AIMTo develop a new synthetic route for olmesartan medoxomil.

METHODSOlmesartan medoxomil was prepared from ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate via hydrolysis and lactonization to afford 4,4- dimethyl-2-propyl-4,6-dihydrofuro [3,4-d]-1H-imidazole-6-one which was condensed with 2-(triphenylmethyl)-5-[4'-(bromomethylbiphenyl)-2-yl] tetrazole, followed by esterification with 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and deprotection. The chemical structure of the major impurity in condensation reaction is the regio-isomer in the imidazole moiety, and confirmed by single crystal X-ray diffraction. The corresponding regio-isomer of olmesartan medoxomil was synthesized from the impurity by similar method. Optimization of the condensation conditions reduced the impurity to a negligible quantity.

RESULTSSynthesis of olmesartan medoxomil by the new route gave a product of 60% yield and above 99.0% purity. The content of olmesartan medoxomil regio-isomer was effectively controlled to less than 0.1%.

CONCLUSIONA novel synthetic route for olmesartan medoxomil was developed successfully. The olmesartan medoxomil regio-isomer is reported for the first time.

Angiotensin II Type 1 Receptor Blockers ; chemical synthesis ; chemistry ; Animals ; Antihypertensive Agents ; chemical synthesis ; chemistry ; pharmacology ; Blood Pressure ; drug effects ; Imidazoles ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Olmesartan Medoxomil ; Rats ; Stereoisomerism ; Tetrazoles ; chemical synthesis ; chemistry ; pharmacology

Objective To comparative study of the immunomodulatory effects of Hedysarum polybotrys polysaccharides (HPS) etc.four species TCM polysaccharides on immunocompromised mice model made by cyclophosphamide.Methods Low-immunity model mice made by cyclophosphamide 40 mg · kg-1.The KM mice were divided into seven group:normal,model,control,experimental-HPS,experimental-Astragalus polysaccharides (ASPS),experimental-Codonopsis pilosula polysaccharides (CPS) and experimental-Angelica polysaccharides (ANPS) groups randomly.The control group was administrated Shenqi particle 5 g · kg-1.The other tested groups were administrated the corresponding test samples 2 g · kg-1.The normal and model group were administrated the same quantity of normal saline.Give the medicine 1 time each day for 15 days.The visceral index was counted by weighted.The peritoneal macrophage phagocytic count by intraperitoneal injection 5％ chicken red blood-cell were meaeured (OD value).The serum hemolysin OD through delayed type hypersensitivity maded by 50％ dinitrochlorobenzene.The reticuloendothelial system phagocytic count were meaeured by caudal vein injection carbon inkl.Results Compared with the normal,the difference of all indexs of model were statistically significant(all P ＜ 0.01).After dosing,the thymus indexs of model,control,experimental-HPS,experimental-ASPS,experimental-CPS and experimental-ANPS groups were 2.55 ± 0.88,1.04 ± 0.74,2.00 ± 0.89,2.21 ±0.95,1.92 ±0.43,1.67 ±0.41.Compared with the model,difference of experimental-HPS,experimental-ASPS and experimental-CPS were statistically significant (all P ＜ 0.05).The phagocytic counts of mouse peritoneal macrophages of the six groups were 1.31 ±0.18,0.51 ±0.12,1.12 ±O.13,1.19 ±0.09,0.88 ±0.25,0.72 ±0.07.Compared with the model,difference of four species polysaccharides were all statistically significant (all P ＜ 0.01).Compared with the experimental-ANPS,difference of experimental-HPS and experimental-ASPS were statistically significant(P ＜ 0.05,P ＜ 0.01).The phagocytic coefficient of reticuloendothelial system phagocytosis of the six groups were 6.60 ± 0.94,0.99 ±0.83,0.32 ± 1.48,7.28 ± 2.13,5.29 ± 1.97,5.93 ± 1.75.Compared with the model,difference of experimental-HPS and experimental-ASPS were statistically significant (P ＜ 0.05 or P ＜ 0.01).The delayed type hypersensitivity OD of the six groups were 0.53 ± 0.16,0.23 ± 0.09,0.36 ± 0.09,0.38 ± 0.12,0.29 ± 0.10,0.33 ± 0.11.The serum hemolysin OD of the six groups were 0.60 ± 0.12,0.43 ± 0.10,0.53 ± 0.08,0.54 ± 0.11,0.51 ± 0.11,0.52 ± 0.09.Compared with the model,difference of experimental-HPS,experimental-ASPS and experimental-ANPS were statistically significant (P ＜ 0.05 or P ＜ 0.01).Conclusion These four kinds of polysaccharides have the function of enhancing nonspecific immunity function,specific humoral immunity and cellular immune function in mice.HPS and ASPS were more comprehensive and significant for the regulation of immune indexes than CPS and ANPS.

