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At least 19 recordsLinked to original sources
PubMed1985

Preparations of agglomerated crystals of polymorphic mixtures and a new complex of indomethacin-epirizole by the spherical crystallization technique.

Agglomerated crystals of indomethacin and epirizole were prepared by the spherical crystallization technique. The solvent used was ethanol-water-chloroform, ethyl acetate-water, or ethyl acetate-aqueous sodium chloride. From the ethanol-chloroform-water system, we obtained agglomerated crystals of a polymorphic mixture of the beta form of indomethacin (original form, gamma) and amorphous epirizole. When the mole percent of epirizole loaded into the system was less than 63 and 38% for the ethyl acetate-water and ethyl acetate-aqueous sodium chloride systems, respectively, the agglomerated crystals consisted of a polymorphic mixture of the alpha form of indomethacin and amorphous epirizole. When the respective mole percent of epirizole loaded was more than 65 and 43% in the aforementioned systems, a new complex of indomethacin-epirizole (molecular ratio equal to 2:1) was obtained. Recovery of complex from the drugs loaded in the ethyl acetate-aqueous sodium chloride system was higher than that in the ethyl acetate-water system, as a result of a salting-out effect. The solubility of indomethacin in the agglomerated complex in a solution of 30% aqueous ethanol and in disintegration test solution no. 2 (composition, 0.05 M KH2PO4 plus 0.0236 M, NaOH, pH 6.8), specified in the Japanese Pharmacopeia X (JPX), was higher than in the physical mixture (molecular ratio of indomethacin to epirizole equal to 2:1). In the ethanol solution, indomethacin was transformed into the gamma form during dissolution, and a decrease in solubility occurred. The process of dissolution of the tablet of the agglomerated complex was described by zero-order kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Calorimetry, Differential Scanning↗
PubMed1991

Decrease of duodenal calcitonin gene-related peptide- and substance P-like immunoreactivity in rat duodenal ulcers.

We have investigated the endogenous levels of duodenal calcitonin gene-related peptide- (CGRP) and Substance P- (SP) like immunoreactivity (li) following the induction of duodenal ulcers in rats. Using three duodenal ulcerogens, namely cysteamine, dulcerozine or mepirizole given in a single oral dose, a decrease of duodenal CGRP-li and SP-li was observed. Time-relationship studies of this phenomenon show that CGRP-li and SP-li were decreased concomitantly to the formation of gastroduodenal ulcers after the administration of cysteamine (900 mg/kg p.o.). Pretreatment with the selective sensory neurotoxin capsaicin induced CGRP-li decrease in the duodenum, which was not further decreased by an ulcerogenic dose of cysteamine, indicating that cysteamine induced a release of CGRP-li of capsaicin-sensitive origin. Otherwise duodenal SP-li was not sensitive to capsaicin pretreatment and its duodenal content decreased by cysteamine originates from an intrinsic source. Our observations indicate that CGRP and SP may play an important local role in duodenal ulcerogenesis.

Animals↗
PubMed1984

Effects of a proton pump inhibitor, omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats.

The effects of omeprazole, a proton pump inhibitor, on gastric secretion and gastric or duodenal ulcers or erosions in rats were studied. Omeprazole, given intraduodenally, dose-dependently inhibited the gastric secretion (volume, acid and pepsin output) of pylorus-ligated rats. The antisecretory activity of omeprazole at 100 mg/kg persisted for 14 hr after treatment. Acutely induced gastric ulcers or erosions such as Shay ulcers, water-immersion stress-, indomethacin-, aspirin-, or prednisolone-induced erosions were all markedly inhibited by oral or intraduodenal administration of 10-100 mg/kg of omeprazole. The development of duodenal ulcers and gastric erosions caused by mepirizole was also potently inhibited by omeprazole at 3-10 mg/kg given orally. Repeated administration of omeprazole, 200 mg/kg/day in two divided doses for 14 days, significantly accelerated the spontaneous healing of acetic acid-induced gastric ulcers. The mechanism by which omeprazole inhibits the development of acute ulcers and accelerates healing of preexisting ulcers appears to be mainly due to its potent and long-lasting antisecretory activity. The antisecretory and antiulcer activities of omeprazole are equal to or exceed those of cimetidine, both in the maximum inhibitory response and ED50 values.

Animals↗
PubMed1982

Mepirizole-induced duodenal ulcers in rats and their pathogenesis.

