| Gastric ulcer is a common diseases, multiple and serious threat to human health. According to reports, patients with peptic ulcer or about one-tenth of the world's population, mainly for gastric ulcer and duodenal ulcer.As a high incidence of gastric ulcer, easy to recur, it is difficult to cure this disease, on the labour resources and constituted a serious hazard People need to find the anti-ulcer drug specific effects, which have less adverse reactions, not relapse. Therefore, the study of drug treatment of such diseases is a more broad social prospects.The mechanism of gastric ulcer is the enhance of attack factor or the weaken of protection factor, the disturbance of the two factors result in gastric ulcer, in which the weaken factor is the main one. In years, peptic ulcer study focuses on how to inhibit or eliminate attack factors, while the study of enhance the protection factor has less attention. Rosa for the small acetate resin has highly selectivity and competitive antagonist, it can deduce the gastric acid and protect the mucosa. Its bioavailability>95%, not disturbed eating, not inhibit liver oxidase system, no important drug interaction and has mild reaction for long use, so it is the hot spot for domestic medicine institutions. BRD molecular formula is C18H29N3O2, is the first derivatives of Rosatidine which we synthesised and reported. BRD shows increased fat-solubility and acid-inhibility compared with Rosatidine in vitro study. There has no report about the pharmacological effects and the mechanism of BRD. Therefore we study the toxicology, pharmacology and pharmacodynamics of the new compound, in order to reveal its mechanism. Through the study, we may fill the blank of BRD pharmacological role and for the development of efficient H2 receptor antagonist drugs provide valuable information, to make BRD a new drug, both at home and abroad market.Methods1,Acute Toxicity TestIn order to understand the relationship between activity and toxicity of BRD, we conducted the drug gavage acute toxicity experiments using mice, and using probability units of the drug to determine BRD LD50, for the pharmacological evaluation of the drug dose design basis. The results showed that: BRD LD50 in mice gavage is 663.64 mg / kg, compaired with small Rosa acid resin (LD50 was 561.11 mg / kg) is more secure,so the BRD has good security.2,The treatment and mechanism of BRD to the pyloric ligation rats with gastric ulcer48 rats were randomly divided into normal control group, gastric ulcer model group(non-treated group), ranitidine, BRD large, medium and small three dose groups and each group has eight rats, of either sex. Non-treated group and the normal group give 0.9% NaCl, ranitidine one given ranitidine 27 mg / kg, BRD high, medium and low dose group were given BRD (28mg/kg, 14mg/kg and 7 mg / kg ).Shay's method is used in pyloric ligation. Intragastric administration for three days, after the 2nd gavage, fasting without water 48 h preoperative .4th day, ether anesthesia and put rats supine on board.From Xiphoid along the abdominal medium line cut a incision about 2-3 cm. In the left rib, push up with fingers gently, exposure stomach. Avoid vessels, threads under the pyloric and ligate pyloric , after ligation each group inject medicine into the duodenum (the non-treated group to the same volume of saline), the control group do the same without ligation, and then suture and disinfect abdominal incision,. Feeding back into the cage, fasting, prohibiting water. Helicobacter pylori 18 h after ligation Pulpotomy executed and quickly open abdominal cavity, collecting samples, respectively, for the following indicators observation.â‘ observation the impact of BRD to the general morphology and the ulcer area of the ulcer rats.â‘¡gastric juice content analysis: the total acidity of gastric juice (acid-base titration method), pepsin activity (amino acid reduction)â‘¢biochemical indicators: xanthine oxidase method (as ammonia) and thiobarbituric acid were used to detect blood-rat gastric ulcer and gastric mucosa in the superoxide dismutase (SOD) activity, malondialdehyde (MDA) concentration. To explore the role of BRD to the mucosa of gastric ulcer rats and its mechanism.Statistically: All data used spss10.0 t-test analysis, (x disabilities S) shows results.Results1,Observation of lesions ulcersThe ulcer of rats in each group is round or oval, scattered distribute in the rumen, model group ulcer area is bigger, more distributeg points, and deep into the myometrial layer. BRD small dose group ulcer scattered in the many points and have larger ulcers. BRD large dose distribution points less and the gastric mucosa is fresh.2,The impact on ulcer index of the pyloric ligation ratBRD each group could reduce the pyloric ligation rat gastric ulcer index, BRD large dose group and the dose group compare with the non-treated group has a significant difference (P <0.01), its role has no difference with ranitidine (P> 0.05), but the inhibition of ulcers percentage changelittle, may be related to the short time use of the drug.3,Analysis of the gastric juice of the pyloric ligation ratsBRD large and medium dose group and Ranitidine group can be very significant inhibite gastric secretion, reducing the total acidity of gastric juice, compared with the non-treated group has a significant difference (P <0.01), large dose group superior to ranitidine group on reduced gastric secretion and drop acidity (P <0.01); B BRD large and medium dose group and ranitidine group could reduce the activity of pepsin, but ranitidine one is better when compare with non-treated group ,BRD large, medium-dose