ABSTRACT
We found indomethacin aggravates healed gastric ulcers (ulcer relapse) in rats. In the present study, we examined the effects of human basic fibroblast growth factor (bFGF) mutein CS23 (TGP-580) and histamine H2-receptor antagonists (H2-RAs) on ulcer relapse in this model. In male SD rats, gastric ulcers were induced in the antrum by injection of acetic acid. Indomethacin (1 mg/kg/day) given s.c. for 2 weeks starting 4 weeks after the operation aggravated the healed ulcer; the areas with and without indomethacin were 4.8 +/- 1.4 and 0.4 +/- 0.3 mm2, respectively. Drugs were given orally once daily for 4 weeks starting 2 days after the operation or for the 2-week indomethacin administration period. Treatment with ranitidine (100 mg/kg), cimetidine (100 mg/kg) and TGP-580 (0.1 mg/kg) for 4 weeks accelerated the healing. The aggravation by indomethacin was significantly inhibited by pretreatment with TGP-580 and mildly inhibited by cimetidine but not ranitidine. When the drugs were co-administered with indomethacin for 2 weeks, the aggravation was significantly prevented by ranitidine and mildly inhibited by cimetidine and TGP-580. Both TGP-580 and H2-RAs can prevent the ulcer relapse induced by indomethacin but via different modes of action: TGP-580 inhibits relapse mainly by acting on the process of healing, while H2-RAs act mainly on the process of aggravation.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Anti-Ulcer Agents/therapeutic use , Fibroblast Growth Factor 2/chemistry , Fibroblast Growth Factors/analogs & derivatives , Histamine H2 Antagonists/therapeutic use , Indomethacin/toxicity , Stomach Ulcer/prevention & control , Acetic Acid/administration & dosage , Acetic Acid/toxicity , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/pharmacology , Cimetidine/administration & dosage , Cimetidine/pharmacology , Cimetidine/therapeutic use , Disease Models, Animal , Drug Interactions , Fibroblast Growth Factors/administration & dosage , Fibroblast Growth Factors/pharmacology , Fibroblast Growth Factors/therapeutic use , Gastric Acid/metabolism , Histamine H2 Antagonists/administration & dosage , Histamine H2 Antagonists/pharmacology , Humans , Immunohistochemistry , Indomethacin/administration & dosage , Injections, Subcutaneous , Male , Peroxidase/metabolism , Ranitidine/administration & dosage , Ranitidine/pharmacology , Ranitidine/therapeutic use , Rats , Rats, Sprague-Dawley , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Recurrence , Stomach/drug effects , Stomach/enzymology , Stomach/pathology , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Wound Healing/drug effectsABSTRACT
The effects of lansoprazole given intravenously on gastric mucosal lesions, gastric bleeding and acid secretion were investigated in rats in comparison with those of omeprazole, famotidine and ranitidine. Lansoprazole inhibited the formation of gastric mucosal lesions in rats induced by water-immersion stress or aspirin with ID50 values of 0.26 and 0.99 mg/kg, respectively, and also inhibited gastric bleeding induced by hemorrhagic shock or water-immersion stress with ID50 values of 0.46 and 1.22 mg/kg, respectively. Lansoprazole was more potent than omeprazole, famotidine and ranitidine in inhibiting gastric mucosal lesions and hemorrhagic shock- or stress-induced bleeding. Famotidine and ranitidine showed negligible inhibition of water-immersion stress-induced gastric bleeding. Lansoprazole strongly inhibited water-immersion stress-stimulated acid secretion in rats, whereas famotidine and ranitidine did not show a potent inhibitory effect. These results indicate that lansoprazole exerts prominent inhibitory actions against the formation of gastric mucosal lesions and gastric bleeding by inhibiting acid secretion, and they show that it is superior to histamine H2-receptor antagonists in inhibiting stress-induced gastric bleeding.
Subject(s)
Anti-Ulcer Agents/administration & dosage , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Omeprazole/analogs & derivatives , 2-Pyridinylmethylsulfinylbenzimidazoles , Acute Disease , Animals , Famotidine/therapeutic use , Gastrointestinal Hemorrhage/prevention & control , Histamine H2 Antagonists/therapeutic use , Injections, Intravenous , Lansoprazole , Male , Omeprazole/administration & dosage , Omeprazole/therapeutic use , Ranitidine/therapeutic use , Rats , Rats, Sprague-Dawley , Stress, PhysiologicalABSTRACT
White rabbits in a family, which were clinically diagnosed as moderately or severely diseased with spirochetosis, were bacteriologically and immunologically examined. The specimens from the diseased rabbits, including affected prepuces, scrotum, or skins with an occasional presence of the spirochetes, did not, however, result in growth in six conventional culture media. Serological tests, including quantitative complement fixation test, rapid plasma reagin card test, Treponema pallidum hemagglutination test, and microscopic agglutination test for leptospires using sera from diseased rabbits showed no differences when compared with those of pooled normal rabbit sera. Immunoblot analysis of the polypeptides from three human oral treponemes and three non-oral spirochetes demonstrated that antibodies against several treponemal polypeptides were detected.