Duodenal ulcers were produced in rats following either an oral or parenteral administration of 200 mg/kg of mepirizole, a nonsteroidal antiinflammatory agent. Deep ulcers, including perforated ones, were induced in the proximal duodenum with an incidence of over 90%. Mortality due to perforation was less than 5%. The agent also induced several erosions in the antrum. Feeding of animals after the ingestion of mepirizole markedly suppressed the development of both duodenal ulcers and gastric erosions. Antacids, anticholinergic agents, a histamine H2-receptor antagonist and 16-DMPGE2 dose-dependently inhibited mepirizole-induced duodenal ulcers. Gastric erosions were also significantly inhibited by antacids and anticholinergic agents but not by a histamine H2-receptor antagonist and 16-DMPGE2. Intraduodenally administered mepirizole dose-dependently inhibited the gastric secretion in pylorus-ligated rats. This ulcer model should be useful for screening antiulcer agents and for the study of pathogenesis of duodenal ulcers and gastric erosions.

Administration, Oral↗
PubMed1987

Prostaglandin deficiency by itself is not the cause of mepirizole-induced duodenal ulcers in rats.

The purpose of these studies was to determine the role played by endogenous prostaglandins in the development of gastric ulcers produced by indomethacin, and of duodenal ulcers produced by mepirizole in rats. Indomethacin (10 mg/kg subcutaneously) produced gastric ulcers, whereas mepirizole (100 mg/kg subcutaneously) produced exclusively duodenal ulcers. Both drugs, given at ulcerogenic doses, reduced the gastric and duodenal generation of PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2. In this regard, the extent of reduction was more pronounced after indomethacin than after mepirizole. Despite this greater inhibition of prostaglandin synthesis by indomethacin, this drug did not produce duodenal ulcers, whereas mepirizole was duodenoulcerogenic. In addition, mepirizole increased gastric acid secretion by 74%, whereas indomethacin had no effect on acid secretion. Oral administration of 16,16-dimethyl PGE2, given at nonantisecretory doses (0.5-5 micrograms/kg), prevented formation of indomethacin-induced gastric ulcers, whereas antisecretory doses were required to prevent formation of mepirizole-induced duodenal ulcers. We conclude that a reduction of prostaglandin formation in the duodenal mucosa is not by itself sufficient to induce duodenal ulcers. We hypothesize that three changes, produced by mepirizole, must be present for duodenal ulcers to develop: increased gastric acid secretion, decreased duodenal bicarbonate secretion (as demonstrated earlier), and decreased duodenal content of prostaglandins. The decreased prostaglandin formation, although not causing duodenal ulcers, may lower the resistance of duodenal mucosa to the hyperacidity induced by mepirizole. On the other hand, in the case of gastric ulcers following administration of indomethacin, a decrease in gastric mucosal levels of prostaglandins may play a more important role than changes in gastric acidity.

16,16-Dimethylprostaglandin E2↗
PubMed1983

Species and strain differences in mepirizole-induced duodenal and gastric lesions.

Species and strain differences in mepirizole-induced duodenal and gastric lesions were studied. Mepirizole at 200 mg/kg given orally induced deep duodenal ulcers and gastric erosions in nonfasted Sprague-Dawley, Fisher, Wistar, and Donryu rats at an incidence of over 75%. Mepirizole at 300 mg/kg given orally also induced penetrating duodenal ulcers in nonfasted rabbits at an incidence of 50%. There was little or no damage to the duodenum and stomach in mice and dogs given 200-300 mg/kg of mepirizole orally or subcutaneously. The stomachs of fasted guinea pigs given 200 mg/kg of mepirizole had superficial erosions at a high incidence (93.3%). Mepirizole at 200 mg/kg given intraduodenally significantly reduced the volume of gastric juice but increased the acidity and pepsin activity in both pylorus-ligated and acute fistula rats. In chronic fistula rabbits, however, the agent at 200 mg/kg given orally reduced the volume and acidity, but increased the pepsin activity. The mechanism of duodenal ulceration by mepirizole differs slightly in rats and rabbits.

Animals↗
PubMed1986

Mechanisms of protective activity of 16,16-dimethyl PGE2 and acetazolamide on gastric and duodenal lesions in rats.

