OBJECTIVE: To establish a clinically applicable model of rapid identification of adverse drug reaction program (RiADP) for risk management and decision-making of clinical drug use. METHODS: Based on the theory of disproportion analysis, frequency method and Bayes method, a clinically applicable RiADP model in R language background was established, and the parameters of the model were interpreted by MedDRA coding. Based on the actual monitoring data of FDA, the model was validated by the assessing hepatotoxicity of lopinavir/ritonavir (LPV/r). RESULTS: The established RiADP model included four parameters: standard value of adverse drug reaction signal information, empirical Bayesian geometric mean value, ratio of reporting ratio and number of adverse drug reaction cases. Through the application of R language parameter package "phViD", the model parameters could be output quickly. After being encoded by MedDRA, it was converted into clinical terms to form a clinical interpretation report of adverse drug reactions. In addition, the evaluation results of LPV/r hepatotoxicity by the model were matched with the results reported in latest literature, which also proved the reliability of the model results. CONCLUSIONS In this study, a rapid identification method of adverse reactions based on post marketing drug monitoring data was established in R language environment, which is capable of sending rapid warning of adverse reactions of target drugs in public health emergencies, and providing intuitive evidence for risk management and decision-making of clinical drugs.
Databases, Pharmaceutical ; Decision Making, Computer-Assisted ; Drug Monitoring ; Drug-Related Side Effects and Adverse Reactions ; HIV Protease Inhibitors ; adverse effects ; pharmacology ; Humans ; Liver ; drug effects ; Lopinavir ; adverse effects ; toxicity ; Models, Statistical ; Reproducibility of Results ; Software ; standards

Objective: To evaluate the relationship between p38 mitogen-activated protein kinase (p38MAPK) and G protein-coupled receptor kinase 2 (GRK2) in the development of persistent postoperative pain in rats. Methods: Pathogen-free healthy male Sprague-Dawley rats, weighing 200-250 g, aged 2 months, were used in this study.Sixty rats in which intrathecal catheters were successfully implanted were divided into 6 groups (n=10 each) using a random number table method: sham operation group (group S), sham operation plus dimethyl sulfoxide (DMSO) group (group D), sham operation plus GRK2 degradation inhibitor MDL28170 group (group M), persistent postoperative pain group (group PPP), persistent postoperative pain plus DMSO group (group PPP+ D) and persistent postoperative pain plus MDL28170 group (group PPP+ M). Persistent postoperative pain was evoked by skin/muscle incision and retraction (SMIR). Immediately after operation and at 1, 2 and 3 days after operation, normal saline 20 μl was intrathecally injected once a day in S and PPP groups, 5% DMSO 10 μl was intrathecally injected once a day in D and PPP+ D groups, and MDL28170 10 μl (50 μg) was intrathecally injected once a day in M and PPP+ M groups.The mechanical paw withdrawal threshold (MWT) was measured at 1 day before operation and 3, 7, 14 and 21 days after operation (T_1-4). Four rats in each group were selected after behavioral testing at T₃ and sacrificed, and the L_4-6 segments of the spinal cord were removed for determination of the expression of phosphorylated p38MAPK (p-p38MAPK) by Western blot. Results: There was no significant difference in MWT at each time point or expression of p-p38MAPK among group S, group D and group M (P>0.05). Compared with group S, the MWT was significantly decreased, and the expression of p-p38MAPK was up-regulated in PPP, PPP+ D and PPP+ M groups (P<0.05). Compared with group PPP, the MWT was significantly increased, and the expression of p-p38MAPK was down-regulated in group PPP+ M (P<0.05), and no significant change was found in the MWT or expression of p-p38MAPK in group PPP+ D (P>0.05). Conclusion Down-regulated expression of spinal GRK2 can promote the activation of p38MAPK in the spinal cord and is involved in the development of persistent postoperative pain in rats.

