The aim of this paper was to observe the combination therapy with total triterpenoids of Chaenomeles speciosa and omeprazole on indomethacin-induced gastric ulcer in rats, and explore its possible mechanism. Rats were randomly divided into normal group, model group, omeprazole monotherapy(3.6 mg·kg~(-1)) group, total triterpenoids of C. speciosa monotherapy(100 mg·kg~(-1)) group, total triterpenoids of C. speciosa and omeprazole combination therapy(100 mg·kg~(-1)+3.6 mg·kg~(-1)) group. Except for the normal group, the other groups were given indomethacin(20 mg·kg~(-1)) by oral once a day for 7 consecutive days. Then the treated groups were given corresponding drugs by gavage, once a day for 14 consecutive days. The next day after the last administration, half of the rats in each group were measured the gastric mucosal blood flow, gastric juice volume and serum TNF-α, IL-1β, IL-6, IL-4 and IL-10. After the remaining rats in each group were underwent pyloric ligation 4 hours after the last administration, the gastric endocrine volume, pH value and total acidity of gastric secretion were measured, then histological analysis was performed, MPO activity, cAMP content and histomorphological analysis were conducted. Real-time PCR was applied to detect the mRNA expressions of gastric tissue TNF-α,IL-1β, IL-6, IL-4, IL-10, VEGFA, A_(2A)R; the protein expressions of VEGFA, A_(2A)R, PKA, p-PKA, CREB, p-CREB, EGF, EGFR, p-EGFR, MUC6, TFF2 in gastric tissue were detected by Western blot. The results indicated that total triterpenoids of C. speciosa and omeprazole combination therapy might significantly increase gastric mucosal blood flow, gastric mucus volume, reduce gastric endocrine volume, secretion acidity and mucosal damage, decrease the levels of TNF-α,IL-1β and IL-6, increase the levels of IL-4 and IL-10 in blood and gastric tissue, inhibit the activity of MPO, increase the content of cAMP in gastric tissue, up-regulate the mRNA expressions of VEGFA, A_(2A)R and protein expressions of VEGFA, A_(2A)R, PKA, p-PKA, CREB, p-CREB, EGF, EGFR, p-EGFR, MUC6, TFF2 in gastric tissue, elevate p-PKA/PKA, p-CREB/CREB and p-EFGR/EFGR. Moreover, the combination therapy with total triterpenoids of C. speciosa and omeprazole was more obvious than those of two monotherapies. These aforementioned findings suggested that the combination therapy with total triterpenoids of C. speciosa and omeprazole on indomethacin-induced gastric ulcer have significant therapeutic effect on indomethacin induced gastric ulcer in rats, its mechanism might be related to regulating A_(2A)R/AKT/CREB, A_(2A)R/VEGFA, EGF/EGFR and MUC6/TFF2 signaling pathways, inhibiting pro-inflammatory factors, increasing gastric mucosal blood flow, up-regulating mucosal cell proliferation factors and promoting mucosal protective factors.
Animals ; Cytokines ; Gastric Mucosa ; Indomethacin ; Omeprazole ; pharmacology ; Phytochemicals ; pharmacology ; Random Allocation ; Rats ; Rosaceae ; chemistry ; Stomach Ulcer ; chemically induced ; drug therapy ; Triterpenes ; pharmacology ; Tumor Necrosis Factor-alpha

OBJECTIVETo observe the effect of pungent dispersion bitter purgation method (PDBPM) on the esophageal mucosal intercellular space of reflux esophagitis (RE) model rats.

METHODSTotally 100 Wistar rats were randomly divided into the control group, the model group, the Western medicine group (WM), the Chinese medicine group (CM), 25 rats in each group. Rats in the control group only received switch operation. Rats in the rest three groups received modified partial cardia muscle incision combined pylorus ligation of external parts to prepare the RE rat model. Starting from the 3rd day after operation, WM mixture (Motilium 3. 2 mg/kg + Omeprazole Capsule 4.3 mg/kg + Hydrotalcite Tablet 161.4 mg/kg) was administered by gastrogavage to rats in the WM group. Rats in the CM group was administered by gastrogavage with Modified Banxia Xiexin Decoction (5.7 g/kg), 2.5 mL each time, twice daily for 14 consecutive days. Equal volume of normal saline was administered by gastrogavage to rats in the control group and the model group. On day 7 and 14, the lower esophagus pH value, general specimen of mucosa and histopathologic changes were observed. Intercellular spaces of esophageal epithelium were measured for a control study.

