Tyrosine kinase inhibitory activity of dehydroabietylamine derivatives tested by homogeneous time-resolved fluorescence based high throughput screening model / 中国天然药物

Protein tyrosine kinases (PTKs) are attractive targets in searching for therapeutic agents against many diseases. In this study, a series of dehydroabietylamine derivatives were first determined to show PTK inhibitory activity using a high-throughput screening (HTS) method based on homogeneous time-resolved fluorescence (HTRF) technology. The structure-activity relationships of the dehydroabietylamine derivatives were established, and it was found that the compounds with a nitrogen-containing side chain had better inhibitory activity. Further studies showed that the compounds substituted with halogen in the phenyl ring resulted in higher inhibitory activity on the epidermal growth factor receptor (EGFR), and can be a guide to modify the structure of dehydroabietylamine derivatives. Dehydroabietylamine derivatives might be a new class of multi-targeted and effective PTK inhibitors with structure modifications.

Acute responses to inhalation of Iloprost in patients with pulmonary hypertension / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Iloprost has been used to test acute pulmonary vasoreactivity in idiopathic pulmonary arterial hypertension (PAH). We aimed to investigate the acute hemodynamic and oxygenation responses and tolerability to 20 µg aerosolized Iloprost in Chinese patients with pulmonary hypertension.</p><p><b>METHODS</b>Between March 2005 and May 2010, 212 pulmonary hypertension patients inhaled a single dose of 20 µg Iloprost over 10 - 15 minutes for vasoreactivity testing. The acute hemodynamic and oxygenation responses and adverse events were recorded.</p><p><b>RESULTS</b>Iloprost decreased total pulmonary resistance ((1747 ± 918) dyn×s×cm(-5) vs. (1581 ± 937) dyn×s×cm(-5), P < 0.001), increased stroke volume ((45.0 ± 22.1) ml vs. (47.0 ± 24.2) ml, P = 0.002), and cardiac output ((3.7 ± 1.7) L/ml vs. (3.9 ± 1.9) L/min, P = 0.009). Heart rate and systemic vascular resistance remained stable during inhalation. However, systemic arterial blood oxygen saturation fell slightly ((91.0 ± 6.8)% vs. (90.3 ± 6.7)%, P = 0.002). Pulmonary and systemic arterial blood pressures declined within 1 - 3 minutes after inhalation initiation and reached their lowest levels within 10 - 15 minutes. Idiopathic PAH responded more favorably than pulmonary hypertension due to other causes (P £0.001) and patients with less severe pulmonary hypertension have better responses to Iloprost. No adverse events requiring medical care or leading to termination of inhalation occurred.</p><p><b>CONCLUSIONS</b>Inhalation of 20 µg Iloprost showed potent and selective pulmonary hemodynamic effects and was well tolerated in the Chinese pulmonary hypertension patients. Patients with idiopathic PAH and less severe pulmonary hypertension responded more favorably to inhalation of Iloprost.</p>

