Study of integrative evidence chain in clinical trial of Guizhi Fuling Capsules based on "Yibing Tongzhi" in clinical applications / 中国中药杂志

Guizhi Fuling Capsules is a new-type traditional Chinese medicine preparation made by modern process method. It was widely used to treat uterine fibroids, pelvic inflammation, dysmenorrhea, endometriosis, mammary gland hyperplasia and other gynecological diseases. Under the combination of disease and syndrome, the diagnosis and treatment model of "Yizheng Tongbing, Yibing Tongzhi" with Chinese patent medicine has been widely used in clinical practice. Meanwhile, the effectiveness and safety have been given more and more attention. Based on the effectiveness of Guizhi Fuling Capsules, this paper preliminarily summarized the dominant diseases in randomized controlled trials and systematic reviews of Guizhi Fuling Capsules. On the basis of the basic theory of traditional Chinese medicine and modern pharmacological mechanism, the clinical efficacy and mechanism of Guizhi Fuling Capsules were explored. Finally, according to the traditional Chinese medicine theory of "Yizheng Tongbing, Yibing Tongzhi", all the clinical evidences were integrated to form an integrated evidence chain, so as to provide guidance for the safe and rational use of Guizhi Fuling Capsules.

Effects of Guizhi Fuling Capsules and Its Main Components on Intestinal Flora of Primary Dysmenorrhea Model Rats / 中国药房

OBJECTIVE：To investigate the effects of Guizhi ful ing capsules and its principal components （paeoniflorin， paeonol and amygdalin ）on the intestinal flora of primary dysmenorrhea model rats. METHODS ：Female SD rats were randomly divided into normal group ，model group ，capsule group（Guizhi fuling capsule ，1 000 mg/kg），paeoniflorin group （15.0 mg/kg）， paeonol group （10.3 mg/kg）and amygdalin group （12.1 mg/kg），with 6 rats in each group. Except for normal group ，other groups were given estradiol benzoate subcutaneously on the back of rats and oxytocin intraperitoneally to induce primary dysmenorrhea model. From the 4th day after subcutaneous injection of estradiol benzoate ，normal group was given constant volume of normal saline intragastrically ；model group was given constant volume of 0.5％CMC-Na solution intragastrically ；administration groups were given relevant medicine intragastrically ，once a day ，for consecutive 7 days. The writhing times and the contents of and MDA in uterus tissue of rats were determined ，and then com the contents of short-chain fatty acids （SCFAs）such as acetic acid，propionic acid ，butyric acid in colonic contents were detected by GC method. Using diver sity index as index ， Rep-PCR and Eric-PCR were used to evaluate the d iversity of intestinal flora in feces of rats. RESULTS ：Compared with normal group，the writhing times of rats were increased significantly in model group ；the contents of NO and MDA in uterus were increased significantly ，while the contents of acetic acid ，propionic acid and butyric acid in colonic contents and total content of SCFAs were decreased significantly （P＜0.05 or P＜0.01）；the number of DNA electrophoresis bands of intestinal flora was significantly reduced ，the brightness of most bands was significantly reduced ，and the diversity indexes （by Rep-PCR and Eric-PCR method ，hereinafter）1 h after administration were significantly reduced （P＜0.05 or P＜0.01）. Compared with model group，writhing times of rats were decreased significantly in capsule group ，paeoniflorin group and paeonol group ；the contents of NO in uterus of rats in capsule group and paeoniflorin group as well as the contents of MDA in capsule group ，paeoniflorin group and paeonol group were decreased significantly （P＜0.05 or P＜0.01）；the propionic acid content and total content of SCFAs in colon of rats in capsule group ，the contents of acetic acid ，propionic acid and butyric acid ，total content of SCFAs in paeoniflorin group as well as the contents of propionic acid and butyric acid ，total content of SCFAs in paeonol group were increased significantly；the content of isovaleric acid was decreased significantly in paeoniflorin group （P＜0.05 or P＜0.01）；DNA electrophoresis bands and its brightness of intestinal flora changed to different extents in administration groups ，and the diversity indexes of intestinal flora 1 h after administration were increased significantly in capsule group and paeoniflorin group ，while those indexes were decreased significantly in paeonol group and amygdalin group （P＜0.05 or P＜0.01）. CONCLUSIONS ：Guizhi fuling capsules can significantly reduce writhing times and the contents of NO and MDA in uterus of primary dysmenorrhea model rats. At the same time ，the capsules also can regulate SCFAs content in colonic contents and intestinal flora diversity of rats. The above effects may be related to paeoniflorin and paeonol in the capsules.