RESULTSCompared with the same group at day 7, the lower esophagus pH value increased at day 14 (P < 0.01); the naked eye integral of esophageal mucosa and intercellular spaces of esophageal epithelium also decreased at day 14 in the CM group and the WM group (P < 0.05). Compared with the control group at the same time point, the lower esophagus pH value decreased in the model group (P < 0.01). The naked eye integral of esophageal mucosa, and intercellular spaces of esophageal epithelium increased in the model group with increased intercellular spaces (P < 0.01). Compared with the model group at the same time point, the lower esophagus pH value increased and the naked eye integral of esophageal mucosa decreased in the CM group and the WM group at day 7 and 14 (P < 0.01). Intercellular spaces of esophageal epithelium of RE model rats at day 14 was lower in the CM group and the WM group than in the model group (P < 0.01). Compared with the WM group, the lower esophagus pH value decreased at day 7 in the CM group (P < 0.05); the naked eye integral of esophageal mucosa and intercellular spaces of esophageal epithelium decreased at day 14 in the CM group (P < 0.05).

CONCLUSIONSPDBPM had favorable treatment effect on RE model rats. The therapeutic effect was more obvious along with the therapeutic course went by. Its mechanism might be achieved through good repair effect on damaged mucosa, increasing the pressure of esophageal sphincter, and inhibiting gastric acid.

Animals ; Anti-Ulcer Agents ; pharmacology ; therapeutic use ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Esophagitis, Peptic ; drug therapy ; Extracellular Space ; Mouth Mucosa ; Omeprazole ; therapeutic use ; Rats ; Rats, Wistar

OBJECTIVETo characterize the effect of omeprazole on the spectrum of gene expression in the cultured human umbilical vein endothelial cell (HUVEC) line (EA.hy926), and explore the underlying molecular mechanism.

METHODSAffymetrix U133 plus2.0 oligonucleotide microarray was used to detect the alteration in the gene expression profiles induced by 1×10(-5) mol/L omeprazole in HUVECs. Real-time PCR was employed to verify the results of selected differentially expressed genes, and Western blotting was performed to test the expression levels of the related proteins.

RESULTSA total of 282 genes were found to show at least 1.5-fold changes in EA.hy926 cells after treatment with omeprazole for 48 h, including 236 up-regulated and 46 down-regulated ones. These genes were involved in the regulation of transcription, inflammatory response, immune response, cell adherence, anti-apoptosis, and signal transduction.

CONCLUSIONOmeprazole modulates the function of endothelial cells by regulating the gene expression profiles of multiple pathways.

Cell Line ; Computational Biology ; Human Umbilical Vein Endothelial Cells ; drug effects ; Humans ; Oligonucleotide Array Sequence Analysis ; Omeprazole ; pharmacology ; Transcriptome ; drug effects

OBJECTIVETo investigate the impact of omeprazole on platelet response to clopidogrel and the effect of polymorphisms of CYP2C19 on the antiplatelet effect of clopidogrel.

METHODSPlatelet aggregation (PA) was assessed before 300 mg aspirin plus 300 mg loading dose of clopidogrel and after 300 mg aspirin plus 75 mg maintenance dose of clopidogrel 7 days later in 414 patients with acute coronary syndrome who have undergone percutaneous coronary intervention (PCI). Thereafter, gastric mucosal protective drugs were given (omeprazolem 20 mg, n=224 or cimetidine 800 mg, n=190). Fourteen days later, PA was measured again. Genotypes of CYP2C19*2 were analyzed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTSAfter taken aspirin and clopidogrel, PA has decreased significantly in both groups. Compared with cimetidine, omeprazole had no significant impact on PA on 7 and 21 days post PCI. Compared with homozygotes or heterozygotes for the wild-type CYP2C19*2, patients with CYP2C19*2 AA genotype had significantly higher PA on 7 and 21 days post PCI (P<0.05).

CONCLUSIONNo attenuating effect on platelet response to clopidogrel has been observed for Omeprazole. The variant of CYP2C19*2 AA genotype is significantly associated with attenuated response to clopidogrel.

Adult ; Aged ; Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP2C19 ; Drug Interactions ; Female ; Humans ; Male ; Middle Aged ; Omeprazole ; pharmacology ; Platelet Aggregation Inhibitors ; pharmacology ; Proton Pump Inhibitors ; pharmacology ; Ticlopidine ; analogs & derivatives ; pharmacology