Clinical analysis of 150 patients with idiopathic pulmonary arterial hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>To explore the demographic characteristics and clinical features of patients with idiopathic pulmonary arterial hypertension (IPAH) in China.</p><p><b>METHODS</b>Between March 2007 and September 2010, IPAH diagnosis was confirmed by right heart catheterization in 150 adult patients from 31 clinical centers in China. Clinical and hemodynamic data were analyzed and patients were divided into WHO functional class I/II and WHO functional class III/IV group.</p><p><b>RESULTS</b>The mean age of 150 patients were 36 ± 13 years with female patient/male patient ratio of 2:1, and mean BMI was (21.3 ± 3.5) kg/m(2). Fatigue (n = 123, 82.0%) and dyspnea (n = 112, 74.7%) are the most common symptoms. Accentuated pulmonic second sound (P(2)) was detected in 92.0% (n = 138) of patients during physical examination, which was also the most common sign. About 49.0% (n = 73) patients were WHO functional class I/II patients and 46.0% (n = 68) patients were WHO functional class III/IV patients. Six minutes walking distance (6MWD) and Borg dyspnea score was (337 ± 101) m and 2.0 (2.0, 4.0), respectively. Right ventricular hypertrophy was suggested by ECG in 93.1% (n = 140) patients. Right atrial pressure was (10 ± 6) mm Hg, mean pulmonary artery pressure was (61 ± 16) mm Hg, cardiac index was (2.3 ± 0.8) L×min(-1)×m(-2) and pulmonary vascular resistance (1484 ± 699) dyn×s(-1)×cm(-5) in this cohort. 6 MWD (305 m ± 89 m vs. 377 m ± 88 m) was significantly shorter while Borg dyspnea score [3.0 (3.0, 5.0) vs. 2.0 (2.0, 3.0)] was significantly higher in WHO functional class III/IV patients than in WHO functional class I/II patients. Similarly hemodynamic parameters were also worse in WHO functional class III/IV patients than in WHO functional class I/II patients (all P < 0.05).</p><p><b>CONCLUSION</b>Idiopathic pulmonary arterial hypertension patients in this cohort affect mostly young adults, dominated by female gender and lower body mass index. Fatigue and dyspnea are the most common symptoms and accentuated pulmonic second sound (P(2)) is the most common sign. IPAH patients are often displaying severe functional and hemodynamic disturbance at first visit to hospitals. Dyspnea and hemodynamic impairment are related to 6MWD and WHO functional class.</p>

Hemodynamic effects and safety of pulmonary angiography in Chinese patients with pulmonary hypertension / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pulmonary angiography is widely performed in pulmonary hypertension patients, but its immediate effects on right heart hemodynamics and safety are not well known. The objective of this study was to investigate the right heart hemodynamic effects and safety of pulmonary angiography in Chinese patients with pulmonary hypertension.</p><p><b>METHODS</b>Between January 2008 and June 2009, pulmonary hypertension patients undergoing pulmonary angiography were consecutively enrolled. Pulmonary angiography was performed during breath-holding after deep breathing. The baseline clinical data, hemodynamic measurements before and after pulmonary angiography and complications occurring within 48 hours after angiography were recorded.</p><p><b>RESULTS</b>Ninety-five patients were included. All received non-ionic contrast medium with a volume of (75.7 ± 29.8) ml. Angiography reduced heart rate in patients with baseline mean pulmonary arterial pressure ≥ 60 mmHg (change of heart rate: (-3.1 ± 7.0) beats/min, P = 0.005), increased mean right atrial pressure, diastolic and end-diastolic right ventricular pressure in patients with baseline mean pulmonary arterial pressure < 60 mmHg (all P < 0.05). Patients with decreased mean pulmonary arterial pressure (change of mean pulmonary arterial pressure ≤ -10 mmHg) had the highest total pulmonary resistance (P = 0.009 vs. no change in mean pulmonary arterial pressure (change of mean pulmonary arterial pressure, -10 mmHg to 10 mmHg); P = 0.03 vs. increased mean pulmonary arterial pressure (change of mean pulmonary arterial pressure ≥ 10 mmHg)) and the lowest cardiac output (P = 0.018 vs. no change in mean pulmonary arterial pressure; P = 0.013 vs. increased mean pulmonary arterial pressure). There were 7 complications (7%), with 6 related to catheter and only 1 directly related to angiography. All complications were mild and no death occurred.</p><p><b>CONCLUSION</b>Pulmonary angiography has minimal effect on right heart hemodynamics and is safe in pulmonary hypertension patients.</p>

18F-FDG SPECT myocardial imaging of right ventricle in patients with idiopathic pulmonary hypertension / 中华核医学杂志