Analysis on 1 500 adverse reactions of Guizhi Fuling Capsules based on spontaneous response system / 中国中药杂志

To understand the characteristics of adverse reactions and find early warning signs after intake of Guizhi Fuling Capsules. The 1 500 adverse reaction(ADR) cases of Guizhi Fuling Capsules obtained by spontaneous reporting system(SRS) from 2008 to 2017 were analyzed by proportional reporting ratios method(PRR), Bayesian confidence propagation neural network method(BCPNN) and propensity score method. The number of ADR reports increased year by year, and reached the peak in the fourth quarter of 2014. A total of 1 500 ADR cases were monitored, including 10 severe ADR cases. There were a total of 934 cases aged between 18-44 years old, accounting for 62.27%. All patients were orally administered. Among them, 1 398 patients received a single dose according to the package insert, and 57.4% had ADR within 24 h. The top five clinical manifestations of ADR were gastric dysfunction, abdominal pain, nausea, vomiting and rash, which mainly damaged the digestive system. The ADR signals were analyzed. PRR suggested that "gastric dysfunction" and "abdominal pain" were the early warning signals of Guizhi Fuling Capsules. BCPNN suggested that "nausea" and "abdominal pain" were the early warning signals of Guizhi Fuling Capsules. After the propensity score weighting method was used to control the confounding factors, the warning signals remained unchanged. The results show that Guizhi Fuling Capsules has fewer adverse reactions and is relatively safe. This study provides a basis for studying ADR of Guizhi Fuling Capsules, and guidance for drug vigilance and risk management of Guizhi Fuling Capsules.

Study on on-line near-infrared spectroscopic for moisture monitoring in a fluidized bed drying process of Guzhi Fuling Capsules / 中草药

Objective: To establish a real-time moisture monitoring model for the fluidized bed drying process of Guizhi Fuling Capsules (GFC) by using online near-infrared spectroscopy (NIRS). Methods: A total of 176 samples from 16 production batches were collected by NIRS diffuse reflection probe for modeling. The moving window average smoothing method was used for spectral preprocessing. The characteristic variables were 4 759.45—5 338.00 cm−1, 5 503.84—6 101.67 cm−1, and 8 512.25—8 809.24 cm−1, which were screened by the interval partial least squares method (siPLS) combined with the moving window partial least squares (mwPLS). The partial variable least squares (PLS) method was used to build a multivariate correction model for moisture. Results: The root mean square error of cross-validation (RMSECV) of predicted moisture was 0.243%, the ratio of predicton to deviation (RPD) was 13.384, and the relative standard error of prediction (RSEP ) was 0.270%. The reliability of the online monitoring method was continuously verified by eight production batches. The relative error of 40 samples was less than 4.7%, indicating that the PLS quantitative model prediction performance was robust and accurate. The real-time monitoring trend chart of the moisture in the drying process can accurately determine the drying end point, and the moisture content of the end sample was within the control limit. Conclusion: The quantitative model established by online NIRS combined with PLS can be applied to the on-line monitoring of moisture content in the fluidized bed drying process of production scale GFC and the prediction performance was robust and accurate.

Therapeutic Observation of Fire-needle Therapy plus Chinese Medication for Ovarian Cysts / 上海针灸杂志

Objective To observe the clinical efficacy of fire-needle therapy plus oral administration ofGuizhi Fuling capsules in treating ovarian cysts.Method Seventy-six patients with ovarian cysts were randomized into a treatment group and a control group, 38 cases each. The treatment group was intervened by fire-needle therapy plus oral administration ofGuizhi Fuling capsules, while the control group was intervened by oral administration ofGuizhi Fuling capsules alone. Before and after the treatment, ultrasound B-scanning was adopted to measure the sizes of ovarian cysts, and the therapeutic efficacies were compared between the two groups.Result The sizes of ovarian cysts were significantly changed after the treatment in both groups (P<0.01). The sizes of ovarian cysts in the treatment group were significantly different from those in the control group after the intervention (P<0.05). The total effective rate was 86.8% in the treatment group versus 65.8% in the control group, and the between-group difference was statistically significant (P<0.05).Conclusion Fire acupuncture plus oral administration ofGuizhi Fuling capsules is an effective approach in treating ovarian cysts.

