It is the objective of this paper to study pharmacokinetics-pharmacodynamics (PK-PD) characteristics of ginsenoside Rg1 and Rb1 on the effect of inducing nitric oxide (NO) release after intravenous administration of Shengmai injection to rats with myocardial ischemia. The model of myocardial ischemia rats was produced by subcutaneous injection of isoproterenol. The serum samples were collected at different time points after intravenous administration of Shengmai injection to rats with the dose of 10.8 mL x kg(-1). The concentrations of ginsenoside Rg1 and Rb1 in serum were determined, and then the concentration-time curves were drawn. Pharmacokinetic parameters of ginsenoside Rg1 and Rb1 were calculated after the construction of pharmacokinetic models. Meanwhile, NO2- and NO3-, the metabolites of NO, in serum were determined, and then the effect-time curve was drawn. The combined PK-PD model was established based on the theory of effect compartment by Sheiner et al. Then pharmacodynamic parameters were calculated. The results indicated that the pharmacokinetics of ginsenoside Rg1 and Rb1 conformed to a two-compartment model. Ginsenoside Rg1 and Rb1 exhibited quick and slow elimination in rats respectively. The effect of Shengmai injection on inducing NO release did not relate directly with and lagged behind the concentrations of ginsenoside Rg1 and Rb1 in serum. The effect exhibited good correlation with ginsenoside Rg1 and Rb1 levels in effect compartment. The relationship between effect and serum concentration fits Sigmoid-E(max) model. This study successfully established the combined PK-PD model of ginsenoside Rg1 and Rb1 after intravenous administration of Shengmai injection to rats. The model can efficiently predict the concentration and effect of Shengmai injection in vivo.
Administration, Intravenous ; Animals ; Ginsenosides ; administration & dosage ; pharmacokinetics ; Humans ; Male ; Myocardial Ischemia ; drug therapy ; metabolism ; Nitric Oxide ; metabolism ; Rats ; Rats, Sprague-Dawley

AIMTo Investigate the effect of glutamate (Glu) and gamma-aminobutyric acid(GABA) in orbitofrontal cortex (OFC) on regulation of gastric motility.

METHODSUsing microinjection in OFC,together with lesion of related nucleus,and recording the intragastric pressure(IGP).

RESULTS(1) Microinjection of Glu in OFC caused a significant reduce of the amplitude of gastric motility, this effect could be reverse by lesion of amygdala, while lesion of LC had no influence on the effect of Glu. (2) microinjection of GABA in OFC could increase the amplitude of gastric motility significantly,and lesion of LC could abolish this effect,while lesion of amygdala could enhance the effect of GABA more.

CONCLUSIONMicroinjection of Glu in OFC may enhance the normal inhibitory effect of amygdale on gastric motility, and the effect of microinjection of GABA in OFC on gastric motility is closely related with LC.

Amygdala ; physiology ; Animals ; Female ; Frontal Lobe ; metabolism ; physiology ; Gastrointestinal Motility ; drug effects ; Glutamic Acid ; pharmacology ; Locus Coeruleus ; physiology ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; gamma-Aminobutyric Acid ; pharmacology

Objective To establish qualitative and quantitative analysis methods for identification and determination of multi-constituent of Chanfukang granules (CFKG) using high performance liquid chromatography-time-of-flight mass spectrometry (HPLC-TOF-MS) and high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS/MS),and a preliminary pharmacokinetic study was carried out.Methods An Agilent ZORBAX Eclipse Plus C1s column (100 mm × 3.0 mm,1.8 μm) and a Waters XBridge(R) BEH C18 column (150 mm × 4.6 mm,2.5 μm) were used with 0.1％ formic acid aqueous solution-acetonitrile as mobile phases by gradient elution.The compounds were detected by electrospray ion source in both positive and negative mode with multiple reaction monitoring (MRM) mode.SD rats were ig with CFKG (0.5,5 g/kg).Blood samples of 0.2 mL were taken from jugular vein at different time points and plasma components and contents were determined by HPLC-MS/MS.Results Twenty-four constituents were identified by HPLC-TOF-MS qualitative analysis and thirteen constituents were quantitatively detected by HPLC-MS/MS.The established HPLC-MS/MS method had a good separation,and all the legal verification met the requirements.The content of stachydrine,Leonurine,and astragaloside Ⅳ were high,which may be the main active ingredient The pharmacokinetic results showed that,only when the dose was 5 mg/kg,stachydrine and Leonurine can detected.Elimination of stachydrine was slow and elimination of Leonurine was fast.Conclusion A rapid and efficient method for studying the chemical constituents was established,which could provide reference for the quality control of Chanfukang granules.