ObjectiveTo investigate the value of 18F-FDG SPECT myocardial imaging in evaluating haemodynamic change,treatment outcome and prognosis for idiopathic pulmonary arterial hypertension (IPAH).MethodsAll 24 patients with IPAH underwent 18 F-FDG SPECT myocardial imaging.Right ventricle/left ventricle (RV/LV)-FDG uptake was calculated by ROI method drawing over the central areas of left and right ventricular free walls.All patients underwent right heart catheterization within 3 days after imaging studies.Mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) were recorded.After six month pharmaceutical treatment,15 IPAH patients were re-examined with 18F-FDG SPECT myocardial imaging followed by repeated right heart catheterization within 3 days.Plasma N-terminal pro-brain naturetic peptide (NT-proBNP) and endothelin-1 ( ET-1 ) were measured in 17 patients using electrochemiluminescent immunoassay and enzyme immunoassay respectively.All patients were followed up for 12 months at least.Correlations between RV/LV-FDG uptake and mPAP and PVR were determined by simple linear regression analysis.Change of RV/LV-FDG before and after treatment was calculated using Student's t-test.Survival in groups with RV/LV FDG uptake ≥ 1.15 and RV/LV-FDG uptake ＜ 1.15 were compared using Log-rank test.ResultsSignificant correlations were found between RV/LV-FDG uptake and mPAP (r =0.562,P ＜ 0.01 ),and between RV/LV-FDG uptake and PVR ( r =0.574,P ＜ 0.01 ).There were no significant correlation between RV/LV-FDG uptake and NT-proBNP( r =0.18 1,P ＞ 0.05 ),but a significant correlation between RV/LV-FDG and ET-1 was observed (r =0.669,P ＜ 0.01 ).The RV/LV-FDG uptake in patients with positive treatment outcome ( n =6) decreased from 1.38 ± 0.52 to 0.92 ±0.26 (t =4.018,P ＜ 0.05) after 6 months treatment.In contrast,no significant change of RV/LV-FDG uptake was seen in those patients (n =9) with negative treatment outcome ( t =1.861,P ＞ 0.05 ).The mean follow-up time was (21 ±8) months.Mean survival time for the patients with RV/LV- FDG uptake ≥ 1.15was 28 months (95％ confidence interval:24-32 months),which was significantly lower than 34 months survival (95％ confidence interval:33-35 months) for the patients with RV/LV-FDG ＜ 1.15 (x2 =3.956,P ＜0.05 ).Conclusions Detection of right ventricle myocardial glucose metabolism level with 18F-FDG SPECT may be a practical method for evaluating haemodynamic change,treatment outcome and prognosis of IPAH.

Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in idiopathic pulmonary arterial hypertension / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>An echocardiographic right/left ventricular end-diastolic diameter ratio (RV/LV ratio) ≥ 0.9 is an independent predictor of poor prognosis in patients with acute pulmonary embolism. Right ventricular dilation is a common characteristic of both acute pulmonary embolism and idiopathic pulmonary arterial hypertension (IPAH). However, the prognostic value of the RV/LV ratio in patients with IPAH is unknown.</p><p><b>METHODS</b>Ninety-five consecutive patients with newly diagnosed IPAH were included, 17 were re-evaluated by echocardiography after 3 - 12 months of targeted therapy. Follow-up data were obtained by telephone interviews and review of the patients' records.</p><p><b>RESULTS</b>Higher RV/LV ratios were associated with greater functional impairment. The RV/LV ratio was positively correlated with pulmonary vascular resistance (r = 0.549, P < 0.001) and plasma N-terminal pro-brain natriuretic peptide level (r = 0.575, P < 0.001), but negatively correlated with cardiac output (r = -0.517, P < 0.001) and mixed venous oxygen saturation (r = -0.599, P < 0.001). Twenty-seven patients died during follow-up period. Sensitivity and specificity of an RV/LV ratio ≥ 0.84 for predicting death were 85.2% and 51.5%, respectively. The RV/LV ratio and body mass index were independent predictors of death by multivariate Cox analysis (P < 0.01). A baseline RV/LV ratio ≥ 0.84 or a further increase in the RV/LV ratio during targeted therapy indicated a poor prognosis (P < 0.01).</p><p><b>CONCLUSION</b>The RV/LV ratio helps to assess the severity of IPAH and may serve as an independent predictor of prognosis in patients with IPAH.</p>