The cardiovascular circulation feedback control treatment instrument (CFCTI) is an automatic feedback control treatment system, which has the function of monitoring, alarming, trouble self-diagnosis and testing on the line in the closed loop. The instrument is designed based on the successful clinical experiences and the data are inputted into the computer in real-time through a pressure sensor and A/D card. User interface window is set up for the doctor's choosing different medicine. The orders are outputted to control the dose of medicine through the transfusion system. The response to medicine is updated continually. CFCTI can avoid the man-made errors and the long interval of sampling. Its reliability and accuracy in rescuing the critical patients are much higher than the traditional methods.
Automation ; instrumentation ; Cardiovascular System ; Feedback ; Medication Systems

To investigate the influence of Anxin granules combined with tirofiban on acute myocardial infarction (AMI) Patients after elective percutaneous coronary intervention (PCI). One hundred and twenty AMI patients were randomly divided into treatment group and control group. The patients in the two groups were all given Tirofiban 30mins before PCI . The treatment group was added Anxin granules 30 mins before and after PCI. Tissue factor (TF) and von willebrand factor (vWF) were tested at 6 hours after operation. Syndromatology alteration of traditional Chinese medicine (TCM) and bleeding complications were observed at 4 weeks after operation. Both TF and vWF at 6 hours after operation of the treatment group was lower than the control group significantly (P < 0.01), while the condition of myocardial ischemia at 90 mins after operation of the treatment group was better than control group with significance. The syndromatology alteration of TCM especially spontaneous perspiration and hypodynamia of the treatment group were improved significantly compared to control group 4 weeks after operation. All patients in both groups had no bleeding complications and thrombopenia. The study suggests that Anxin granules combined with tirofiba can improve the clinical efficacy and the endothelial function of AMI patients after PCI with no increase in bleeding events.
Aged ; Angioplasty, Balloon, Coronary ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Middle Aged ; Myocardial Infarction ; complications ; metabolism ; surgery ; Postoperative Hemorrhage ; drug therapy ; etiology ; metabolism ; prevention & control ; Thromboplastin ; metabolism ; von Willebrand Factor ; metabolism

Objective To evaluate the change of treatment gap of epilepsy after intervention in rural areas of China.Method Six months after being stopped from the intervention project in 2004,using the same method as the first survey at the baseline,a door-to-door epidemiological survey was conducted again in 5 rural areas where the intervention measures had been carried out for about 3 years.Results Three hundred and twenty cases of epilepsy were diagnosed in the total sample population,yielding a prevalence rate of 0.62% and the prevalence of active epilepsy 0.44%.The prevalence and the active prevalence of epilepsy in the survey in 2000 were 0.70% and 0.46% respectively.Of the people with epilepsy,39.1% were treated regularly which increased about 14% than that in the baseline survey (24.8%).The treatment gap for active epilepsy was 49.8%,which decreased by 12.8% than that in the first survey (62.6%). Conclusion The treatment gap of epilepsy in the demonstration areas has decreased remarkably,proving that the intervention measures used in the study are effective and feasible in rural areas of China.