We revisited the "Xiao Chaihu Decoction event (XCHDE)" occurred in late 1980s in Japan and the Bupleuri Radix related adverse drug reaction (ADR) reports in China After careful review, comparison, analysis and evaluation, we think the interstitial pneumonitis, drug induced Liver injury (DILI) and other severe adverse drug envents (ADEs) including death happened in Japan is probably results from multiple factors, including combinatory use of XCHDE with interferon, Kampo usage under modern medicine theory guidance, and use of XCHD on the basis of disease diagnosis instead of traditional Chinese syndrome complex differentiation. There are less ADE case reports related to XCHD preparation in China compared to Japan, mostly manifest with hypersensitivity responses of skin and perfuse perspiration. The symptoms of Radix Bupleuri injection related ADEs mainly manifest hypersensitivity-like response, 2 cases of intravenous infusion instead of intramuscular injection developed hypokalemia and renal failure. One case died from severe hypersensitivity shock. In Chinese literatures, there is no report of the interstitial pneumonitis and DILI associated with XCHDG in Japan. So far, there is no voluntary monitoring data and large sample clinical research data available. The author elaborated the classification of "reevaluation" and clarified "re-evaluation upon events" included the reaction to the suspected safety and efficacy events. Based on the current status of the clinical research on the Radix Bupleuri preparations, the author points out that post-marketing "re-evaluation upon suspected event" is not only a necessity of continuous evaluation of the safety, efficacy of drugs, it is also a necessity for providing objective clinical research data to share with the international and domestic drug administrations in the risk-benefit evaluation. It is also the unavoidable pathway to culture and push the excellent species and famous brands of TCM to the international market, in that it enhances the pharmaceutical manufactures the ability to control enterprise risk and eliminate the negative impact on traditional Chinese medicine. With the widely used and ADR report concentrated Radix Bupleuri injection as an example, the author provide a new approach to post-marketing clinical research.
Bupleurum ; chemistry ; Drug Compounding ; Drug-Related Side Effects and Adverse Reactions ; etiology ; Drugs, Chinese Herbal ; adverse effects ; Humans ; Product Surveillance, Postmarketing ; methods ; Safety

Background: Dysfunction of vascular endothelial cells (ECs) plays a central role in the pathogenesis of cardiovascular complications in diabetes. SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5) is a key regulator of chromatin structure and DNA repair, but its role in ECs remains surprisingly unexplored. The current study was designed to elucidate the regulated expression and function of SMARCA5 in diabetic ECs. Methods: SMARCA5 expression was evaluated in ECs from diabetic mouse and human circulating CD34+ cells using quantitative reverse transcription polymerase chain reaction and Western blot. Effects of SMARCA5 manipulation on ECs function were evaluated using cell migration, in vitro tube formation and in vivo wound healing assays. Interaction among oxidative stress, SMARCA5 and transcriptional reprogramming was elucidated using luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. Results: Endothelial SMARCA5 expression was significantly decreased in diabetic rodents and humans. Hyperglycemia-suppressed SMARCA5 impaired EC migration and tube formation in vitro, and blunted vasculogenesis in vivo. Contrarily, overexpression of SMARCA5 in situ by a SMARCA5 adenovirus-incorporated hydrogel effectively promoted the rate of wound healing in a dorsal skin punch injury model of diabetic mice. Mechanistically, hyperglycemia-elicited oxidative stress suppressed SMARCA5 transactivation in a signal transducer and activator of transcription 3 (STAT3)-dependent manner. Moreover, SMARCA5 maintained transcriptional homeostasis of several pro-angiogenic factors through both direct and indirect chromatin-remodeling mechanisms. In contrast, depletion of SMARCA5 disrupted transcriptional homeostasis to render ECs unresponsive to established angiogenic factors, which ultimately resulted in endothelial dysfunction in diabetes. Conclusion Suppression of endothelial SMARCA5 contributes to, at least in part, multiple aspects of endothelial dysfunction, which may thereby exacerbate cardiovascular complications in diabetes.