Subject(s)
Rabbits , Treponema/immunology , Treponemal Infections/veterinary , Animals , Antibodies, Bacterial/blood , Antigens, Bacterial/analysis , Female , Immunoblotting , Male , Treponemal Infections/immunologyABSTRACT
Lansoprazole, a proton pump inhibitor, exerts prominent antiulcer activity via both antisecretory and mucosal protective actions. Although the antisecretory action has been explained by inactivation of (H+, K+)-ATPase in parietal cells, the mode of mucosal protective action remains to be elucidated. In the present study, the effect of lansoprazole on duodenal bicarbonate secretion was studied in anesthetized rats to clarify the mode of the mucosal protective action. Lansoprazole (0.1 mM) applied topically to the duodenum significantly (P < 0.01) increased bicarbonate secretion by 0.36 +/- 0.11 microeq/15 min (21 +/- 5%) compared with the value in the vehicle control. Topical administration of capsaicin (10 mg/ml) in the duodenum and intravenous infusion of vasoactive intestinal peptide (10 micrograms/kg/hr) increased bicarbonate secretion. Five-minute perfusion of the duodenal loop with 100 mM HCl increased bicarbonate secretion. Administration of lansoprazole (0.3 and 1 mg/kg, intravenously) 60 min before luminal acidification enhanced the acid-induced bicarbonate secretion dose-dependently and significantly (P < 0.01). In the capsaicin-pretreated rats, the effects of lansoprazole on basal and acid-induced bicarbonate secretion were significantly (P < 0.05) decreased compared with that of control group. These results indicate that lansoprazole increases basal and acid-induced bicarbonate secretion in the duodenum in rats and that capsaicin-sensitive sensory neurons may be involved in the mode of action for these effects.
Subject(s)
Anti-Ulcer Agents/pharmacology , Bicarbonates/metabolism , Capsaicin/pharmacology , Duodenum/metabolism , Neurons, Afferent/physiology , Omeprazole/analogs & derivatives , 2-Pyridinylmethylsulfinylbenzimidazoles , Animals , Duodenum/drug effects , Famotidine/pharmacology , Histamine H2 Antagonists/pharmacology , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Lansoprazole , Male , Neurons, Afferent/drug effects , Omeprazole/pharmacology , Proton Pump Inhibitors , Rats , Rats, Sprague-Dawley , Stimulation, Chemical , Vasoactive Intestinal Peptide/pharmacologyABSTRACT
We describe a family line with an autosomal recessive disease of muscular dystrophy of the diaphragmatic muscles in Holstein-Friesian cattle. Histopathological examination in the present cases revealed various degenerative changes in the diaphragmatic and other thoracic muscles as follows: variation in muscle fiber diameter, fiber splitting, sarcoplasmic masses, ring fiber, vacuolar and hyalinized degeneration of muscle fibers. In addition, central core-like structures were the prominent features in the diaphragmatic muscles, occupying the center of the fiber or scattered within the fiber. These pathological alterations are consistent with the diaphragmatic myopathy previously reported in Meuse-Rhine-Yssel cattle in the Netherlands. The fibers containing core-like structures consisted of three distinct zones which could be well distinguished by NADH-tetrazolium reductase activity. This activity was absent in the innermost zone, decreased in the intermediate zone, and normal or increased in the periphery. Electron microscopically, this structure appeared to be composed of focal myofibrillar degeneration beginning with streaming or disintegration of the Z disk. We discuss here the similarity between this core-like structure and the other alternative organelles that have been reported previously, and a possible defect or storage in the cytoskeleton from the findings of the Z disk abnormalities.
