Polymeric delivery of the active isomer of misoprostol reduces systemic availability and uterotonic activity.

SC-30249 is the active isomer of misoprostol responsible for its mucosal protective effects against nonsteroidal anti-inflammatory drugs (NSAIDS). Linkage of SC-30249 to a polybutadiene polymer results in a delivery system (SC-55307) that releases the active component only under the acidic conditions of the stomach. This approach could be used to minimize side effects and systemic availability of synthetic prostaglandins. These studies were done to determine whether uterotonic activity could be recorded after treatment with SC-55307. Female beagles were implanted with uterine strain gauge force transducers, allowed 10 days for recovery and treated with estrogen to sensitize the uterus to the actions of prostaglandins. Base-line responses were determined with SC-30249, i.v., and then a randomized series of four treatments were given: SC-30249, IG, 10 micrograms/kg; SC-55307, IG, equivalent to 30 and 100 micrograms/kg of SC-30249; and a blank polymer control. HCI was given IG to provide an acid environment in the stomach, uterine responses were obtained for up to 4 h and plasma concentrations of SC-30249 free acid was determined. No uterotonic effect was seen after a low dose of SC-55307, whereas the high dose caused a brief but statistically significant increase equal to 8.8% and 17.8% of the responses to SC-30249, i.v. and IG, respectively. Peak plasma levels of SC-30249 free acid were 176.4 +/- 17.4 and 59.5 +/- 10.6 pg/ml after SC-30249, i.v. and IG, respectively, but were only 3.9 +/- 1.7 and 15.5 +/- 6.6 pg/ml after low and high doses of SC-55307, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

SC-49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism.

SC-49518 (N-[exo-(hexahydro-1H-pyrrolizine-1-yl)methyl]-2-methoxy-4- amino-5-chlorobenzamide HCl), a new benzamide gastrointestinal prokinetic compound, was investigated to determine its ability to stimulate gastrointestinal motility in vivo and whether these actions could be mediated by agonist activity at the putative 5-hydroxytryptamine (5-HT)4 receptor. In conscious fasted dogs with strain gauge transducers and myoelectrodes, SC-49518 disrupted gastric and small intestinal migrating motility complex cycling for more than 3.5 hr. It stimulated gastric antral contractile and intestinal myoelectric spike burst activities during the normally quiescent Phase I of the migrating motility complex at doses as low as 0.01 and 0.03 mg/kg i.v., respectively. In a canine model of gastroparesis, SC-49518 reversed completely alpha-2 adrenergically delayed gastric emptying of a solid meal with an ED50 value of 0.1 mg/kg intragastrically and partially reversed delayed emptying of a liquid meal. SC-49518, like 5-HT, cisapride and renzapride, acted as an agonist (EC50 = 6.6 +/- 1.1 x 10(-8) M) at the putative 5-HT4 receptor in rat esophageal tunica muscularis mucosae by relaxing carbachol-induced contractions. SC-49518 was a partial agonist at 5-HT4 receptors, but also blocked high affinity (5-HT4-mediated) responses to 5-HT (10(-9) M to 3 x 10(-7) M) in guinea pig ileum with a pA2 value of 8.39.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs.

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid pH enhances the effects of taurodeoxycholate on water and solute transport in the human and rat jejunum.

The relative rate of unspecific binding of bile acids to brush border membrane vesicles resembles their relative potencies as intestinal secretagogues. This interaction of bile acids with brush border membranes is enhanced in an acid environment. We, therefore, studied the effects of taurodeoxycholate and taurocholate on water and solute transport at pH 7.6 and pH 4.0 in the human and rat jejunum. Five mM taurodeoxycholate induced significantly greater fluid secretion in the human jejunum at pH 4.0 than at pH 7.6 (p less than 0.02; n = 5), 10 mM taurocholate (n = 4) had no effect at either pH. In the rat 15 mM taurodeoxycholate at pH 4.0 induced greater fluid secretion (p less than 0.01; n = 6), released more phospholipid (p less than 0.001; n = 4) and enhanced absorption of mannitol more than at pH 7.6 (p less than 0.05; n = 6). In contrast fluid secretion and release of phospholipids induced by Triton X-100 were not affected by pH (n = 6), nor was fluid secretion induced by cholera toxin (n = 8). The data suggest that the enhancement of the secretory effect of taurodeoxycholate in an acid environment is due to its increased interaction with the mucosal surface, and support the concept that the ability of detergents to interact with the intestinal brush border membrane determines their effectiveness as intestinal secretagogues.

Effects of auranofin and myochrysine on intestinal transport and morphology in the rat.