Objective To construct an hybrid bioartificial liver supporting system,and observe its effectiveness and safety on patients with acute on chronic liver failure.Methods Hybrid bioartificial liver supporting system (HBALSS) was constructed using bioreactor with HepG2 cells transfected with human augmenter of liver regeneration (hALR) gene.12 acute on chronic liver failure patients were divided into 2 groups randomly.The treatment group was treated with the hybrid bioartificial liver support system.The group underwent plasma exchange was used as control.Results In the treatment group,four patients recovered,one patient died of hepatic encephalopathy,one patient died of hepatorenal syndrome,one patient recovered,but died of gastrointestnal bleeding after 1 year.In control group,two patients recovered,one patient underwent orthotropic liver transplantation,and three patients died of liver failure.Conclusion The hybrid bioartificial liver supporting system with HepG2 cell line was established successfully and have certain safety and effectiveness on acute on chronic liver failure patients.

Objective To obtain guiding recommendations for the development of fertility preservation in female patients of reproductive age,so as to promote the scientific,standardized and orderly implementation of fertility preservation work.Methods A previous questionnaire survey was used to determine the preliminary recommendations,a modified Delphi method was used to invite 18 domestic experts of fertility preservation to conduct two rounds of expert consultation.Then we adjusted and summarized recommendations according to the results of the consultation.Results Finally,14 guiding recommendations for the development of fertility preservation in female patients of reproductive age were obtained according to the results of the Delphi consultation,including 5 recommendations at technical level,5 recommendations at political level and 4 recommendations at educational level.At technical level,it was proposed to establish a standardized operation process;at political level,it was proposed to improve the relevant legislation of fertility preservation in China to protect the safety and interests of patients;at educational level,it was suggested to take various forms to promote the mass dissemination of fertility preservation knowledge.Conclusion Guiding recommendations for fertility preservation in female patients of reproductive age can provide detailed and comprehensive guidance for promoting fertility preservation in female patients of reproductive age in Shanghai,and provide reference for carrying out fertility preservation in other regions.

Chinese medicine (CM) clinical efficacy evaluation research involves the longitudinal multivariate measurement which means that patients are measured repeatedly and each patient is measured by several indicators on each fixed cross-section. Although each indicator can be evaluated separately with a longitudinal linear mixed model, it is important to consider all the endpoints together especially when researchers pay special attention to the change of the conjoint efficacy for several indicators in one patient. In this article, we introduce a latent variable linear mixed model to the CM conjoint efficacy evaluation and discuss why and how to analyze the longitudinal multivariate endpoint data in the clinical CM efficacy evaluation research. It may lead to the new insight of using such methodology in the field of conjoint efficacy evaluating of CM study. And with the definition of syndrome and symptom in the CM theory, the applied discussion brings the insight of CM syndrome evaluating in future. We illustrate this methodology using an example of CM efficacy evaluation from an ischemic stroke research.
Biomedical Research ; methods ; statistics & numerical data ; Data Interpretation, Statistical ; Endpoint Determination ; methods ; statistics & numerical data ; Humans ; Linear Models ; Medicine, Chinese Traditional ; methods ; Multivariate Analysis ; Research Design ; statistics & numerical data ; Stroke ; drug therapy ; epidemiology ; Treatment Outcome

