The antiulcer and autonomic pharmacology of pyridyl-2-thioacetamide (CMN 131)

Pyridyl-2-thioacetamide-CMN 131-possess high ulcer-protective activity which seems closely related to its gastric antisecretory properties previously described. This activity is demonstrated using experimental models whose ulcerogenic stimulus can be related to various origins: 4-hr and 24-hr restraint stress ulcers and aspirin or phenylbutazone gastric erosions in rats, histamine-induced ulcers in guinea pigs, reserpine-induced ulcers in cats. In the same dose range used in the ulcer study, and even at higher doses, CMN 131 fails to show any systemic activity on the cholinergic or adrenergic pathway. At a systemic level no antihistaminic, antiserotonin, or ganglion properties can be observed either. Furthermore, CMN 131 modifies neither the salivary and lacrymal secretions, nor the gastric emptying or the blood pressure. Finally, CMN 131 can be considered an original pharmacological agent whose wide antiulcer and antisecretory properties could enable us to understand more clearly the intrinsic mechanism of gastric secretion.     

Gastric antisecretory activity of arbaprostil as affected by gastric pH

Arbaprostil [15(R), 15-methyl prostaglandin E₂] is inactive. In the presence of acid it is converted to the active 15(S) configuration. The degree of acidity needed for the conversion is not known. We inferred the degree of conversionin vivo in man at different gastric pHs by administering arbaprostil to normal volunteers whose gastric pH was maintained constant at various levels by intragastric titration. A pH-dependent inhibition of gastric acid secretion after stimulation with a peptone meal was observed, with 100 g inhibiting 98% of acid production at pH 2, but only 15% at pH 6. Significant gastric acid inhibition occurred with the gastric pH at, or less than, 5.     

The treatment of gastric ulcer with antisecretory drugs

Published clinical trials (N = 56) of antisecretory drugs in the treatment of benign gastric ulcer were reviewed. Composite healing rates for various drug regimens were calculated using a method previously described for duodenal ulcer. Healing rates were compared with data on suppression of intragastric acidity to see if any relationship was evident. No significant correlations between the two existed, unless placebo data were included in the analysis. Correlations were stronger with suppression of total 24-hr rather than nocturnal acidity. Using Williams' method for assessing trends, it was found that an increase in antisecretory effect is not associated with a concomitant increase in healing rates. Duration of medical treatment is the single most important factor in healing of benign gastric ulcer; healing rates for all drug regimens and placebo show a consistent increase with prolongation of treatment.     

Oral antisecretory activity of prostaglandin E2 in man

We studied the oral gastric antisecretory activity of prostaglandin E₂ in three groups of six normal volunteers. Each volunteer was studied twice, once after receiving prostaglandin E₂ (0.5, 1.0, or 2.0 mg) and the other time after receiving placebo administered in a double-blind, randomized fashion. Gastric acid secretion was stimulated with a liquid protein meal from 1/2 to 1 1/2hr after drug administration. Acid secretion was quantitated using the technique of intragastric titration. Acid secretion after 0.5 mg of prostaglandin E₂ was no different than after placebo administration, but 1.0 mg and 2.0 mg of prostaglandin E₂ inhibited 58% (6.68±7.64 meq vs 14.67±6.75 meq, P<0.02) and 76% (2.38±2.38 meq vs 11.50±3.51, P<0.01) respectively, of gastric acid production compared to placebo therapy. After oral administration, prostaglandin E₂ in man is antisecretory with an ED₅₀ of 1.1 mg.     

Expression of gastric antisecretory and prostaglandin E receptor binding activity of misoprostol by misoprostol free acid

In enriched canine parietal cell preparations, misoprostol, an analog of prostaglandin E1 methyl ester, was rapidly deesterified to misoprostol free acid. Under this circumstance, misoprostol and misoprostol free acid exhibited equal antisecretory potency against histamine-stimulated acid secretion and bound equally well to prostaglandin E receptors. When the deesterification of misoprostol was inhibited by paraoxon, an esterase inhibitor, the antisecretory and receptor binding activity of misoprostol was markedly reduced, with potency much less than misoprostol free acid. These results indicate that misoprostol free acid is the active biological form of misoprostol that binds to prostaglandin E receptors and mediates the antisecretory action of misoprostol.     