16,16-Dimethyl PGE2 (16,16-dmPGE2), given orally at 10-30 micrograms/kg, had no effects on gastric acid secretion, or carbonic anhydrase activity, but did increase HCO3- secretion in both the stomach and duodenum of rats. 16,16-dmPGE2, at nonantisecretory doses, potently inhibited indomethacin- and water-immersion stress-induced gastric lesions and mepirizole-induced duodenal lesions in rats. Acetazolamide, given orally at 50 mg/kg, markedly inhibited carbonic anhydrase activity, but had no effects on gastric acid secretion and the basal and 16,16-dmPGE2-stimulated HCO3- secretion. Acetazolamide, at a nonantisecretory dose, had no effects on indomethacin-induced gastric lesions and mepirizole-induced duodenal lesions, but significantly inhibited water-immersion stress-induced gastric lesions. Combined administration of 16,16-dmPGE2 and acetazolamide did not influence the protective activity of 16,16-dmPGE2 on these lesions. The mechanism of the cytoprotective activity of 16,16-dmPGE2 may involve an increase in HCO3- secretion (nonmediated by carbonic anhydrase), while mechanisms involved in the effects of acetazolamide are apparently different.

16,16-Dimethylprostaglandin E2↗
PubMed1988

Biphasic effect of duodenal ulcerogens on gastric emptying in the rat.

The effect of the duodenal ulcerogen cysteamine on gastric emptying of a liquid meal was compared to that of two newly identified duodenal ulcerogens, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and mepirizole. Emptying rates after acute and chronic treatment with duodenal ulcerogens were obtained. Acute administration of cysteamine, MPTP, or mepirizole significantly delayed gastric emptying of the meal. Chronically treated rats, however, showed either no change or accelerated gastric emptying after cysteamine, MPTP, or mepirizole. Gastric emptying in chronically treated animals was faster in rats that developed the most severe duodenal ulcers. These results indicate that delayed gastric emptying instead of accelerated emptying is a more common abnormality during duodenal ulceration. After the ulcer develops, however, unaltered or accelerated gastric emptying is observed experimentally, thus suggesting that accelerated gastric emptying in duodenal ulcers is an acquired alteration. The implications that these experimental findings may have in the pathogenesis of duodenal ulcer, in light of the clinical data available, are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Effects of mepirizole and basic antiinflammatory drugs on HCl-ethanol-induced gastric lesions in rats.

Mepirozole, a basic antiinflammatory drug and duodenal ulcerogen in laboratory animals, macroscopically protected the gastric mucosa of rats from HCl-ethanol-induced damage in a dose-dependent manner. These effects were evident when the agent was given orally, intraperitoneally, or subcutaneously at 3 or 10 mg/kg 0.5 hr before HCl-ethanol administration. Histologically, the surface epithelial and pit cells were not protected by mepirizole, but most of the mucosal cells located in the deeper portions were well preserved. Gastric acid secretion in the pylorus-ligated or acute fistula preparation was not affected by 10 mg/kg of mepirizole. Gastric motility determined by a balloon method was dose-dependently inhibited by the agent. Mepirizole protection was significantly reduced by pretreatment with subcutaneous indomethacin (5 mg/kg) and N-ethylmaleimide (10 mg/kg). The gastric motility inhibited by mepirizole was not reversed by indomethacin and N-ethylmaleimide treatment. These results suggest that the mechanism underlying mepirizole protection relates to both endogenous prostaglandins and sulfhydryl compounds present in the gastric mucosa, but does not relate to an inhibition of gastric motility. Dulcerozine and other basic antiinflammatory drugs (tiaramide, tinoridine, and benzydamine) given either orally or intraperitoneally at 10-100 mg/kg also dose-dependently prevented the development of HCl-ethanol-induced lesions. Mepirizole and other basic antiinflammatory drugs are cytoprotective in the rat stomach.

Animals↗
PubMed1989

Effect of duodenal ulcerogens cysteamine, mepirizole, and MPTP on duodenal myoelectric activity in rats.

Increased gastric acid secretion, enhanced acid delivery to the duodenum, and reduced alkaline secretion in the proximal duodenum are relatively well-established pathophysiologic abnormalities in duodenal ulcer. Impaired duodenal motility, however, may also contribute to duodenal ulceration by altering the distribution of acid and alkaline secretions along the upper digestive tract. We tested the hypothesis that the duodenal ulcerogens cysteamine, MPTP, and mepirizole modify duodenal motility in the rat and that motility changes might be a common and early alteration in experimental duodenal ulceration. All three duodenal ulcerogens rapidly produced extensive changes in duodenal myoelectric activity and reduced the frequency of myoelectric slow waves. Cysteamine induced marked hypermotility for at least 6 hr; MPTP rapidly decreased motility and fragmented the myoelectric migrating pattern. Mepirizole induced biphasic changes: an early hypermotility phase of about 30 min was followed by profound hypomotility. These results indicate that marked alterations of duodenal motility are common during experimental duodenal ulceration. In light of the differential effect of the ulcerogens on duodenal motility, it remains to be determined how these changes influence acid neutralization in the proximal duodenum. Nevertheless, our results suggest that all three duodenal ulcerogens, which are different in structure, alter duodenal motility.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Role of prostanoids in experimental duodenal ulcer in rat.