Objective To observe the therapeutic effect of Lai's acupuncture therapy combined with Chinese herbal decoction for the treatment of infertility with ovulatory dysfunction, and to summarize the experience of Professor Lai Xin-Sheng in treating infertility. Methods Ninety-six infertility patients with ovulatory dysfunction were randomized into treatment group and control group, 48 cases in each group. The treatment group was treated with Lai's Tongyuan acupuncture therapy for regulating Governor Vessel to tranquilize mind, inducing meridian Qi to original Qi, and was also given oral use of Chinese herbal decoction of Lai's Yiyun Recipe for promoting gestation. The control group was treated with Chinese herbal decoction alone. The treatment began exactly after the completion of menstruation period and lasted 15 days for one treatment course, covering 3 courses. And then the patients of the two groups were followed-up for 3 months. Therapeutic effect and pregnancy rate were evaluated after treatment, serum levels of estradiol and progesterone were examined, and abdominal ultrasonography was used for monitoring the maximum diameter of the dominant follicles and endometrial thickness before and after treatment. Results (1) Three cases from the treatment group and 5 cases from the control group were dropped out, and the final case number in the treatment group and control group was 45, 43 respectively. (2) The total efficiency of the treatment group was 88.9％, and that of the control group was 81.4％. The effect of the treatment group was better than that of the control group (P < 0.05). (3) The pregnancy rate of the treatment group was 73.3％, higher than that of the control group (51.2％), the difference being significant (P < 0.05). (4) After treatment, the maximum diameter of the dominant follicles and endometrial thickness in the two groups were obviously improved(P < 0.05 compared with those before treatment), and the improvement in the treatment group was superior to that in the control group (P < 0.05). (5) After treatment, the serum levels of estradiol and progesterone in the two groups were obviously improved(P < 0.05 compared with those before treatment) , and the improvement in the treatment group was superior to that in the control group(P < 0.05). Conclusion The therapeutic effect of Lai's acupuncture therapy combined with Chinese herbal decoction is superior to that of Chinese herbal decoction alone, showing an obvious synergistic effect by shortening the course of treatment and enhancing pregnancy rate.

OBJECTIVETo explore the mechanism of 'erythroblast island (EI)' formation in the bone marrow of patients with immun-related hemocytopenia (IRP).

METHODSThe category of BM-auto antibody (au Ab) in 48 patients with IRP was detected with FCM. The BM-au Ab in the 'EI' of these cases were explored with immuonhistofluorescence (IF). Clinical and laboratory characteristics of these cases were also analyzed retrospectively.

RESULTSIgG could be detected in the 'EI' on the BM smear of 14 cases (29.17%), BM-au Ab mainly deposited at the edge/membranes between macrophage and erythroblasts rather than cyto plasm. Positive reaction were seen in all the cases with GlycoAIgG. The red blood cell count [(1.8 ± 0.5) × 10(12)/L] and hemoglobin level [(59.6 ± 16.2)g/L] were significantly lower than that in the IF(-) group [(2.5 ± 0.9) × 10(12)/L and (83.4 ± 25.0) g/L] (P < 0.05). The percentage of reticulocyte [(2.0 ± 0.8)%], serum level of IBIL [(9.4 ± 4.7) µmol/L], percentage of erythroblats in sternum BM (0.441 ± 0.139) and response rate to therapy (85.7%) in IF(+) group were significantly higher than that in IF(-)group [(1.3 ± 1.0)%, (6.6 ± 6.7)µmol/L, 0.298 ± 0.082, 61.3%, respectively] (P < 0.05).

CONCLUSIONMacrophage was connected with erythroblasts through autologous IgG in the 'EI's of some patients with IRP. 'EI' were the places where macrophages devoured and destroyed erythroblasts rather than erythroid development and differentiation. The pathogenetic mechanism of IRP might be associated with macrophages phagocytosing and destroying BM hematopoietic cells.

Blood Cell Count ; Bone Marrow ; Bone Marrow Cells ; immunology ; Coombs Test ; Erythroblasts ; Humans