Clinical studies reported hypomagnesaemia in long-term omeprazole usage that was probably due to intestinal Mg2+ wasting. Our previous report demonstrated the inhibitory effect of omeprazole on passive Mg2+ transport across Caco-2 monolayers. The present study aimed to identify the underlying mechanism of omeprazole suppression of passive Mg2+ absorption. By using Caco-2 monolayers, we demonstrated a potent inhibitory effect of omeprazole on passive Mg2+, but not Ca2+, transport across Caco-2 monolayers. Omeprazole shifted the %maximum passive Mg2+ transport-Mg2+ concentration curves to the right, and increased the half maximal effective concentration of those dose-response curves, indicating a lower Mg2+ affinity of the paracellular channel. By continually monitoring the apical pH, we showed that omeprazole suppressed apical acid accumulation. Neomycin and spermine had no effect on passive Mg2+ transport of either control or omeprazole treated monolayers, indicating that omeprazole suppressed passive Mg2+ transport in a calcium sensing receptor (CaSR)-independent manner. The results of western blot analysis showed that omeprazole significantly suppressed claudin (Cldn)-7 and -12, but not Cldn-2, expression in Caco-2 cells. By using apical solution of pH 5.5, 6.0, 6.5, and 7.0, we found that apical acidity markedly increased passive Mg2+ transport, Mg2+ affinity of the paracellular channel, and Cldn-7 and -12 expression in Caco-2 monolayers. Apical acidity abolished the inhibitory effect of omeprazole on passive Mg2+ transport and Cldn-7 and -12 expression. Our results provided the evidence for the regulation of intestinal passive Mg2+ absorption by luminal acidity-induced increase in Cldn-7 and -12 expression.
Absorption/drug effects ; Caco-2 Cells ; Calcium/metabolism ; Claudins/genetics/*metabolism ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Humans ; Hydrogen-Ion Concentration ; Magnesium/*metabolism ; Omeprazole/*pharmacology ; Proton Pump Inhibitors/*pharmacology ; Receptors, Calcium-Sensing/metabolism

OBJECTIVETo evaluate the impact of different proton pump inhibitors on the antiplatelet activity of clopidogrel.

METHODSA total of 60 hospitalized patients undergoing percutaneous coronary intervention were randomly assigned to receive omeprazole group 40 mg/d (20 patients), pantoprazole group 40 mg/d (20 patients) and control group (20 patients). All patients also received standard clopidogrel therapy, continuing 30 days treatments. The percentage clotting inhibition was measured by the use of thrombelastogram and the maximal platelet aggregation rate (MPAR) was measured by turbidity method at the first day before admission and 15 or 30 days after treatment. Major adverse cardiac and cerebral events (MACCE) and hemorrhagic events within 30 days were recorded.

RESULTSThe baseline clinical characteristics, angiography and PCI result were compared among the three groups. At the first day before admission and 15 or 30 days after treatment, no significant difference was shown in the percentage clotting inhibition measured by thrombelastogram and the maximal platelet aggregation rate (MPAR) measured by turbidity method among the three groups. Though the platelet agglutination inhibition rate measured at 15 and 30 days increased and MPAR measured at 15 and 30 days declined compared with the baseline data (P < 0.05), no significant difference was found between levels measured at 15 and 30 days (P > 0.05). The rates of MACCE had no significant difference among the three groups. Compared with control group, the rates of hemorrhagic event were significantly decreased in omeprazole or pantoprazole group (P < 0.05), but no significant difference was shown between the omeprazole and pantoprazole group.

CONCLUSIONNo significant impact of different proton pump inhibitors on the antiplatelet activity of clopidogrel has been found in patients undergoing coronary stent implantation and short-time combined administration is safe.

2-Pyridinylmethylsulfinylbenzimidazoles ; pharmacology ; therapeutic use ; Adult ; Aged ; Angioplasty, Balloon ; Aspirin ; pharmacology ; therapeutic use ; Coronary Disease ; therapy ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Omeprazole ; pharmacology ; therapeutic use ; Platelet Aggregation ; drug effects ; Postoperative Period ; Proton Pump Inhibitors ; pharmacology ; therapeutic use ; Stents ; Ticlopidine ; analogs & derivatives ; pharmacology ; therapeutic use

BACKGROUNDHelicobacter pylori (H. pylori) infection could lead to most gastroduodenal diseases and is even identified as a carcinogen of gastric cancer. Total alkaloids of sophora alopecuroides (TASA) is widely used in herbal remedies to treat various infectious diseases, including stomach-associated diseases. This study is aimed at evaluating the antimicrobial activity of TASA on H. pylori-infected BALB/c mice mouse gastritis.