Efficacy of a new antisecretory agent (40 749 RP) on human gastric secretion induced by a meal (intragastric titration)

An antisecretory drug of a new series, 40 749 RP, without anticholinergic or H2 receptor antagonist activities, was tested on meal-induced gastric acid secretion in 6 healthy volunteers. Gastric acid secretion and emptying of liquid were measured using intragastric titration. Oral dosages tested were 1, 2 and 4 mg/kg versus placebo. Inhibitions obtained were dose-related and expressed in percentage of the placebo values: 36 +/- 10 p. 100 for 1 mg/kg; 51 +/- 13 p. 100 for 2 mg/kg and 83 +/- 5 p. 100 for 4 mg/kg. Statistically significant correlation (p less than 0.001) was observed between maximal blood concentration of 40 749 RP and the percentage of secretory inhibition during the 90 min of the test. No change in gastrin response or in gastric emptying was observed whatever the dose.     

Maytenus erythroxylon Reissek(Celastraceae) ethanol extract presents antidiarrheal activity via antimotility and antisecretory mechanisms

AIM To investigate the acute toxicity,phytochemical profile,antidiarrheal activity and mechanisms of action of Maytenus erythroxylon(M.erythroxylon)ethanol extract.METHODS A castor oil-induced diarrhea model was used to evaluate antidiarrheal activity.Intestinal transit and gastric emptying protocols were used to evaluate a possible antimotility effect.KATP channels,nitric oxide,presynapticα2-adrenergic and tissue adrenergic receptors were investigated to uncover antimotility mechanisms of action and castor oil-induced enteropooling to elucidate antisecretory mechanisms.RESULTS All tested doses of the extract(62.5,125,250 and 500 mg/kg)possessed antidiarrheal activity,with a significant decrease of the evacuation index.This activity is possibly related to a reduced gastric emptying(125,250 and 500 mg/kg)and to a decreased percentage of intestinal transit for all tested doses.That last effect seems to be modulated by nitric oxide,KATP channels and tissue adrenergic receptors.Besides,the extract also presented antisecretory effect due to a decrease of intestinal fluid accumulation.CONCLUSION The antidiarrheal effect of M.erythroxylon found in this study involves antimotility and antisecretory mechanisms that may be attributed to the chemical compounds found in this species:saponins,flavonoids,tannins,triterpenes and steroids.     

Healing of gastric body ulcer with gastroprotective versus antisecretory treatment

The aim of this study was to compare the healing effect of a gastroprotective agent and antisecretory drugs in gastric body ulcer where failure of the mucosal defense might be an important factor. Eighty-five patients with benign gastric ulcer were divided into four groups: treated with antacids (I), cimetidine (II), ranitidine (III), and colloidal bismuth subcitrate (De-Nol) (IV). Endoscopically confirmed complete healing was achieved in 57, 61, and 63% in groups I, II, and III, respectively, and in 88% in group IV (P<0.05). Gastric secretion did not change significantly. Relapses during the next three years occurred several times more frequently in groups I, II and III than in group IV.Helicobacter pylori was positive in about half the relapsing patients in groups I, II, and III but negative in those of group IV. It is concluded that De-Nol treatment of gastric body ulcer was more efficient than antisecretory drugs both initially and in reducing relapses.     