Auranofin (SKF-D 39162) is an oral gold preparation for the treatment of rheumatoid arthritis. One of its major side effects is diarrhoea. To determine one possible mechanism for this we compared the effects of auranofin and myochrysine on intestinal water and solute transport in the rat. Jejunal perfusion with 2 mM auranofin (n = 5) induced fluid and electrolyte secretion and inhibited glucose absorption (p less than 0.01). Auranofin (0.2 mM) induced fluid secretion in the jejunum (n = 5; p less than 0.01) and colon (n = 6; p less than 0.01). In contrast, 2 mM myochrysine enhanced jejunal water and electrolyte absorption (n = 6; p less than 0.02). Both compounds enhanced absorption of mannitol (p less than 0.01). Perfusion of 0.2 mM auranofin for two hours had no significant effect on mucosal c-AMP levels (n = 4). After perfusion for two hours with 2 mM auranofin the jejunal mucosa showed severe injury by light and scanning electronmicroscopy while myochrysine had no apparent effect. The damage after perfusion with 0.2 mM auranofin for two hours was less severe. Auranofin was more rapidly absorbed than myochrysine (p less than 0.05). These effects provide an explanation for the diarrhoea associated with auranofin therapy.

Effects of sulfodeoxycholate on rat and rabbit small intestine.

To determine how sulfation alters the biological properties of dihydroxy bile acids, we compared the effects of 3-sulfodeoxycholate (SDC) and deoxycholate (DC) in the rat and rabbit intestine. While 5 mM DC induced water and electrolyte secretion and inhibited glucose absorption in the rat, SDC enhanced jejunal and ileal water and solute absorption. SDC had no effect in the rabbit ileum. In the rat jejunum DC caused mucosal injury and enhanced mucosal permeability while SDC had no effect. In vitro in the rabbit ileum, 10 mM SDC enhanced net sodium flux and decreased net residual flux, while 0.5 mM DC reduced net sodium flux and induced Cl- secretion. Both bile acids increased short-circuit current and potential difference and decreased tissue conductance. During reversed-phase, high-performance liquid chromatography SDC was more polar than DC. Sulfation reduced the ability of DC to destroy large unilamellar liposomes by a factor of 10. Thus, sulfation abolishes the effects of DC on the intestine by enhancing the polarity of this molecule. The enhancement of intestinal solute and water absorption by SDC requires further study.

Effects of amphotericin B and cholera toxin on intestinal transport in the rat. An in vivo model for the effects of dihydroxy bile acids and fatty acids on intestinal transport.

In vivo perfusion experiments were performed in the rat jejunum and colon to test the hypothesis that the changes in intestinal solute transport induced by dihydroxy bile acids and fatty acids are the result of the combined effects of fluid secretion and enhancement of mucosal permeability. The hypothesis predicts that absorption of organic solutes will be reduced in inverse relationship to the absorption rates under control conditions and that absorption of small, nonabsorbable solutes such as mannitol will be enhanced by these agents. Fluid secretion was induced either by administering cholera toxin or by increasing the osmolality of the perfusion solution to 365 mOsm/L. Permeability was enhanced by adding amphotericin B, 50 micrograms/ml, to the perfusion solutions. The isotonic perfusion solutions contained 11.2 mM glucose and 4 mM triethylene, tetraethylene, pentaethylene, and hexaethylene glycol or mannitol as probes of passive permeability. In the jejunum cholera toxin induced fluid and electrolyte secretion and reduced organic solute absorption to a small but significant degree (p less than 0.05). Amphotericin B alone enhanced absorption of organic solutes, water, and electrolytes (p less than 0.01). In the presence of fluid secretion induced by an osmotic load, only absorption of triethylene and pentaethylene glycol was reduced. Addition of amphotericin B after exposure to cholera toxin or to the hypertonic solutions resulted in a further significant reduction of absorption of glucose and ethylene glycols (p less than 0.05). The combination of amphotericin B and cholera toxin resulted in enhanced absorption of mannitol (p less than 0.02). Similarly, 5 mM deoxycholate enhanced jejunal absorption of mannitol (p less than 0.01) and reduced the absorption of glucose and the low-molecular-weight ethylene glycols (p less than 0.01). In the colon the administration of amphotericin B after the exposure to cholera toxin resulted in enhanced absorption of glucose (p less than 0.05) in spite of continuing fluid secretion. The combination of fluid secretion and enhancement of mucosal permeability, therefore, reproduced all in vivo effects of bile acids and fatty acids on intestinal transport of organic solutes.