The purposes of this study were to determine whether inhibition of cyclooxygenase is a mechanism by which cysteamine and mepirizole produce duodenal ulcers, identify qualitative or quantitative differences in prostanoid production between gastric mucosa and duodenum, and determine whether differences in cyclooxygenase sensitivity to inhibition by aspirin exist between these two tissues. In fed female rats, gastric mucosal prostaglandin E2 (PGE2) and prostacyclin (PGI2) generation was 235 +/- 25 and 832 +/- 40 ng/g/min, respectively, whereas full-thickness duodenal PGE2 and PGI2 generation was 665 +/- 46 and 662 +/- 49 ng/g/min, respectively. Over an intraperitoneal dose range of 0-25 mg/kg, aspirin-induced cyclooxygenase inhibition was dose-dependent and similar for the two tissues. Duodenal ulceration (16.7 mm2) produced by cysteamine, 425 mg/kg, was associated with a 46% reduction in duodenal PGE2 generation, while having no effect on PGI2 generation; however, cysteamine, 213 mg/kg, produced no visible duodenal mucosa injury yet reduced duodenal PGE2 generation 39% compared to control values. In fed male rats, gastric mucosal PGE2 and PGI2 generation was 179 +/- 18 and 813 +/- 61 ng/g/min, respectively, whereas duodenal PGE2 and PGI2 generation was 321 +/- 27 and 454 +/- 38 ng/g/min, respectively. Duodenal ulceration (7.7 +/- 2.3 mm2) produced by oral mepirizole was associated with a 63% reduction in duodenal PGE2 generation compared to control values, while having no effect on PGI2 generation. Subcutaneous aspirin, 100 mg/kg, which reduced duodenal PGE2 generation to a greater degree than either ulcerogen, given in conjunction with pentagastrin, did not produce visible duodenal ulceration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Tobacco cigarette smoke attenuates duodenal ulcer margin hyperemia in the rat. Comparison of IAP clearance and hydrogen gas clearance techniques for measurements of gastrointestinal blood flow.

The hyperemia at the duodenal ulcer margin is important for ulcer healing. We studied the effect of tobacco cigarette smoke on the hyperemia at the margin of mepirizole-induced duodenal ulcer. Duodenal mucosal blood flow values measured by iodo[14C]antipyrine (IAP) autoradiography and hydrogen gas clearance (HGC) were compared. Twenty-four hours after rats were injected with an ulcerogenic dose of mepirizole, they were exposed to tobacco cigarette smoke and duodenal mucosal blood flow was measured by IAP autoradiography. There is a significant correlation between the blood flow measurements by HGC and IAP autoradiography. The hyperemia at the ulcer margin previously demonstrated in our laboratory is absent after exposure of the rats to tobacco cigarette smoke. We speculate that the inhibition of ulcer margin hyperemia could explain the aggravation of duodenal ulcer by tobacco cigarette smoke.

Animals↗
PubMed1995

Effects of nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on duodenal alkaline secretory and ulcerogenic responses induced by mepirizole in rats.

The inhibition of nitric oxide (NO) production by NO synthase inhibitors stimulates HCO3- secretion in the rat duodenal mucosa. Therefore, we examined the effects of NG-nitro-L-arginine methyl ester (L-NAME, the NO synthase inhibitor) and nitroprusside (the exogenous NO donor) on the duodenal HCO3- and ulcerogenic responses in anesthetized rats. Animals were administered mepirizole (200 mg/kg, subcutaneously) for induction of duodenal ulcers, and gastric acid and duodenal HCO3- secretions were measured with or without pretreatment with L-NAME (5 mg/kg, intravenously) or nitroprusside (4 mg/kg, intravenously). Mepirizole increased acid secretion, decreased the acid-induced duodenal HCO3- secretion, and induced hemorrhagic lesions in the proximal duodenum. The inhibition of NO production by L-NAME potentiated the acid secretory response, increased the duodenal HCO3- secretion, and prevented the duodenal lesions, and these changes were all antagonized by simultaneous administration of L-arginine (200 mg/kg, intravenously) but not D-arginine. On the other hand, nitroprusside slightly reduced the acid response but further decreased the HCO3- output, resulting in aggravation of duodenal lesions induced by mepirizole. These data suggest that the inhibition of endogenous NO production by the NO synthase inhibitor L-NAME increases duodenal HCO3- secretion and protects the duodenal mucosa against acid injury.

Animals↗
PubMed1994

Acid secretory and duodenal ulcerogenic responses induced by mepirizole in anesthetized rats. Relation to body temperature.