C-reactive protein decreases interleukin-8 production in human endothelial progenitor cells by inhibition of p38 MAPK pathway / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>C-reactive protein (CRP) has been reported to damage the vascular wall by inducing endothelial dysfunction and inflammation, and it is also speculated to have a role in attenuating angiogenic functions of human endothelial progenitor cells (EPCs). Interleukin-8 (IL-8) is an important mediator of the paracrine mitogenic effect of EPCs, which has direct angiogenic effects on mature endothelial cells. We, herein, investigated the direct effect of CRP on IL-8 production and gene expression in cultured human EPCs.</p><p><b>METHODS</b>EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in EndoCult liquid medium in the absence and presence of CRP at clinically relevant concentrations (5 to 25 microg/ml) for different durations (3 to 48 hours). IL-8 protein and mRNA of cultured EPCs were evaluated using ELISA and real-time PCR.</p><p><b>RESULTS</b>The results showed that CRP at a concentration of 10 microg/ml significantly reduced IL-8 secretion of cultured EPCs with a peak at 25 microg/ml, and also decreased mRNA expression in EPCs with a peak at 12 hours. In addition, preincubation of EPCs with SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK) decreased CRP inhibition of IL-8 mRNA expression at 12 hours in EPCs.</p><p><b>CONCLUSIONS</b>Our study, for the first time, demonstrates that CRP directly inhibits EPCs IL-8 secretion, a key cytokine player of angiogenesis induced by EPCs. Inhibition occurred in part via an effect of CRP to active the p38 MAPK signal transduction pathway in EPC. The ability of CRP to inhibit EPCs IL-8 secretion may represent an important mechanism that further links inflammation to cardiovascular disease.</p>

The prognosis study of 108 idiopathic pulmonary arterial hypertension patients / 中华心血管病杂志

<p><b>OBJECTIVE</b>To analyze the characteristics of idiopathic pulmonary arterial hypertension (IPAH) and predict the prognosis of IPAH by Echocardiogram and Right Heart Catheterization.</p><p><b>METHODS</b>108 IPAH patients who was diagnosed as IPAH in Fuwai hospital from Jan 2003 to Jun 2007 were retrospectively analyzed and followed up to June 2008, the statistical analysis software was SPSS 13.0.</p><p><b>RESULT</b>The mean age of the 108 IPAH patients was (32.5 +/- 12.6) years, the ratio of female and male was 2.86:1, the average time from appearing symptom to diagnosis was (34.9 +/- 36.3) months, the incidence of syncope, hepatomegaly, hemoptysis and Edema of lower extremity was 32.4%, 27.8%, 15.7% and 14.8% respectively. A total of 94 patients (87.0%) were followed up for (27.6 +/- 14.7) months, forty-two patients (38.9%) died of right heart failure, the mean death time was (11.6 +/- 9.4) months after diagnosis, the survival rate of 1, 2 and 3 years was 74%, 58% and 44% respectively. These following variables could predict survival in univariate analysis: Systolic Blood Pressure (SBP) (P < 0.01, RR = 0.937), pulse Pressure (PP) (P < 0.01, RR = 0.930), left ventricular End-Diastolic Dimension (LVEDD) (P = 0.004, RR = 0.924), right ventricular End-Diastolic Dimension (RVEDD) (P = 0.029, RR = 1.045), RVEDD/LVEDD (P = 0.003, RR = 3.222), Pulmonary Arterial Systolic Pressure (PASP) measured by echocardiogram (P = 0.002, RR = 1.022), PASP (P = 0.030, RR = 1.026), mean Pulmonary Arterial Pressure (mPAP) (P = 0.031, RR = 1.037) and Pulmonary Vascular Resistance (PVR) measured by right heart catheter (P = 0.019, RR = 1.001). in multivariate analysis, PP (P < 0.01, RR = 0.923), RVEDD/LVEDD (P = 0.006, RR = 3.126) and PASP measured by Echocardiogram (P = 0.002, RR = 1.022), PASP, mPAP, PVR measured by right heart catheter (P = 0.017, RR = 1.001) were predictive.</p><p><b>CONCLUSION</b>IPAH was prone to attack young women with a poor prognosis, the diagnosis of IPAH at an early stage was difficult because of nonspecific symptom, syncope, hepatomegaly and Edema of lower extremity can predict the severity of IPAH, PVR measured by right heart catheterization, PP and PASP were independently predictive factors for IPAH.</p>

