SC-29333: A potent inhibitor of canine gastric secretion

Dajani, Esam Z.; Driskill, Doyle R.; Bianchi, Robert G.; Collins, Paul W.; Pappo, Raphael

doi:10.1007/bf01071862

Cited by 75 publications

(11 citation statements)

References 21 publications

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“…(a) Misoprostol possesses gastric antisecre tory properties and effectively inhibits basal and stimulated (meal, histamine, betazole, coffee and tetragastrin) gastric secretion in animals [32,33] and in man [34], The reduc tion of intraluminal acidity removes one ag gressive factor involved in the pathogenesis of peptic ulcer disease.…”

Section: Synthetic Prostaglandinsmentioning

confidence: 99%

Prevention of IMonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Ulcers: Role of Mucosal Protective and Gastric Antisecretory Drugs

Dajani

Agrawal²

1995

Dig Dis

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One of the most serious side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is upper gastrointestinal mucosal damage that may result in erosions, ulcerations and other serious complications. NSAIDs reduce endogenous prostaglandins, and this reduction is relevant to their pharmacology and toxicity. The stomach and to some extent the duodenum are the major organs involved in the mucosal toxicity of NSAIDs. With the availability of the synthetic prostaglandin misoprostol, it has become possible to prevent NSAID-induced gastroduodenal ulcers without compromising the beneficial antirheumatic and analgesic effects of NSAID therapy. In fact, misoprostol is the only drug with established long-term efficacy in preventing NSAID-induced gastroduodenal ulcers in rheumatic patients. The purpose of this communication is to critically review the efficacy of gastric antisecretory drugs, mucosal protective drugs and misoprostol when used for the prevention of NSAID-induced ulcers, considering only data from well-controlled, randomized, double-blind clinical studies. The histamine H₂-receptor antagonist ranitidine has been shown to be effective in preventing NSAID-induced duoenal ulcers, but has no efficacy in preventing NSAID-induced gastric ulcers. In a direct comparative trial with ranitidine, misoprostol (200 µg qid) was significantly more effective than ranitidine (150 mg bid) in preventing gastric ulcers in chronic NSAID users. The inactivity of ranitidine in preventing gastric ulcers indicates that the pathogenesis of NSAID-induced gastric ulcers is not related to gastric acid. Limited but conflicting data exist with omeprazole. The mucosal-coating drug sucralfate has not been found effective in preventing NSAID ulcers. In fact, in a direct comparative trial, misoprostol (200 µg qid) was significantly more effective than sucralfate (1 g qid) in preventing gastric ulcers in patients receiving chronic NSAID therapy. No meaningful data exist with organic bismuth salts, a group of drugs which has mucosal coating and protective properties. From this brief overview, we conclude: (1) mucosal-coating compounds have no therapeutic role in preventing NSAID-induced ulceration; (2) gastric antisecretory drugs are not effective in preventing NSAID-induced gastric ulcers, and (3) misoprostol is the only antiulcer drug proven to be effective for preventing NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAID. Misoprostol represents a major therapeutic advance for the management of NSAID-induced mucosal injury.

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Section: Synthetic Prostaglandinsmentioning

confidence: 99%

Prevention of IMonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Ulcers: Role of Mucosal Protective and Gastric Antisecretory Drugs

Dajani

Agrawal²

1995

Dig Dis

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“…Natural and synthetic PGs have been shown to be potent inhibitors of gastric acid secretion and offer protection against peptic ulcers in animals and humans (26)(27)(28)(29)(30)(31). PG induced cytoprotective effects may involve increased blood flow (32,33), bicarbonate secretion (34), mucus release (35), restoration of active sodium transport (36), decrease in back diffusion of acid or local stimulation of surface-active phospholipids (37), and maintenace of normal mucosal levels of DNA, RNA or protein (38).…”

Section: Discussionmentioning

confidence: 99%

Different modes of inhibition of rat gastric mucosal 6-keto-PGF1.ALPHA. production by indomethacin, aspirin and aminopyrine.