The role of body temperature in the acid stimulatory mechanism by mepirizole, a duodenal ulcerogen, was investigated in urethane-anesthetized rats. Subcutaneous administration of mepirizole (60 and 200 mg/kg) increased acid secretion in a dose-dependent manner and resulted in duodenal lesions within 8 hr. The acid secretory and ulcerogenic responses induced by mepirizole were inhibited completely by vagotomy and significantly reduced by subcutaneous pretreatment with atropine (1 mg/kg), hexamethonium (10 mg/kg), or clonidine (1 mg/kg). During anesthesia, body temperature was decreased to 34 degrees C in control rats but further reduced to 31 degrees C after administration of mepirizole. When body temperature was maintained at 36 degrees C during a test period, mepirizole caused significantly less effect on acid secretion and produced less damage in the duodenum. In addition, intracisternal administration of antiserum of thyrotropin-releasing hormone (TRH: 5 mu1/rat) also significantly inhibited acid hypersecretion and development of duodenal lesions in response to mepirizole. When acid output induced by mepirizole was plotted against duodenal lesion score from one group to another, a significant linear relationship was found between these two values (r = 0.814, P < 0.05). We conclude that mepirizole induced vagally mediated acid secretion and duodenal lesions in anesthetized rats. These responses may occur centrally in association with lowering of body temperature, which potentiates the acid stimulatory effect of mepirizole, probably through a TRH-dependent mechanism.

Animals↗
PubMed1980

Mepirizole, a non-steroidal antiinflammatory compound, its ulcerogenicity and inhibitory action on lesions induced by acidic antiinflammatory agents in the rat stomach.

Gastric lesions were produced in rats by the administration for 2 weeks of 300 mg/kg/day of mepirizole, a basic non-steroidal antiinflammatory compound. Although the single administration of 200 mg/kg of mepirizole had no effect, the addition of water-immersion stress for one hour induced lesions not only in the corpus but also in the pyloric antrum. The administration of 250 mg/kg of mefenamic acid, an acidic non-steroidal antiinflammatory compound (insufficient for producing gastric lesions at this dose alone) with the addition of one hour of water-immersion stress induced gastric lesions. The addition of 200 mg/kg of mepirizole reduced the ulcer index from 8.1 to 4.7 in the corpus and from 4 to 0.5 in the pyloric antrum. It is suggested that basic antiinflammatory compounds inhibit gastric lesions induced by combination of acidic antiinflammatory compounds and water-immersion stress.

Animals↗
PubMed1998

Biochemical and pharmacological properties of a new proton pump inhibitor, 2-amino-4,5-dihydropyrido[1,2-a]thiazolo [5,4-g] benzimidazole (YJA20379-5).

This study was designed to determine biochemical and pharmacological properties of a newly synthesized benzimidazole derivative, 2-amino-4,5-dihydropyrido [1,2-a] thiazolo [5,4-g] benzimidazole (YJA20379-5) in vitro and in vivo. In the leaky membrane vesicles of pig gastric mucosa, YJA20379-5 inhibited the K(+)-stimulated H+,K(+)-ATPase activity in a concentration- and time-dependent manner, with IC50 values being 43 microM and 31 microM at pH 6.4 and 7.4, respectively. YJA20379-5, given intraduodenally, had a potent inhibitory effect on the gastric acid secretion in pylorus-ligated rats. The ED50 value for acid secretion was 15.4 mg/kg. YJA20379-5, administered orally, also suppressed gastric damages induced by water-immersion stress, indomethacin and ethanol, and duodenal damage induced by mepirizole in rats; the ED50 values were 17.6, 4.7, 3.0 and 18.7 mg/kg, respectively. Furthermore, repeated oral administration of YJA20379-5 accelerated the spontaneous healing of acetic acid-induced gastric ulcers in rats. It is concluded that the antisecretory activity of YJA20379-5 appears to be associated with inhibition of H+,K(+)-ATPase, while its antigastric and antiduodenal lesion activities are primarily related to the antisecretory effect.

Animals↗
PubMed1989

Duodenal ulcers are associated with a depletion of duodenal calcitonin gene-related peptide-like immunoreactivity in rats.

Calcitonin gene-related peptide-like immunoreactivity (CGRP-li) was decreased in duodenal samples from animals treated with ulcerogens such as dulcerozine, cysteamine or mepirizole. The degree of these experimental ulcers was inversely correlated with the levels of duodenal CGRP-li. These findings show that endogenous CGRP may play an important role in duodenal ulcerogenesis.

Animals↗