Value of radionuclide lung scintigraphy in the diagnosis and quantitative analysis of chronic thromboembolic pulmonary hypertension / 中华心血管病杂志

<p><b>OBJECTIVE</b>This study was to assess the reliability of perfusion/ventilation (Q/V) lung scintigraphy in the diagnosis and quantitative analysis of chronic thromboembolic pulmonary hypertension (CTEPH).</p><p><b>METHODS</b>A total of 78 in-patients with pulmonary hypertension who had no history of congenital heart disease, valvular disease and acute pulmonary embolism were included in this study. All patients underwent Q/V scintigraphy for detecting CTEPH. The sensitivity, specificity and accuracy of Q/V scintigraphy were defined by comparing with the results of pulmonary angiography. Percentage of Perfusion Defect score (PPDs%) was calculated in patients with CTEPH confirmed by pulmonary angiography. The correlations between PPDs% and mPAP, PPDs% and SPAP were analyzed.</p><p><b>RESULTS</b>The sensitivity, specificity and accuracy of a high-probability Q/V scintigraphy interpretation were 96.0%, 81.1% and 86.9%, respectively, compared with 100%, 69.8% and 79.5% for the combination of high- and intermediate- probability Q/V scintigraphy interpretation. PPDs% was significantly correlated with mPAP and SPAP (r = 0.538 for mPAP, P < 0.01 and r = 0.456 for SPAP, P < 0.05).</p><p><b>CONCLUSION</b>Perfusion/ventilation lung scintigraphy is a valuable technique for diagnosis and quantitative analysis of CTEPH.</p>

Clinical research about brain oxygen metabolism and neuroelectrophysiology during mild hypothermia in patients with severe head injury / 中华外科杂志

<p><b>OBJECTIVE</b>To observe the changes of brain oxygen metabolism and neuroelectrophysiology after severe brain injury, and the effects of hypothermia on severe brain injury.</p><p><b>METHODS</b>148 patients with severe brain injury (GCS 3 - 8, admitted within 10 hours from injury) were selected for this study. Patients were divided into 3 groups, Group GCS 7 - 8, Group GCS 5 - 6 and Group GCS 3 - 4. Every group were also randomly assigned to normothermia and hypothermia subgroup. Patients in the hypothermia group were cooled to 32 approximately 34 degrees C. SLSEP, BAEP, P(br)O(2) and rSaO(2) were recorded in each group at the same time.</p><p><b>RESULTS</b>In the Group GCS 7 - 8, N20 in SLSEP, I/V in BAEP and rSaO(2) were improved significantly after mild hypothermia treatment, and P(br)O(2) was decreased by hypothermia; In the Group GCS 5 - 6, N20 in SLSEP, I/V in BAEP and rSaO(2) were improved by hypothermia, and P(br)O(2) was decreased in hypothermia subgroup; In the Group GCS 3 - 4, no significant difference was found.</p><p><b>CONCLUSION</b>Mild hypothermia has a significant effect on patients of GCS 7 - 8 and a doubt effect on patients of GCS 5 - 6. It seem no effect on patients of GCS 3 - 4. Brain oxygen metabolism and neuroelectrophysiology are important to value the therapeutic effect on severe brain injury.</p>

