of vericiguat.
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    Clinical research advancement of nanoparticle albumin-bound paclitaxel in anti-cancer treatment
    CAI Xin-jun, XU Ying-ying, NI Jian-jun
    Chinese Journal of Clinical Pharmacology and Therapeutics    2011, 16 (6): 716-720.  
    Abstract890)      PDF (181KB)(613)       Save
    Albumin is a vital drug carrier for nanoparticle paclitaxel in the anti-cancer treatment.This paper reviewed the pharmacokinetics and mechanism of nanoparticle transport of nanoparticle albumin-bound paclitaxel,and summarized the recent clinical trials of nanoparticle albumin-bound paclitaxel in breast cancer,non-small cell lung cancer,and other malignant treatment which could be a reference for its clinical use.
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