Objective To study the effect of Hedysarum po-ybotrys polysaccharides (HPS) on superoxide dismutase (SOD),catalase (CAT),maleic dialdehyde (MDA),nitric oxide (NO),nitric oxide synthetase (NOS),endothelin (ET),calcitonin generelated peptide (CGRP) in local cerebral cerebral ischemia of rats.Methods The SPF degree Wister rats were randomly divided into six groups:model,sham orperation,control (Ginkgo leafdispersible tablet,0.21 g · kg-1),experimental-H,experimental-M,and experimental-L (HPS,0.60,0.3,0.15 g · kg-1) groups.Each group had ten rats.Local cerebral cerebral ischemia rat models were made by 50％ FeCl3on middle cerebral artery.Neurological score was made by blind method of level 5 and 4 points scoring method.Brain water content was detected by weight method.Brain infarction area was detected by TTC staining method.The SOD,CAT,MDA of brain tissue and NO,NOS,ET,CGRP of serum were detected by kits.Results Compared with model group and sham operation group,all factors had significant difference (all P ＜ 0.01).After taking the medicine,the SOD (U · mg-1) in model,experimental-H and experimental-M groups were 107.90 ± 30.12,135.06 ±3.21,129.32 ±20.71;the MDA(μmol · g-1)in the three groups were 6.39 ±2.03,4.08 ± 1.54,4.53 ± 1.21;the NO(μmol · L-1) in the three groups were 66.32 ± 20· 39,48.50 ±20.86,52.39 ±27.01;the NOS(U · mL-1)in the three groups were 29.95 ± 8.05,21.94 ±9.98,20.55 ± 8.06;the ET(pg · mL-1) in the three groups were 96.64 ± 21.51,75.88 ± 19.52,76.42 ±17.76;the CGRP(pg · mL-1) in the three groups were 53.98 ± 10.95,76.43 ± 22.53,67.07 ± 12.12,the differences of all above factors between groups were statistically significant (all P ＜ 0.05).Conclusion The experimental-H and experimental-M groups can protect nerve function injury and brain tissueinjury and improve the damage of the brain tissue antioxidant system in the rat model of focal cerebral ischemia.

Objective: To observe the short- and long-term clinical outcomes of fraction flow reserve (FFR)-guided percutaneous coronary intervention (PCI) in coronary artery disease (CAD) patients with SYNTAX score≥33 unsuitable for coronary artery bypass grafting (CABG). Methods: A total of 117 CAD patients admitted in our hospital from 2012-01 to 2015-06 were enrolled. Since SYNTAX score≥33, EuroSCORE>6, the patients were unsuitable for CABG and treated in 2 groups: Medication group, n=20 and PCI group, during FFR-guided PCI procedure, patients received ROTA or IVUS according to physician's experience, n=97. All patients were followed-up for at least 12 months. Meanwhile, taking "coronary stent and bypass", "CABG and PCI" as key words, we searched relevant documents in VIP Chinese science and technology journal full-text database, WanFang medical database, ChinaNet and Chinese biomedical literature database from 2012-01-01 to 2015-12-31, patients' outcomes were compared with the above references to explore the clinical benefit. Results: ① PCI group and Medication group had similar SYNTAX score and EuroSCORE, P>0.05. The common pathogenesis was LAD involvement, chronic occlusion was 31.3% (5/16) in patients with partial revascularization.②PCI group had 18.6% (18/97) incidence of major adverse cardiac and cerebral events (MACCE), 2 patients died during follow-up period and 9 received revascularization; Medication group had 60% (12/20) incidence of MACCE, 3 patients died during follow-up period; the difference between 2 groups showed statistical meaning, P<0.05.③There were 22 relevant documents retrieved as comparison; in our research, PCI group had similar incidence of MACCE to the documents, P>0.05; Medication group had increased incidence of MACCE than the documents, P<0.05. Conclusion: FFR-guided PCI could bring clinical benefit in CAD patients with SYNTAX score≥33 unsuitable for CABG.

BACKGROUNDThe synovial fluid concentrations of adiponectin are significantly higher in patients with rheumatoid arthritis (RA) than in patients with osteoarthritis (OA). Accumulating evidence suggests that adiponectin may be an inducer of inflammation in arthritis, but the mechanism remains unclear. The objectives of this study were to compare the expression levels of adiponectin receptors in rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF), evaluate the roles of adiponectin receptors in adiponectin-induced prostaglandin E(2) (PGE(2)) production, and then investigate the effects of a nonsteroidal anti-inflammatory drug (NSAID) and a cyclooxygenase (COX)-2-selective inhibitor on adiponectin-induced PGE(2) release.

METHODSThe expressions of adiponectin receptor 1 (AdipoR1) and AdipoR2 mRNA and protein in synovial fibroblasts from seven patients with RA and eight patients with OA undergoing total knee replacement were evaluated by real-time polymerase chain reaction, immunofluorescence microscopy and Western blotting analysis. Adiponectin-induced PGE(2) production was detected by enzyme-linked immunosorbent assay. RNA interference against the AdipoR1 and AdipoR2 genes was performed to investigate the effects of the adiponectin receptors on adiponectin-induced PGE(2) production in both RASF and OASF.