Analysis on inpatient pulmonary hypertension surveillance in Fuwai Cardiovascular Hospital from 1996 to 2005 / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the inpatient pulmonary hypertension (PH) surveillance in a single center of cardiovascular hospital during last ten years.</p><p><b>METHODS</b>In this retrospective analysis, data from patients with discharge diagnosis as PH from Jan. 1996 to Dec. 2005 were collected.</p><p><b>RESULTS</b>A total of 7085 out of 106 640 patients (6.63%) were documented as PH during the survey period and 3.77% PH was idiopathic, 65.93% PH originated from congenital heart diseases, 22.61% from left heart diseases, 5.66% from thrombotic diseases, 0.89% from respiratory diseases, 0.61% from connective tissue diseases, 0.51% from pulmonary vasculitis and 0.03% from portal hypertensive diseases. Both total inpatient number and patients with PH increased year by year during the last 10 years in our hospital. The number of in-hospital patients with PH was significantly higher in 2004 - 2005 than that in 1996 - 2003 (P < 0.0001) and more PH was originated from cardiomyopathy and valvular heart diseases. Idiopathic pulmonary hypertension also tended to increase and PH due to congenital heart diseases was significantly reduced during 2004 - 2005.</p><p><b>CONCLUSION</b>The data from a single center of cardiovascular hospital shows a tendency for increased in-hospital prevalence of pulmonary hypertension during the last ten years.</p>

Changes of the proportion and mortality of pulmonary thromboembolism in hospitalized patients from 1974 to 2005 / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Pulmonary thromboembolism (PTE) has become a common disease that severely endangers people's health. This study analysed the changes in proportion and mortality of PTE in hospitalized patients to provide data for prevention and management of the disease.</p><p><b>METHODS</b>The data of 763 hospitalized patients with PTE from 1974 to 2005 in Fuwai Hospital were analysed.</p><p><b>RESULTS</b>During the 1970s, 0.27% of patients in a cardiovascular hospital had PTE (< 5 cases per year); while so far this century the proportion is 0.94% (48 to 113 per year). The mortality of hospitalized PTE patients fell from 20.00% in the 1970s to 4.10% this century. Prior to 1990, the mortality of hospitalized PTE patients was 12.50%, and in the years after 1990 only 3.40%. The difference was statistically significant (P < 0.005). People with this disease were mostly between the ages of 30 and 69 years. Men were most susceptible between the ages of 30 and 69 years, while women between the ages of 40 and 69 years. Men contracted PTE 10 years earlier than women. The mortality of male PTE patients was 4.70%, not significantly different from female patients, 5.06% (0.50 < P < 0.75). There were not any significant differences between the mortality of patients in the different age groups overall (< or = 39, 40 - 49, 50 - 59, and > or = 60 years, P > 0.1). More people contracted the disease in winter than in other seasons (P < 0.05). There was no obvious difference between the mortality in different seasons overall (0.75 < P < 0.90).</p><p><b>CONCLUSION</b>PTE is an increasingly significant disease and deserves adequate attention.</p>

The expression of Aeromonas hydrophila ompTS gene and the immunogenicity of recombinant OmpTS / 生物工程学报

Primers were designed based on ompTS gene reported recently. With the specific primers, one target fragment about 1024 bp lacking the signal sequence of ompTS gene was amplified from A. hydrophila genomic DNA via PCR. The ompTS gene was hyperexpressed using gene fusion expression vector pRSET system, and the recombinant OMP exhibited a size of 39.9 kD with SDS-PAGE and Western blot analysis, which showed about 51% of total lysate proteins. Antibody to the purified recombinant OMP reacted not only to the recombinant OMP but also to the purified OMPs from A. hydrophila in ELISA and the 36.9 kD OMP in Western blot. The result indicates that the recombinant OMP has the same epitope with the nature one.

Enhancement effect of trans dermal absorption of dipendent on tinidazol / 药学实践杂志

OBJECTIVE：To study the enhancement effect of dipentene in the transdermal absorption of tinidazole.METHODS:In vitro,by means of traditional method to compare the enhancement effect of dipentene with azone at difference concentrations in the transdermal absorption of tinidazole.RESULTS:andCONCLUSION:It was showed that various concentrations of transdermal enhancers could promote absorption of tinidazole in different degrees and 4% Azone and 3%dipentene were the most effective.