group (P <0.05)and ranitidine (P <0.01). Above shows that it can weak the effect caused by injury gastric mucosal barrier of the gastric acid and pepsin, and in order to reach the goal of treatment.4,Effect on the content of SOD and MDA in serum and gastric mucosaModel group i serum and gastric mucosa SOD activity decrease significantly, while the content of MDA significantly increased. With the increase of BRD dose increased SOD activity increase, MDA content reduced, in serum and gastric mucosa BRD large dose group compared with the model group has a very significant difference (P <0.01), BRD medium dose and ranitidine group compare with the model group have significantly different (P <0.05-0.01), BRD large and medium dose group superior to ranitidine group. It shoes that BRD can increase the serum and gastric mucosa level of SOD to protect the gastric mucosa, and lowerthe the level of MDA to reduce the damage effect.DiscussThe causes of peptic ulcer is complexity, which is the pathogenesis of a variety of reasons-led offensive strengthen and / or mucous membrane weakened defense, and only when the defense factor in the balance of attacks, which can maintain the integrity of gastric mucosal barrier play normal function, the protection of gastric mucosa. When offensive and defensive factor balancing factor broken, can lead to the occurrence of peptic ulcer. Recent studies show that the occurrence of ulcers and development is closely related to the attacks of a gastric acid, pepsin, MDA and so on, such as the defense of SOD,NO, antioxidant systems. Acid and pepsin is not only involved in digestion, but also have close relations with peptic ulcer, often as offensive factors. When the acid concentration in blood up to 300 ~ 400 million times, a highly corrosive to gastric; pepsin in the acidic environment can be a strong decomposition of protein, as endogenous stimulation of the stomach wall is a direct attack caused the most important cause of stomach hurt. But under normal circumstances, due to gastric mucosa with a series of defense and repair mechanisms, including the mucus / bicarbonate barrier, the mucosal barrier, mucosal blood flow and cell renewal, prostaglandin and epidermal growth factor, etc. So can withstand high gastric mucosa gastric acid and pepsin damage role in maintaining the integrity of the mucosa. Once weakened defense and repair mechanisms, acid and pepsin will play the role of the gastric mucosal damage, leading to inflammation, occurrence of ulcers.The experimental results show that, BRD with the model in the high and middle dose group compared to the control group, free gastric acid, total acidity significantly decreased, pepsin activity and gastric juice volume decreased. This shows that the BRD can significantly reduce the pyloric ligation secretion of gastric ulcer in rats, reduce gastric acid, and have obvious reduce effect on the increase of pepsin activity caused by pylori helicobactor, suggesting that the anti-ulcer BRD role may be related to reduced gastric secretion, reduce gastric attacks factor - gastric acid and pepsin activity.Helicobacter pylori can cause high acid, pepsin content increased, weakened gastric mucosal barrier, high concentrations of H + can injury gastric mucosa, so there are a series of local inflammatory response, and the inflammatory process can produce large amounts of superoxide anion, rats SOD and superoxide anion balance is broken, when the SOD activity was significantly decreased, the volume of oxygen free radicals in the gastric mucosa increased, the oxygen free radicals both in overall level or cell level can cause gastric mucosa or mucosal cells lipid peroxidation, resulting in gastric mucosal blood flow obstacles caused gastric mucosal injury, which eventually led to ulcer formation. SOD is the first line of defense in body in oxygen free radical scavenging system, and have restored cell function. Enhance the activity of SOD and strengthen radical scavenging, and to reduce lipid peroxidation, is one of the links to improve the stomach membrane protect efforts. Body through enzymatic system and non-enzyme system to produce oxygen free radicals, attack biofilm's polyunsaturated fatty acids (PUFA), lead role of lipid peroxidation, and therefore form a lipid peroxide, oxygen free radicals not only through the biofilm PUFA peroxidation cause cell injury, but also through the lipid product of the decomposition of hydrogen peroxide cause cell injury. MDA content often can reflect the lipid peroxidation in vivo, which also reflect the degree of cell damage indirect. In short, the MDA is a product of lipid peroxidation, SOD is a kind of oxygen free radical scavenger. The results show that BRD can increase the activity of SOD and inhibited lipid peroxidation MDA increased. That display the drug may be due to the inhibition of lipid peroxidation in vivo and scavenging oxygen free radicals so as to protect the gastric mucosa.ConclusionBRD has a protective effect on the gastric mucosa, which can effectively reduce the pyloric ligation gastric ulcer rats gastric mucosal injury, the effect was dose-dependent, with its mechanism may reduce gastric acid secretion, decreased pepsin activity decreased serum and gastric tissue MDA content, increase in gastric tissue and serum SOD dynamism. BRD weakened by gastric attack factor, and increased gastric mucosal protection factor and gastric mucosal blood flow, thereby enhancing the protection of gastric mucosa, BRD is one of the mechanisms to cure acute and chronic gastritis and peptic ulcer in clinical. |
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