Objective To evaluate the role of spinal histone acetylation in persistent postoperative pain in rats. Methods Pathogen?free healthy male Sprague?Dawley rats, weighing 200-250 g, aged 2 months, in which intrathecal catheters were implanted at the lumbar level according to an improved method, were used in the study. Eighty?four rats, in which intrathecal catheters were successfully implanted, were divided intoⅠ-Ⅵgroups(n=14 each)using a random number table. Artificial cerebrospinal fluid 20 μl was intrathecally administered at 1, 2, 3 and 4 days before operation and 1 day after operation inⅠandⅣgroups. At 1, 2, 3 and 4 days before operation and 1 day after operation, dimethyl sulfoxide 10 μl and SAHA(50 μg∕10μl)were intrathecally injected inⅡandⅤgroups and inⅢandⅥgroups, respective?ly, followed by artificial cerebrospinal fluid(10 μl)flush after each injection. Rats underwent sham oper?ation inⅠ?Ⅲ groups. Persistent postoperative pain was evoked by skin∕muscle incision and traction in Ⅳ?Ⅵ groups. The mechanical paw withdrawal threshold(MWT)was measured at 1 day before operation(T0)and 1, 3, 7, 14 and 21 days after operation(T1?5). Four rats were sacrificed in each group after measurement of MWT at T4, and the lumbar segments(L4?6)of the spinal cord were removed for determi?nation of the expression of acetylated histone H3(Ac?H3)and Ac?H4 by Western blot. Results There was no significant difference in each index amongⅠ?Ⅲ groups(P>0.05). Compared with group Ⅰ, the MWT was significantly decreased at T2?5, and the expression of Ac?H3 and Ac?H4 was down?regulated at T4 in group Ⅳ(P<0.05). Compared with group Ⅳ, the MWT was significantly increased at T2?5, and the expression of Ac?H3 and Ac?H4 was up?regulated at T4in group Ⅵ(P<0.05). Conclusion Histone acetylation is involved in the development and maintenance of persistent postoperative pain in rats.

Objective To investigate the change of spinal G protein-coupled receptor kinase 2 (GRK2) expression in persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR) in rats.Methods 40 male Sprague Dawley (SD) rats were divided into 2 groups (n =20) using a random number table:sham operation group and skin/muscle incision and retraction group (SMIR group).A rat model of peristent postoperativepain evoked by SMIR was made according to the method described by Flatters.Pain behavior was assessed by paw mechanical withdrawal threshold (MWT) to yon Frey filament stimulationintensity at 1 d before operation (T0) and 3 d (T1),7 d (T2),14 d (T3) and 21 d (T4) after operation.4 rats in each group were sacrificed at T0-4,the L4-L6 segments of the spinal cord were obtained for determination of GRK2 expression in the spinal cord by Western blot.Results Compared with T0,the MWT was significantly decreased and the expression of spinal GRK2 was down-regulated at T1-T4 in SMIR group (P ＜ 0.05).Compared with sham operation group,the MWT and the expression of spinal GRK2 was decreased at T1-T4 in SMIR group (P ＜ 0.05).Conclusions The down-regulation of expression of spinal GRK2 may be involved in the development and maintenance of persistent postoperative pain in rats evoked by SMIR.

Objective To establish an in vitro accelerated release method of triptorelin acetate microspheres with good in vi-tro/in vivo correlation(IVIVC). Methods The in vivo release of triptorelin acetate from microspheres was obtained by residual method in rats. Influences of pH value,concentration of ethanol,temperature,rotation speed and concentration of antiseptic on the in vitro accel-erated release were studied,then the correlation between in vitro accelerated release and in vivo release of the microspheres was estab-lished by adjusting the release conditions. Results The in vitro accelerated release medium of triptorelin acetate microspheres composed of 15%ethanol solution(containing 0.06%Tween 80 and 0.1%benzalkonium chloride)at 55℃with rotating rate of 200 r/min. The cumulative release of triptorelin acetate from microspheres was 87.35%at 30 h under accelerated release condition,equivalent to in vivo release for 30 days. The established in vitro accelerated release had a good correlation with that of in vivo(y=0.8845x+12.4510, R2=0.9938). Conclusion The in vitro accelerated release of triptorelin acetate microspheres could correlate well with in vivo release and has a potential application in rapid and effective evaluation of triptorelin acetate microspheres.