Gastric antisecretory and antiulcer activity of bovine hemoglobin

AIM: To investigate gastric antisecretory and gastro- protective activity of bovine hemoglobin (B-Hb) in rats. METHODS: Adult Albino-Wistar rats were divided into groups of 6 animals each. B-Hb in doses of 100, 300 and 900 mg/kg body weight was tested for gastric acid secretion and antiulcer activity. Gastric secretions were measured 6 h after pylorus ligation in rats pretreated with B-Hb. The acidity was measured by titrating gastric contents against 0.01 mol/L NaOH to pH 7. Indomethacin ulcers were produced by oral administration of 30 mg/kg bw in the rats pretreated with B-Hb one hour before indomethacin. Six hours after indomethacin stomach removed and ulcer index was recorded. Ethanol ulcer were produced by 1 mL of ethanol in the rats pretreated with B-Hb 30 min before the ethanol.One hour after ethanol stomach were cut open to score ulcers. Histological examination and analysis of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), and myeloperoxidase (MPO) were carried in gastric tissue following ethanol administration. RESULTS: In control rats pylorus ligation for 6 h resulted in the accumulation of 8.1 ± 0.61 mL of gastric secretion. The treatment of the rats with 100, 300 and 900 mg/kg of B-Hb produced a significant decrease in the volume of gastric secretion 5.6 ± 0.63, 5.5 ± 0.75 and 4.7 ± 0.58 mL respectively as compared to the control group [analysis of variance (ANOVA) F = 4.77, P < 0.05]. The lesion area in the control group was found to be 22.4 ± 3.2 mm2 six hours after the administration of indomethacin. Treatment of rats with B-Hb at doses of 100 mg/kg (24.3 ± 3.29 mm2), 300 mg/kg (16.2 ± 1.45 mm2) and 900 mg/kg (12.6 ± 1.85 mm2) produced a dose dependent decreased the lesion scores (ANOVA F = 4.50, P < 0.05). The ulcer index following one hour after 1 mL ethanol was 7.1 ± 0.31. Pretreatment of rats with B-Hb at the doses of 100 mg/kg (2.5 ± 0.42), 300 mg/kg (2.1 ± 0.4) and 900 mg/kg (0.7 ± 0.21) significantly inhibited the formation of gastric lesions (ANOVA F = 63.26     

~(131)I标记槲皮素的方法

目的探索131I标记槲皮素的方法并对其相关实验进行研究。方法用氯胺T法对槲皮素进行131I标记,对标记产物用薄层色谱法分析其标记率及放化纯,产物于37℃温育以观察其体外稳定性,用甲状腺癌细胞FTC-133/8505C观察其生物活性。结果氯胺T法为最佳标记方法,标记率达96.5%,放化纯达98.3%。产物在体外稳定。结论用氯胺T法对Qu进行131I标记简单高效,稳定性好,且标记产物生物活性未受到明显破坏。     

Localization of central prostaglandin E2 antisecretory effects

Intracerebroventricular prostaglandin E2 (PGE2) inhibits stimulated gastric acid secretion; however, the central site of action is unknown. Specific PGE2 binding sites have been localized to the ventromedial hypothalamic nucleus and central amygdala (A). The nuclear accumbens has been shown to play a role in central neurotensin-induced antisecretory effects. These studies tested the hypothesis that microinjections of PGE2 into the ventromedial hypothalamic nucleus, central amygdala, and nuclear accumbens inhibit stimulated gastric acid secretion. The hippocampus served as a cerebral control region. Two days before the experiments, metal cannulas were stereotaxically positioned bilaterally into specific areas of the brain, and metal gastric cannulas were operatively implanted, under nembutal anesthesia, in male 250-g Sprague-Dawley rats. On the experimental day, the rats, fasted for 14 hours, were given saline or PGE2 (0.1-1.0 micrograms in 0.2 microL/side) through the central cannulas 10 minutes before administering pentagastrin (40 micrograms/kg SC). Gastric secretion was measured at 30-minute intervals and expressed as acid output, micromoles per hour. Acid output (mean +/- SE) in control animals was 161 +/- 14 mumol/h. Prostaglandin E2 administration at doses of 0.10, 0.50, and 1.0 micrograms/side (a) into ventromedial hypothalamic nucleus reduced acid output to 53 +/- 11,* 36 +/- 10,* and 27 +/- 11* mumol/h regularly; (b) into NACB reduced acid output to 157 +/- 36, 60 +/- 12,* and 38 +/- 12* mumol/h; and (c) into A reduced acid output to 144 +/- 31, 141 +/- 26, and 90 +/- 19* mumol/h, respectively (*P less than 0.05 by Neuman-Keuls test). Prostaglandin E2 (0.50 micrograms/side) administration into hippocampus had no significant effect on acid output (134 +/- 28 mumol/h). Although central PGE2 administration was associated with hyperthermia, this occurred at lower doses than those required to inhibit acid secretion. Prostaglandin E2 administration into specific brain areas known to have PGE2 receptors, the central amygdala and ventromedial hypothalamic nucleus, and into nuclear accumbens inhibits stimulated gastric acid secretion. These observations suggest that PGE2 may have a physiological role in the central control of gastric acid secretion.     

