Evaluation of antidiarrheal potential of trichodesma indicum root extract in rats.

Trichodesma indicum is found as a weed throughout the greater part of India. The decoction of the root is used for diarrhea, dysentery, and fever in Indian traditional medicine. However, the traditional claims need to be validated by suitable experimental animal models. Therefore, this study was undertaken to evaluate its antidiarrheal potential in several animal models. The extract significantly inhibited the castor oil-induced diarrhea and decreased propulsion of charcoal meal through the gastrointestinal tract; it also reduced the castor oil-induced small intestinal fluid accumulation (enteropooling). The ethanol extract of T. indicum root has significant antidiarrheal activity and substantiates the use of this herbal remedy as a nonspecific treatment for diarrhea in folk medicine.

Synthesis of some 1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones with potential analgesic and antiinflammatory activities.

Starting from 3-substituted-1,2,4-triazole-5-thiones (la-h), eight new 5-carbomethoxy-2-substituted-7H-1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones (2a-h) were synthesized and characterized by spectral and elementary analysis. The obtained compounds were submitted to preliminary pharmacological assay to evaluate their antiinflammatory and analgesic activities as well as gastrointestinal irritation liability and acute toxicity. Among the compounds studied, compounds 2c, 2d, 2e and 2h showed most remarkable antiinflammatory activity in the carrageenan and serotonin induced edema and in the inhibition of castor oil-induced diarrhea tests. The analgesic activity of these active compounds correlated with their antiinflammatory activities in the inhibition of acetic acid-induced writhing test. In gastric ulceration studies, the compounds were found safety at low dose levels (10 and 20 mg/kg).

Anti-diarrheal effect of water extract of Evodiae fructus in mice.

Our previous study showed that Evodiae fructus (the dried, unripe fruit of Evodia rutaecarpa) has an inhibitory effect on the intestinal transit (anti-transit effect) in mice. In the present study, a water extract of Evodiae fructus was used to examine its effect on castor oil-induced diarrhea and to compare with its anti-transit effect in mice. The results indicated that Evodiae fructus had both anti-transit and anti-diarrheal effects with comparable ID(50) (the dose for 50% inhibition) values of 54+/-7 and 76+/-17 mg/kg. The time-courses of Evodiae fructus pretreatment for both anti-transit and anti-diarrheal effects were very similar. Because no significant influences of both nitric oxide (NO) precursor L-arginine (600 mg/kg, i.p.) and NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (25 mg/kg, i.p.) pretreatment, the NO system was not involved in both the anti-transit and anti-diarrheal effects of Evodiae fructus. Like Evodiae fructus, a muscarinic acetylcholine receptor antagonist atropine inhibited castor oil-induced increase in fecal weight and loss of body weight. However, the potencies or time-courses of atropine pretreatment for both anti-transit and anti-diarrheal effects were different. Furthermore, the anti-diarrheal effect of atropine was independent of its anti-transit effect at the lower dose (0.5 mg/kg, i.p.). Therefore, the action of Evodiae fructus appeared to be something different from atropine, suggesting that an action other than the anti-muscarinic action, as previously proposed for Evodiae fructus, may be involved.

Cysteamine protects against diarrhoea induced by castor oil. This protective effect can be potentiated by SH-alkylator treatment.

Cysteamine given orally or subcutaneously protects against diarrhoea induced by castor oil. Pretreatment with N-EM, an SH-alkylator, does not influence the occurrence of diarrhoea. Furthermore, N-EM pretreatment does not influence the protective effect of loperamide or difenoxilate. However, N-EM pretreatment potentiates the protective effects of cysteamine or indomethacin against diarrhoea. These findings indicate that sulfhydryl-sensitive processes may also be involved in the mechanisms of diarrhoea.

Effectiveness of nantradol in blocking narcotic withdrawal signs through nonnarcotic mechanisms.

Male rats were made narcotic dependent through continuous intravenous infusion of morphine. During withdrawal, nantradol, clonidine, and morphine were found to block withdrawal signs in a dose-dependent manner. Almost complete alleviation of withdrawal occurred with nantradol or clonidine at 0.16 mg/kg and with morphine at 40 mg/kg. The effectiveness of morphine, but not of nantradol or clonidine, was reversed by naloxone. Likewise, in naive rats given castor oil, naloxone did not block the antidiarrheal effect of nantradol or clonidine. In order to compare possible subjective effects of nantradol with other antiwithdrawal drugs, naive rats were trained to discriminate either morphine, cyclazocine, or clonidine from vehicle by selecting different levers for reinforcement. Nantradol failed to produce any generalization to morphine, cycloazocine, or clonidine, suggesting that this drug does not produce central subjective effects like those of the training drugs. In additional testing in behavioral experiments, nantradol failed to produce any sign of anxiogenic activity.