Objective The aim of this study was to evaluate the clinical and phychology profile after total cavopulmonary connection procedure and to identify the significant determinants of quality of life.Methods Data from 21 patients underwent total cavopulmonary connection procedure from January 2008 to December 2015 were retrospectively analyzed.Patients under went echocardiography aud cardiopulmonary exercise testing.Used ST-36 questionnaire to perceived health status.The NT-ProBNP levels was test.Results 21 patients aged between 19 to 36 years(mean 26.6 years) were enrolled.The mean follow-up time was(44.2 ± 29.9) months.The mean EF was (59.4 ± 6.2) ％,and the peak oxygen uptake was (19.9 ± 3.6) ml · kg-1 · min-1,perceut predict value was(52.5 ± 8.9) ％.SF-36 score was well.Independent risk for impaired exercise capacity was interval time from surgery.Conclusion The exercise capacity of total cavopulmonary connection patients was impaired.Identify more predict factors of the quality of these patients need further study.

Objective To investigate the changes in acetylation of histone in the spinal dorsal horn in a rat model of persistent postoperative pain.Methods Ninety-six malc Sprague-Dawley rats,weighing 200-250 g,aged 6-8 weeks,were randomly divided into 2 groups (n=48 each) using a random number table:sham operation group (group S) and persistent postoperative pain group (group PPP).The rat model of persistent postoperative pain evoked by skin/muscle incision and retraction was established according to the method described by Flatters.After the rats were anesthetized with intraperitoneal chloral hydrate,the skin and superficial muscle of the medial thigh were incised and retractors inserted.This tissue was retracted for 1 h.The mechanical paw withdrawal threshold (MWT) was measured at 1 day before operation and 1,3,7,14,and 21 days after operation.Four animals were sacrificed in each group after measurement of MWT at each time point for detection of acetylated histone H3 (Ac-H3) and acetylated histone H4 (Ac-H4) expression (by Western blot analysis) and the number of Ac-H3 and Ac-H4 positive cells in the spinal cord horn (by immunofluorescence histochemistry).Results Compared with group S,the MWT was significantly decreased at 3,7,14 and 21 days after operation,the expression of Ac-H3 and Ac-H4b was significantly down-regulated at 3,7 and 14 days after operation,and the number of Ac-H3 and Ac-H4 positive cells was significantly decreased at 7,14 and 21 days after operation in group PPP (P＜0.05 or 0.01).The MWT,expression of Ac-H3 and Ac-H4b,and the number of Ac-H3 and Ac-H4 positive cells were significantly higher at 21 days after operation than at 14 days after operation in group PPP (P＜0.05).Conclusion Acetylation of histone in the spinal dorsal horn is decreased after operation,which may be involved in the development and maintenance of persistent postoperative pain in rats.

Objective To assess the cardiopulmonary exercise testing (CPET) derived performance of oxygen uptake and ventilation efficiency parameters,including oxygen uptake efficiency plateau (OUEP),oxygen uptake efficiency slope (OUES),(V)E/(V)CO2 slope and lowest (V)E/(V)CO2,in patients with end-stage chronic heart failure(CHF) and evaluate their clinical value on monitoring cardiac function and hemodynamic status.Methods A total of 26 end-stage CHF patients considered for heart transplantation were enrolled in this study.CPET,echocardiography and invasive hemodynamic examinations with Swan-Ganz flowing balloon catheter were performed.Correlation analysis was made between oxygen uptake and ventilation efficiency parameters from CPET and echocardiographic and hemodynamic parameters.Results OUEP and OUES showed good correlation with peak oxygen consumption (peak (V)O2) (r =0.535,P ＜ 0.01 ; r =0.840,P ＜ 0.001).In end-stage CHF patients,the slope of OUEP with respect to peak (V)O2 is about 32,but the slope of OUES with respect to peak (V)O2 is only about 2.The difference was 16 times.The change of OUEP was more sensitive and significant than those of OUES and peak (V)O2 (P ＜ 0.05).OUEP,peak (V)O2 (％ pred),(V)E/(V)CO2 slope and lowest (V)E/(V)CO2 were all correlated well with non-invasive hemodynamic parameters peak cardiac output (r=0.535,P＜0.01; r=0.652,P＜0.001; r=-0.640,P＜0.001 ; r=-0.606,P=0.001 respectively) and peak cardiac index (r =0.556,P＜0.01;r =0.772,P ＜0.001; r =-0.641,P ＜ 0.001 ; r =-0.620,P ＜ 0.001 respectively) derived from CPET,but not correlated with invasive hemodynamic parameters cardiac output and cardiac index at rest (P ＞0.05).Both peak (V)O2 (％ pred) and (V)E/(V)CO2 slope were significantly correlated with invasive hemodynamic parameters systolic pulmonary arterial pressure (r =-0.424,P ＜ 0.05 ; r =0.509,P ＜ 0.01) and mean pulmonary arterial pressure (r=-0.479,P＜0.05; r=0.405,P＜0.05).Peak (V)O2(％pred)was also significantly correlated with pulmonary capillary wedge pressure (r =-0.415,P ＜ 0.05),and (V)E/(V)CO2 slope was significantly correlated with pulmonary vascular resistance (r =0.429,P ＜ 0.05).Conclusions The oxygen uptake and ventilation efficiency parameters derived from CPET,including peak (V)O2,OUEP,lowest (V)E/(V)CO2 and (V)E/(V)CO2 slope etc,are objectively monitoring and evaluating cardiac function and hemodynamic status.And they are useful for optimizing clinical management of patients with end-stage CHF.