Nishikawa¹,

Tomori

Yamashita

et al. 1989

Jpn.J.Pharmacol

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Abstract-The actions of aminopyrine on rat gastric mucosal cyclooxygenase activity in vitro were investigated and compared with those of the cyclooxygenase the back-diffusion of H+ through the mucosa, increased the loss of H+ from the lumen, and consequently reduced H+ secretion. The analgesic, antipyretic and anti-inflam matory properties and the PG synthesis inhibiting activities of these drugs have been extensively studied, but little is known about the mechanisms underlying ulcerogenesis in the gastrointestinal tract. The present study compared the effects of aminopyrine, in domethacin and aspirin on rat gastric mucosal cyclooxygenase activity under various experi mental conditions in order to try to establish the mechanisms of ulcerogenesis. Materials and MethodsPreparation of enzyme: Male Wistar rats weighing 150-250 g were killed by ex sanguination after a blow on the head. Following removal of their stomachs, mucosal sections were prepared by separating the overlying muscle by blistering (15). This pro cedure involved inserting the tip of a fine needle (26 gauge) between the muscle and mucosa and injecting 20 mM Tris-HCI buffer (pH 7.4). The raised muscle layer was then carefully cut away. The parts of the mucosal membranes were gently homogenized (200 rpm/min) in a glass-Teflon homogenizer with ten volumes of 50 mM potassium phosphate buffer (pH 7.4). All procedures were perfor med at 0-3'C. The homogenates were used as the source of the enzyme (cyclooxy genase). The enzyme was incubated at 37°C for 6 min, after which the enzyme activity was stopped by addition of 50 Id of ice-cold 2 M citric acid. The mixture was centrifuged at 20,000 g for 10 min at 0-3°C and then assessed for the production of 6-keto-PGF1a (the stable breakdown product of PG12) using radioimmunoassay kits (16). The results were expressed as ng (6-keto-PGF1a)/mg mucosal protein and as the percentage of inhibition of the control value. Mucosal protein concen tration was determined by the method of Lowry et al. (17) with bovine serum albumin as a standard.Reaction medium: Unless otherwise stated, determination of cyclooxygenase activity was carried out at 37°C in a 1-ml reaction mixture of arachidonic acid (2 x 10-5 M), enzymes (0.7 mg gastric mucosal protein/ml), hy droquinone (4x10-4 M), glutathione (5x10-4 M), various concentrations of indomethacin, aspirin or aminopyrine, ethanol (1.0%, v/v) and potassium phosphate buffer (50 mM, pH 7.4). The pH value of the incubation medium was always confirmed to be pH 7.4 before the start of incubation or pre-incubation.Ethanol, used as a solvent for arachidonic acid and inhibitors, had no effect on the reaction at the final concentration (2.0%, v/v) employed. Effects of indomethacin, aspirin and aminopyrine on cyclooxygenase activity under different experimental conditions: The inhi bition of cyclooxygenase by indomethacin, aspirin and aminopyrine was studied under the following three incubation conditions: a) Inhibitors (indomethacin, aspirin and aminopyrine) and arachidonic acid were simultan...

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“…Stability was achieved through methylation of carbon 15 or 16 to block the metabolic oxidation of the 15-hydroxy group. T h e resulting analogues were orally active with prolonged gastric antisecretory effect (38,39). Specificity for parietal cell receptors was achieved by transposing the hydroxy group in PGE from position 15 to 16. T h e resulting compound (15-deoxy, 16-hydroxy PGE, methyl ester) was approximately equipotent with its parent compound, PGE, methyl ester, in its gastric antisecretory action.…”

Section: Introductionmentioning

confidence: 99%

Misoprostol—a Logical Therapeutic Approach to Gastroduodenal Mucosal Injury Induced by Non-Steroidal Anti-Inflammatory Drugs?

Fenn¹,

Robinson²

1991

J Clin Pharm Ther

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SUMMARYMisoprostol is a synthetic analogue of naturally occurring prostaglandin El.T h e basis of the damaging actions of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract is believed to be a consequence of two events: a direct damaging action on mucosal integrity and depletion of endogenous mucosal prostaglandins (PGs). Due to the latter effect, and because current evidence indicates that PGs play an important role in maintaining the integrity of the G I tract, misoprostol has been developed as a logical therapy to prevent and heal gastric and duodenal damage caused b y NSAIDs. T h e purpose of this review is to consider the need for such a therapy, to describe its pharmaceutical development, to review its pharmacology and to review its efficacy compared with other available agents.

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SC-29333: A potent inhibitor of canine gastric secretion

Cited by 75 publications

References 21 publications

Prevention of IMonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Ulcers: Role of Mucosal Protective and Gastric Antisecretory Drugs

Prevention of IMonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Ulcers: Role of Mucosal Protective and Gastric Antisecretory Drugs

Different modes of inhibition of rat gastric mucosal 6-keto-PGF1.ALPHA. production by indomethacin, aspirin and aminopyrine.

Misoprostol—a Logical Therapeutic Approach to Gastroduodenal Mucosal Injury Induced by Non-Steroidal Anti-Inflammatory Drugs?

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