(131)I and thyroid-associated ophthalmopathy

OBJECTIVE: Radioiodine ((131)I) used to obtain euthyroidism in thyrotoxic patients is suspected of having a worsening or provoking effect on thyroid-associated ophthalmopathy (TAO), an autoimmune disease closely related to Graves' disease. DESIGN: This review summarises the existing literature and describes risk factors influencing the course of TAO including thyroid function, cigarette smoking and treatment of Graves' hyperthyroidism (especially (131)I therapy). CONCLUSION: It is recommended that patients who may be at a greater risk of worsening ophthalmopathy are considered when choosing the modality of therapy of hyperthyroidism and also in deciding whether prophylactic systemic glucocorticoid treatment is indicated.     

Evidence that gastric antisecretory action of lipopolysaccharide is not due to a toxic effect on gastric parietal cells

We have recently found that bacterial lipopolysaccharide (LPS) or endotoxin at minute doses inhibits the secretion of gastric acid and pepsin in rats. The present study was performed to determine whether this antisecretory action of LPS was a reversible biological response or a result of the destruction of gastric parietal cells by endotoxin. The intraperitoneal injection of LPS into pylorus-ligated rats resulted in a dose-related (40-4000 ng/kg) decrease in gastric acid secretion, with maximal inhibition being observed at a dose of 4000 ng/kg. The stomach then was examined both macroscopically and microscopically for the presence or absence of mucosal lesions or damaged gastric parietal cells. No morphological changes in the gastric mucosal structure including parietal cells were observed even in the rats injected with 4000 ng/kg of LPS. Next, basal gastric acid output was compared in the rats that had received LPS (4000 ng/kg, intraperitoneal) or saline alone 24 hr before. There was no significant difference in gastric acid secretion between the saline- and LPS-pretreated groups, indicating that the secretory capacity of gastric parietal cells returned to the control level at 24 hr after the injection of a maximal antisecretory dose of LPS. These results clearly suggest that the LPS-induced inhibition of gastric secretion results not from its toxic or destructive effect on the gastric secretory mechanism but from its reversible biological effect on gastric physiology.     

Acute and chronic 24-hour gastric pH and pharmacokinetic studies with a long acting antisecretory drug (40749 RP) in peptic ulcer

The purpose of this work was to compare the effects of a long acting antisecretory drug on 24-h gastric acidity after acute and chronic administration and to correlate the results observed with modifications of pharmacokinetic parameters. 40749 RP is a carbothioamide derivative antisecretory drug with a non anti H2, non anticholinergic mechanism of action. Eleven patients with an endoscopically proven duodenal ulcer received 100 mg of 40749 RP at 8 PM for 3 wk and thereafter a placebo for an additional 3 wk study period. At the end of the active drug treatment period all patients but one had healed. Continuous 24-h gastric pH recordings performed after the first and the last dose of 40749 RP showed a strong and yet still increasing acid inhibition, nine patients being nearly achlorhydric (i. e. pH greater than 3) during night at the end of treatment. Variations of acid inhibition between the start and the end of treatment were significantly correlated with modifications of pharmacokinetic parameters. Eight days after discontinuation of 40749 RP, basal acid secretion remained strongly inhibited. However at the end of the placebo period, endoscopy showed ulcer relapse in 4 patients (previously resistant to H2-blockers). These results confirmed that 40749 RP is a powerful and very long-acting antisecretory drug. They showed that the antisecretory effects of a long-acting drug should be assessed in conditions of chronic administration when therapeutic dose and regimen are to be determined.