Clinical study of Guizhi Fuling capsules combined with fosfomycin trometamol power on pelvic inflammatory disease and pelvic effusion / 中国生化药物杂志

Objective To analyze the clinical value of Guizhi Fuling capsules combined with fosfomycin trometamol power in the treatment of pelvic inflammatory disease and pelvic effusion.Methods A total of 60 patients with pelvic inflammatory disease and pelvic effusion from February 2013 to March 2016 in our hospital were selected and divided into the control group and the observation group , 30 cases in each group.The control group were treated with fosfomycin trometamol power, and the observation group were additionally treated with Guizhi Fuling capsules.The therapeutic effects and changes of TCM syndrome scores were compared between the two groups.The levels of serum C reactive protein ( CRP ) in the two groups were determined before and after treatment and the ultrasound examination was performed and changes of pelvic effusion diameter was determined before and after treatment.Results The total effective rate of the observation group was higher than that of the control group, the difference was statistically significant (P<0.05).There was no significant difference in TCM syndrome scores between the two groups before treatment .After treatment, the TCM symptom scores of both groups were decreased, the difference was statistically significant ( P<0.05 ) .The scores of lumbosacral swelling pain, abdominal pain, morbid leucorrhoea increase, fatigue, low-grade fever and soreness of waist in the observation group were lower than those in the control group, the difference was statistically significant (P<0.05).Before treatment, there was no statistically significant difference in pelvic effusion and CRP levels between the two groups.After treatment, the pelvic effusion diameter and CRP levels were decreased, the difference was statistically significant (P<0.05), and those in the observation group were lower than the control group, the difference was statistically significant (P<0.05). Conclusion Guizhi Fuling capsules combined with the fosfomycin trometamol power is significantly effective in the treatment of pelvic inflammatory disease and pelvic effusion.It can significantly reduce the inflammatory reactions of patients, and improve the TCM syndrome scores.

Simultaneous determination of six triterpenoid acids from Guizhi Fuling capsules by UPLC-MS/MS / 中国中药杂志

To establish a UPLC-MS/MS method for simultaneous determination of six triterpenoid constituents (pachymic acid, dehydropachymic acid, dehydrotumulosic acid, polyporenic acid C, dehydroeburicoic acid and dehydrotra metenolic acid) in Guizhi Fuling capsules (GFC). Chromatographic analysis was conducted on Agilent Porosheell 120 SB-C₁₈ column (4.6 mm×150 mm, 2.7 μm), with 0.1% formic acid aqueous solution-methanol as the mobile phase for gradient elution at a flow rate of 0.4 mL•min-1. The column temperature was 30 ℃ and the sample size was 5 μL. The samples were analyzed by tandem mass spectrometer with negative electrospray ionization (ESI) source, and monitored under a multiple reaction monitoring (MRM) mode, with the quantitative ion pairs m/z 527.8→465.5 (pachymic acid), m/z 525.6→465.6 (dehydropachymic acid), m/z 483.4→337.3 (dehydrotumulosic acid), m/z 481.5→419.5 (polyporenic acid C), m/z 467.4→337.1 (dehydroeburicoic acid), m/z 453.4→337.0 (dehydrotra metenolic acid). Six triterpenoid acids showed good linear relationships within the investigated concentration ranges (r> 0.996 8), with RSDs of precision less than 6.2%, and all RSDs of repeatability less than 5.9%. The average recovery rate was 97.90%, 100.2%, 99.60%, 101.7%, 102.6% and 103.0% respectively. The method was rapid, accurate, repeatable and could be used as a method for quantitative determination of triterpenoid acids in Chinese medicine prescriptions, providing a reference method for the quality control of Guizhi Fuling capsules and providing a reference for the content determination for Chinese medicine prescriptions containing Poria cocos.

Determination of four triterpenoid acids from Guizhi Fuling Capsules by HPLC / 中草药

Objective: To establish an HPLC method for the determination of four triterpene constituents (dehydrotumulosic acid, polyporenic acid C, 3-epi-dehydropachymic acid, and dehydropachymic acid) in Guizhi Fuling Capsules (GFC). Methods: Chromatography conditions were Diamonsic C18 column (250 mm × 4.6 mm, 5 μm), system mobile phase was composed of acetonitrile (A)-0.2% HCOOH aqueous solution (C) in a linear gradient elution mode (0-70 min: 50%-85% A; 70-80 min: 85%-100% A; 80-90 min: 100% A), detective wavelength was set at 242 nm, and column temperature was 40℃. Results: The calibration curve was linear within 0.408-2.04 μg/mL (r = 0.999 9), 0.192-0.96 μg/mL (r = 0.999 5), 0.078-0.39 μg/mL (r = 0.999 5), and 0.075 6-0.378 μg/mL (r = 0.999 5) for dehydrotumulosic acid, polyporenic acid C, 3-epi-dehydropachymic acid, and dehydropachymic acid, respectively. The average recoveries were 97.5% (RSD = 1.4%, n = 5), 98.5% (RSD = 1.6%, n = 5), 97.2% (RSD = 1.2%, n = 5), and 102.3% (RSD = 1.8%, n = 5). Six batches of GFC sample were determined, The average contents of dehydrotumulosic acid, polyporenic acid C, 3-epi-dehydropachymic acid, and dehydropachymic acid were 0.070, 0.015, 0.030, and 0.061 mg/capsule, separately. Conclusion: The method is simple, accurate, and can be used as a quality control method for GFC.