Objective To assess peak oxygen consumption (peak (V)O2) derived from cardiopulmonary exercise testing (CPET),concentrations of NT-proBNP and echocardiographic changes in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF,＜ 40％).Methods Seventy patients were included and divided into two groups according to the New York Heart Association (NYHA) classification:NYHA Ⅱ group (17 cases) and NYHA Ⅲ-Ⅳ group (53 cases).The basic clinical information,plasma concentration of NT-proBNP at rest,echocardiographic parameters and peak (V)O2 from CPET were compared between two groups.Correlation among peak (V)O2,NT-proBNP and echocardiographic parameters in this patient cohort was assessed and their abilities to discriminate the NYHA Ⅲ-Ⅳ grade were analyzed through c-Statistic.Results Left atrial diameter ((51.3 ±7.2) mm vs.(44.0 ±7.4) mm,P ＜0.001) was larger,plasma concentration of NT-proBNP (1 379-4 399 pmol/L vs.1 109-2 356 pmol/L,P ＜ 0.01) was higher and peak (V)O2 ((13.4 ± 3.5) ml · kg-1 · min 1 vs.(18.2 ± 3.7) ml · kg-1 · min-1,P ＜ 0.001) were significantly lower in NYHA Ⅲ-Ⅳ group than those in NYHA Ⅱ group.However,left ventricular end-diastolic diameter (LVEDD) and LVEF were similar between two groups.Peak (V)O2 correlated significantly with NT-proBNP (r =-0.311,P ＜ 0.01),but neither peak (V)O2 nor NT-proBNP correlated with echocardiographic parameters (LA,LVEDD and LVEF).ROC analysis showed that peak (V)O2 had the strongest discriminatory power for detecting NYHA Ⅲ-Ⅳ grade patients (AUC =0.835,P ＜0.001),followed by the NT-proBNP (AUC =0.723,P ＜0.01).Conclusion Peak (V)O2 is a more sensitive parameter to detect the disease aggravation (NYHA Ⅲ-Ⅳ grade) of the CHF patients with reduced LVEF compared to plasma NT-proBNP and echocardiographic parameters (LA,LVEDD,LVEF).

Objective To study the feasibility and necessity of radial artery angiolgraphy in advance on transradial coronary intervention.Methods A total of 682 patients undergoing transradial coronary intervention were divided into two groups by random digits table method.Previous radial artery angiography (pre-RAA) group of 341 cases underwent radial artery angiography;post radial artery angiography (post-RAA) group of 341 cases in the guide wire,catheter in resistance immediately for radial artery angiography.The radial artery imaging characteristics were observed and the radial artery related complications were recorded in two groups.Results The ratio of radial artery spasm in post-RAA group was higher than that in pre-RAA group [11.4％(39/341) vs.6.2％(21/341),P=0.015].The ratio of operation failed in post-RAA group was higher than that in pre-RAA group [3.2％ (11/341) vs.0.6％ (2/341),P =0.014].The radial artery perforation rate and postoperative 1-6 months of radial artery occlusion rate increased significantly in post-RAA group,and there was significant difference between two groups (P ＜ 0.05).Conclusion Transradial coronary intervention in advance for radial artery angiography therapy can effectively observe the radial artery morphology,reduce the radial artery related complications.