Dissociation between opiate-like and antidiarrheal activities of antidiarrheal drugs.

Three synthetic antidiarrheals, diphenoxylate, loperamide and SC 27166, and two narcotics, morphine and codeine, were evaluated in rats by the intravenous and oral route for specificity and duration of their antidiarrheal, opiate-like and acute toxic effects. The activity in the castor oil test, the tail withdrawal test and the acute toxicity test was used to determine the relative antidiarrheal specificity and relative safety margins. An analysis of animal and clinical data indicate these tests to be excellent indicators of clinical usefulness and specificity. Intravenously, all five agents induced opiate-like central effects, loperamide and SC 27166 at near toxic doses only. When administered orally loperamide and SC 27166 were devoid of opiate-like central nervous system activity. Analysis of the plasma levels after oral loperamide indicated that this drug does not attain a concentration high enough to induce opiate-like central effects. All agents were effective antidiarrheals by the oral route with loperamide being the most potent (ED50 = 0.15 mg/kg), longest acting (ED50 8 hr = 1.81 mg/kg) and most specific (relative antidiarrheal specificity, 8 hr greater than or equal to 88) and having the greatest relative safety margin (8 hr = 102).

Comparative pharmacology of a 1:10 combination of indomethacin-sodium salicylate.

It has been found that gastrointestinal side-effects of indomethacin could be abolished when administered in combination indomethacin:sodium salicylate (ratio 1:10). In this paper comparative pharmacological data of this combination and its basal compounds are presented. Acute toxicity of the combined preparation was 72 times less in rats than that of indomethacin alone. All therapeutic indexes were markedly increased in the combination of indomethacin-sodium salicylate compared with the separate drug treatments.

Delay of castor oil diarrhoea in rats: a new way to evaluate inhibitors of prostaglandin biosynthesis.

Forty-four non-steroidal anti-inflammatory compounds were tested for possible effects on castor oil-induced diarrhoea in rats. A small but significant delay of intestinal evacuations was found with all compounds. Quantitatively, the oral doses required to delay diarrhoea beyond the first hour after castor oil challenge reflected the acute anti-inflammatory potency of the tested compounds. Qualitatively, the evolution of the effective doses with increasing delay was linear for potent inhibitors of prostaglandin biosynthesis. The evolution for less potent compounds was markedly different and suggested the earlier occurrence of non-specific drug effects. Suprofen, the most potent of the series of compounds, produced the 1 h delay at an oral dose of 1.11 mg kg-1; the ED50 increased linearly to 115 mg kg-1 for a 4 h delay. Compared with other compounds the activity pattern of suprofen was consistent with that of a very potent, short-acting inhibitor of prostaglandin biosynthesis, which maintains its specific action over a wide dose range. It is concluded that delay of castor oil-induced diarrhoea in rats allows a detailed characterization of aspirin-like compounds, and that inhibition of prostaglandin biosynthesis is insufficient to suppress the intestinal effects of the oil.

The narcotic discriminative stimulus complex: relation to analgesic activity.

The ability of drugs to produce the narcotic discriminative stimulus complex is found to be highly correlated with their analgesic activity; in contrast, no relation with their antidiarrhoeal activity is evident. The findings suggest that the narcotic discriminative stimulus complex is a centrally mediated effect of narcotic drugs.

Loperamide antagonism of castor oil-induced diarrhea in rats: a quantitative study.

The time-course of castor oil-induced diarrhea in fasted rats was quantified by weighing stools every 15 minutes for 8 hours after the challenge and then after 24 hours. Diarrhea began within 1 hour as a series of rapidly occurring evacuations over 20 to 40 minutes. The mean weight of these stools was 5.7 g; later irregular evacuations increased the weight to 9.4 g at 8 hours. The area of individual time-weight diagrams had a median value of 432 units. Pretreatment with 0.16 mg/kg of loperamide, a new antidiarrheal drug, significantly decreased the area of similarly obtained diagrams; 0.31 mg/kg caused a 50% reduction. This antagonism by loperamide of castor oil-induced diarrhea may involve reduction in the severity of inflammatory changes in the intestinal wall.