Subject(s)
Cattle Diseases/genetics , Diaphragm/pathology , Muscular Diseases/genetics , Muscular Diseases/veterinary , Animals , Cattle , Cattle Diseases/pathology , Cytoskeleton/physiology , Diaphragm/ultrastructure , Female , Genes, Recessive , Histocytochemistry , Microscopy, Electron , Muscular Diseases/pathology , NADPH-Ferrihemoprotein Reductase/metabolism , PedigreeABSTRACT
Five patients underwent mandibular reconstruction using the double barrel fibular graft from 1989 to 1994. Bony defects ranged from 7 to 14 cm. In three patients, two skin flaps were taken with the fibular graft for composite reconstruction. In order to overcome the main disadvantage of the fibular graft, i.e., small circumference of the bone, a harvested fibula was osteotomized into several portions, folded into two parallel lengths, and fixed along the inferior border of the mandible and the alveolar ridge. The double barrel fibular graft provided more than 4-cm alveolar height without damaging bone viability. In Orientals, a fibula is approximately 1.5 cm thick, and using a single fibular strut for mandibular reconstruction may result in subsequent difficulty in wearing conventional dentures or osseointegrated implants. All patients acquired good mandibular contour and enough thickness of the alveolar ridge, and could wear a conventional denture and eat a solid diet. This procedure seems to be superior to the iliac bone graft for major mandibular reconstruction because of its length, the possibility of three-dimensional composite reconstruction, increased bone thickness, and minimal donor-site morbidity.
Subject(s)
Fibula/transplantation , Mandible/surgery , Mandibular Diseases/surgery , Mandibular Neoplasms/surgery , Osteoradionecrosis/surgery , Surgery, Plastic/methods , Adolescent , Ameloblastoma/surgery , Carcinoma, Squamous Cell/surgery , Female , Gingival Neoplasms/surgery , Humans , Male , Microsurgery , Middle Aged , Surgical Flaps , Treatment Outcome , Vascular Surgical ProceduresABSTRACT
Six Holstein-Friesian cows suffering from recurrent rumenal tympany were pathologically investigated. Macroscopical lesions associated with the clinical symptoms were confined to the diaphragmatic muscles which were pale, and stiff on palpation. Histopathological examination revealed various degenerative changes in diaphragmatic muscles as follows: variation in muscle fiber diameter, vacuolar and hyalinized degeneration of muscle fibers, fiber splitting, central core-like structures, sarcoplasmic masses and ring fibers. These characteristic features in the present cases were consistent with dystrophy of the diaphragmatic muscles in Meuse-Rhine-Yssel cattle. From these observations, it is confirmed that muscular dystrophy of the diaphragmatic muscles dose occur in Holstein-Friesian cows, although a genetic mode was not proven.
Subject(s)
Cattle Diseases , Muscle, Skeletal/pathology , Muscular Dystrophy, Animal/pathology , Animals , Cattle , Diaphragm/pathology , Female , Muscle Fibers, Skeletal/pathology , Sarcoplasmic Reticulum/pathologyABSTRACT
The antisecretory and antiulcer activities of 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were investigated in dogs and rats. AG-1749 inhibited both the (H+ + K+)-adenosine triphosphatase activity in canine gastric microsomes and dibutyryl cyclic AMP-stimulated acid formation in isolated canine parietal cells and suppressed the acid secretion stimulated by histamine, pentagastrin, bethanechol or a peptone meal in Heidenhain pouch dogs; the ID50 values were between 0.2 and 0.7 mg/kg p.o. AG-1749 inhibited both the histamine-stimulated and the basal acid secretion in pylorusligated rats and prevented water immersion stress or aspirin-induced gastric lesions and mepirizole or cysteamine-induced duodenal ulcers in rats; the ID50 values were between 0.3 to 3.6 mg/kg p.o. or i.d. Furthermore, AG-1749 prevented gastric lesions induced by absolute ethanol or acidified aspirin, and accelerated the healing of acetic acid-induced gastric or duodenal ulcers in rats. The inhibitory potency of AG-1749 in dogs was much the same as that of omeprazole and about half that of ranitidine. However, it was about 2 to 10 times more potent than omeprazole and 4 to 34 times more potent than ranitidine in rats. These results suggest that AG-1749 exerts prominent antiulcer activities mainly by suppressing acid secretion via an inhibition of a proton pump in gastric parietal cells and partly by protecting the gastrointestinal mucosa against various ulcerative stimuli.
Subject(s)
Adenosine Triphosphatases/antagonists & inhibitors , Anti-Ulcer Agents/pharmacology , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Omeprazole/analogs & derivatives , 2-Pyridinylmethylsulfinylbenzimidazoles , Animals , Dogs , Gastric Mucosa/enzymology , Gastric Mucosa/metabolism , Gastrins/blood , H(+)-K(+)-Exchanging ATPase , In Vitro Techniques , Lansoprazole , Male , Omeprazole/pharmacology , Pepsin A/metabolism , Peptic Ulcer/drug therapy , Protons , Rats , Rats, Inbred StrainsABSTRACT
The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog (10(-4)-10(-3) M) as well as prostaglandin E2 (PGE2, 10(-8)-10(-5) M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.