RESULTSAdipoR1 and AdipoR2 mRNA and protein were expressed by both RASF and OASF. Compared with OASF, RASF exhibited higher levels of AdipoR1, but there was no significant difference for AdipoR2. Adiponectin induced the production of PGE(2) by the synovial fibroblasts in a concentration-dependent manner, and this was more obvious in RASF. RNA interference showed that the difference may be mediated by the diverse distribution of AdipoR1. The adiponectin-induced PGE(2) production was efficiently relieved by the NSAID and COX-2-selective inhibitor.

CONCLUSIONThe present findings suggest that AdipoR1 may mediate the difference in adiponectin-induced PGE(2) production in RASF and OASF.

Adiponectin ; pharmacology ; Arthritis, Rheumatoid ; metabolism ; Blotting, Western ; Cells, Cultured ; Dinoprostone ; metabolism ; Female ; Fibroblasts ; drug effects ; metabolism ; Humans ; Immunoassay ; Male ; Microscopy, Fluorescence ; Middle Aged ; Osteoarthritis ; metabolism ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Receptors, Adiponectin ; genetics ; metabolism ; Synovial Membrane ; cytology

OBJECTIVETo investigate the dynamic expression of hypoxia inducible factor-1alpha (HIF-1alpha) and its clinical values in hepatocellular carcinoma (HCC).

METHODSThe dynamic changes of liver pathology, HIF-1alpha transcription and expression were observed through the hepatoma model. The self-control specimens from 35 human HCC patients were collected and the expression, cellular distribution, and clinicopathological features of HIF-1alpha and its gene was analyzed by immunohistochemistry, western blotting and nested- PCR, respectively.

RESULTSBoth levels of hepatic HIF-1alpha and HIF-1alpha mRNA expression increased during the HCC development course. The incidence of HIF-1alpha and the ratio of HIF-1alpha to beta-actin was 0% and 0.16+/-0.02 in the control rats, 77.8% and 0.29+/-0.04 in the denatured rats, 88.9% and 0.52+/-0.03 in the precancerous rats, and 100% and 0.84+/-0.02 in the cancerous rats respectively, with significant difference between the control group and any of the experimental groups (P = 0.000). The positive HIF-1alpha was brown and granule-like and mainly presented in cytoplasm and few in nucleus. The incidence of HIF-1alpha was 80% (28/35) in HCC and 100% (35/35) in its surrounding tissues. The clinical pathological features indicated HIF-1alpha expression associated with tumor size and differentiation degree the of HCC. No correlation was found between HIF-1alpha and tumor numbers or positive-HBsAg.

CONCLUSIONSHIF-1alpha expression is associated with occurrence and development of HCC, and is perhaps a target molecule for HCC therapy.

Adult ; Aged ; Animals ; Carcinoma, Hepatocellular ; metabolism ; pathology ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; metabolism ; Liver ; metabolism ; pathology ; Liver Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effect of overexpression of Smad7 gene on cell proliferation in human bronchial epithelial cell lines.

METHODSHuman bronchial epithelial cell lines, BEP2D and BERP35T2 cells, were cotransfected with the mammalian expression vectors PCISmad7.neo and pMyc-SEAP, the latter was ac-myc cis-acting enhancer element fused with alkaline phosphatase (SEAP) reporter gene. Expression of c-myc, p15 and p21 mRNA was detected by RT-PCR before and after stable transfection of Smad7 into BEP2D and BERP35T2 cells in order to study the regulation of TGF-beta-mediated growth inhibition.

RESULTSAfter BEP2D and BERP35T2 cells transfected with Smad7, the transcriptional activity of c-myc was significantly increased. Smad7 overexpressing cells showed upregulation of c-myc expression and downregulation of p15 and p21 expression, which contributed to the loss of TGF-beta responses in these cells.

CONCLUSIONOverexpression of Smad7 may facilitate cell proliferation by antagonizing TGF-beta-mediated antiproliferative gene responses.

Bronchi ; cytology ; Cell Proliferation ; Cell Transformation, Neoplastic ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p15 ; biosynthesis ; genetics ; Cyclin-Dependent Kinase Inhibitor p21 ; biosynthesis ; genetics ; Epithelial Cells ; cytology ; Humans ; Proto-Oncogene Proteins c-myc ; biosynthesis ; genetics ; Signal Transduction ; Smad7 Protein ; biosynthesis ; genetics ; Transfection ; Transforming Growth Factor beta ; biosynthesis ; genetics