METHODSTotally 120 BALB/c mice were orally inoculated with H. pylori Bacterial liquid to construct BALB/c mice H. pylori infection gastritis animal model, after the model was successfully created. We randomly assigned 100 infected mice into 10 treatment groups, the first group (normal saline); the second group (bismuth pectin); the third group (omeprazole); the fourth group (TASA 2 mg/d); the fifth group (TASA 4 mg/d); the sixth group (TASA 5 mg/d); the seventh group (TASA + bismuth pectin); the eighth group (TASA + omeprazole); the ninth group (bismuth pectin + clarithromycin + metronidazole); the tenth group (omeprazole + clarithromycin + metronidazole), 5 other non-infected mice as negative control. Mice were orally inoculated twice a day and 7 days continuously. Then the mice were killed 4 weeks after treatment, we used realtime PCR to detect 16sDNA of H. pylori to test both the colonization and the clearance mice of bacteria of each treatment. We applied hematoxylin and eosin (HE) staining and immunostaining of mice gastric mucosa to observe the general inflammation and related factors interleukin 8 (IL-8), cyclooxygenase 2 (COX-2), and nuclear factor-kappa B (NF-κB) expression change after treatments.

RESULTSFirstly, we ensured that after 6-week intragastric administration, the bacteria colonization reached an exceed peak which is far higher than positive threshold (P < 0.001); secondly, after treatments, it is revealed that TASA combined with omeprazole or bismuth pectin showed promising antimicrobial activity against H. pylori as well as conventional triple therapy (P < 0.001); thirdly, HE staining showed that the inflammation on mice gastric mucosal membrane were also relieved obviously in TASA combined treatments and conventional triple therapy compared with normal saline treated mice, moreover, from immunohistochemistry results, H. pylori-induced IL-8, COX-2, and NF-κB were consistently suppressed in seventh, eighth, ninth, and tenth group to a certain extent.

CONCLUSIONThese results open the possibility of taking TASA as an anti-inflammatory agent for H. pylori gastritis.

Alkaloids ; pharmacology ; therapeutic use ; Animals ; Anti-Inflammatory Agents ; pharmacology ; therapeutic use ; Cyclooxygenase 2 ; metabolism ; Female ; Helicobacter Infections ; drug therapy ; Helicobacter pylori ; drug effects ; metabolism ; Immunohistochemistry ; Interleukin-8 ; metabolism ; Mice ; Mice, Inbred BALB C ; NF-kappa B ; metabolism ; Omeprazole ; therapeutic use ; Real-Time Polymerase Chain Reaction ; Sophora ; chemistry

BACKGROUNDGastroesophageal reflux disease (GERD) is a common disorder. Dilation of intercellular spaces of esophageal epithelium has been revealed at transmission electron microscopy both in the rabbit acid-perfused esophagus and in esophageal biopsies from GERD patients. This study aimed to observe the changes of the intercellular spaces of squamous epithelium of lower esophagus in patients with GERD and the changes of intercellular spaces of patients with erosive esophagitis (EE) before and after omeprazole treatment.

METHODSOutpatients having GERD symptoms for more than 3 months and volunteers were collected. All of them underwent gastroendoscopy and 24-hour ambulatory pH monitoring. Biopsies were taken from the lower esophagus (2 cm above Z-line) for electron microscope examination. Five healthy volunteers, six non-erosive reflux disease (NERD) patients, and five EE patients were enrolled. Intercellular spaces of GERD patients and controls were calculated. Then we selected 20 patients with EE diagnosed by gastroendoscopy. All of them were treated with omeprazole (Losec, 20 mg bid) for 4 weeks then underwent gastroendoscopy again. Biopsies were taken from 2 cm above Z-line for electron microscope examination. All the patients completed the questionnaire about reflux symptoms before and after treatment.

RESULTSIntercellular spaces of esophageal epithelial cell in volunteers, NERD patients and EE patients were (0.37 +/- 0.07) microm, (1.31 +/- 0.08) microm, and (1.33 +/- 0.14) microm, respectively, with significant differences between the control group and the NERD group (P = 0.000). In the 20 EE patients, the mean intercellular space before treatment was (1.14 +/- 0.15) microm. After treatment the intercellular space was (0.51 +/- 0.18) microm, a significant difference compared with pre-treatment measurements (P = 0.000).

CONCLUSIONSDilated intercellular spaces (DIS) were seen in both NERD and EE cases. The dilated intercellular spaces of esophageal epithelium in EE patients could be recovered after a short time of treatment with omeprazole.

Adult ; Anti-Ulcer Agents ; pharmacology ; therapeutic use ; Esophageal pH Monitoring ; Esophagitis, Peptic ; drug therapy ; pathology ; Extracellular Space ; drug effects ; Female ; Gastroesophageal Reflux ; drug therapy ; pathology ; Gastroscopy ; Humans ; Intercellular Junctions ; drug effects ; ultrastructure ; Male ; Microscopy, Electron, Transmission ; Middle Aged ; Omeprazole ; pharmacology ; therapeutic use