Subject(s)
Anti-Ulcer Agents/pharmacology , Benzofurans/pharmacology , Duodenum/drug effects , Intestinal Mucosa/metabolism , Prostaglandins E/pharmacology , 1-Methyl-3-isobutylxanthine/pharmacology , Animals , Dinoprostone , Female , Hydrogen-Ion Concentration , In Vitro Techniques , Indomethacin/pharmacology , Male , Rana catesbeianaABSTRACT
The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25-200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H+ and Na+ caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E2, exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E2. The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.
Subject(s)
Anti-Ulcer Agents , Benzofurans/pharmacology , Gastric Mucosa/drug effects , Animals , Aspirin , Dinoprostone , Electrolytes/metabolism , Ethanol , Indomethacin , Male , Prostaglandins E/pharmacology , Rats , Rats, Inbred Strains , Stomach Ulcer/chemically inducedABSTRACT
The effects of 5-acetylspiro[benzofuran-2(3H),1'-cyclopropan]-3-one (AG 629), a newly synthesized compound, on various experimentally induced ulcers were investigated. Oral or intraduodenal administration of AG 629 in a dose range of 25-100 mg/kg inhibited water-immersion stress ulcer, exertion ulcer, Shay ulcer, indometacin- and acetylsalicylic acid (ASA)-induced gastric ulcer, and indomethacin-induced small intestinal ulcer in rats, histamine-induced gastric ulcer in guinea pigs, and ASA-induced gastric ulcer in dogs, though it was not effective against cysteamine-induced duodenal ulcer in rats. AG 629 in doses of 6.3-25 mg/kg p.o. twice a day significantly promoted the healing of acetic acid- or thermal-cortisone-induced gastric ulcers and acetic acid-induced duodenal ulcers in rats. AG 629 (25-100 mg/kg i.d.) inhibited the secretion of gastric acid and pepsin in pylorus-ligated rats and the acid secretion stimulated by distension of the rat stomach with air, whereas this compound did not affect acid secretion stimulated by histamine, pentagastrin, carbachol or 2-deoxy-D-glucose. This study shows that AG 629 has both prophylactic and curative effects on various ulcers. The anti-ulcer effect of this agent seems to be mediated primarily by increasing mucosal resistance and secondarily by an antisecretory activity.
Subject(s)
Anti-Ulcer Agents/pharmacology , Benzofurans/pharmacology , Duodenal Ulcer/drug therapy , Stomach Ulcer/drug therapy , Acetates , Acetic Acid , Acute Disease , Animals , Anti-Ulcer Agents/therapeutic use , Aspirin , Benzofurans/therapeutic use , Chronic Disease , Cysteamine , Dogs , Duodenal Ulcer/chemically induced , Duodenal Ulcer/physiopathology , Female , Gastric Acid/metabolism , Guinea Pigs , Histamine , Hot Temperature , Indomethacin , Male , Physical Exertion , Rats , Rats, Inbred Strains , Stomach Ulcer/etiology , Stomach Ulcer/physiopathology , Stress, Psychological/complicationsABSTRACT
Indomethacin produces gastric corpus erosions in the fasted rat and small intestinal ulcers in the conventionally fed rat. We found that in rats fed chow pellets for 1 h after a 24-h fast, indomethacin given within 2 h after refeeding produced lesions in the gastric antrum, primarily along the lesser curvature, and also in the small intestine. The antral lesions reached a maximum size in 6-10 h, penetrated the muscularis mucosae within 3 days, and did not diminish for at least 7 days. The formation of the antral ulcer was prevented by prostaglandins or adrenalectomy, but was not affected by cimetidine, atropine, and/or vagotomy. In contrast, the gastric corpus erosions produced by indomethacin in the fasted rat were prevented by antisecretory drugs or vagotomy, and were aggravated by adrenalectomy. It is concluded that: (a) the chronic antral ulcers produced by indomethacin in a refed rat mimic human gastric ulcer with regard to location and histology; and (b) the mechanism of antral ulcer formation is different from corpus erosion formation, in that it was resistant to antisecretory drugs and vagotomy and was prevented by adrenalectomy. This experimental ulcer model could prove useful for studies of the etiology and therapy of gastric ulcer disease.