zy-17617b and Diarrhea

This article presents a review of causes, presentation, and diagnosis of traveler's diarrhea. Treatment and prevention of this common problem is described in some detail. Finally, a practical and cost-effective approach to evaluating and treating a returning traveler is presented.

Topics: Adolescent; Adult; Antidiarrheals; Aztreonam; Benzimidazoles; Diarrhea; Humans; Infant; Loperamide; Monobactams; Travel

The present study was undertaken to compare the efficacy of a new calmodulin antagonist, zaldaride maleate, with that of placebo or loperamide in persons with traveler's diarrhea. One hundred seventy-nine patients were randomized to receive loperamide (4 mg followed by 2 mg after each unformed stool), zaldaride maleate (20 mg four times per day), or placebo. During the initial 48 hours of therapy, zaldaride maleate decreased the number of unformed stools by 30% and the duration of illness by 23% when compared with placebo. Loperamide was superior to both zaldaride maleate and placebo during the initial hours of treatment. However, after 48 hours of treatment, loperamide and zaldaride maleate were equally efficacious, decreasing by > 50% the number of unformed stools passed in a 24-hour interval (P, not significant), and were both superior when compared with placebo (P < .0001 and P = .0048, respectively). The apparent superiority of loperamide early in the course of therapy appeared to be related to a loading-dose effect and not to any differences in antidiarrheal properties.

Topics: Acute Disease; Adult; Antidiarrheals; Bacteria; Benzimidazoles; Calmodulin; Diarrhea; Double-Blind Method; Feces; Female; Humans; Loperamide; Male; Mexico; Travel; Treatment Outcome

To compare zaldaride maleate, a calmodulin inhibitor with gastrointestinal antisecretory properties, with loperamide and a placebo in the treatment of travellers' diarrhoea.. Randomized, double-blind, double-dummy study.. Study clinic staffed by European residents on Nile cruise ships.. Tourists (n = 436) who acquired travellers' diarrhoea during the Nile cruise.. (1) Zaldaride 20 mg four times daily, (2) zaldaride 2 x 20 mg as initial loading dose followed by three doses of 20 mg on the first day and four doses of 20 mg on the second day, (3) loperamide 2 x 2 mg loading dose following by a flexible dosage of 2 mg after each unformed stool (maximum of 16 mg daily), (4) placebo.. Number of unformed stools, rate of improvement of patients with diarrhoea, rate of relief from diarrhoea.. Among the 331 compliant and fully evaluated patients, the zaldaride with loading dose group showed no significant differences in cure rates from the loperamide group. For most parameters, zaldaride without a loading dose and the placebo resulted in significantly lower cure rates.. A zaldaride regimen including a loading dose was shown to be well tolerated and as effective as loperamide.

Topics: Adolescent; Adult; Aged; Antidiarrheals; Benzimidazoles; Diarrhea; Double-Blind Method; Drug Administration Schedule; Female; Humans; Loperamide; Male; Middle Aged; Travel; Treatment Outcome

The therapeutic value of zaldaride maleate (Zm), an intestinal calmodulin inhibitor, was examined in patients with travelers' diarrhea, known to be caused by enterotoxigenic Escherichia coli (ETEC) and other bacterial agents.. One hundred seventy-six American students acquiring diarrhea in Mexico during the summer of 1991 were given Zm in doses of 5 mg, 10 mg, or 20 mg, or a matching placebo, four times a day for 48 hours.. The duration of diarrhea was reduced by 53% in the group given the 20-mg Zm dose (overall P < 0.01). Curative antibiotics were required post-treatment only in the placebo and 5-mg Zm groups (P < 0.01). The number of unformed stools passed during 0-48 hours of therapy with the highest Zm dose was reduced compared with placebo by 36% for all subjects (P < 0.05), by 39% for ETEC diarrhea (NS), by 45% for those with any bacterial agents (NS), and by 38% for those without an identifiable bacterial agent (NS).. The fact that a calmodulin inhibitor decreases the severity and duration of travelers' diarrhea has therapeutic implications and suggests that calmodulin and intracellular calcium may serve as mediators of diarrhea in bacterial enteric infection.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antidiarrheals; Benzimidazoles; Calmodulin; Diarrhea; Escherichia coli Infections; Female; Humans; Male; Middle Aged; Travel

The amelioration of secretory diarrhea has been reported after the administration of zaldaride maleate (ZAL), a selective calmodulin inhibitor, to male rodents. In this study, the antidiarrheal effect of ZAL in female rats was compared with that in male rats. In female and male rats, ZAL significantly ameliorated 16,16-dimethyl prostaglandin E2-induced diarrhea at doses of 1 and 3 mg/kg (p.o.), respectively, with ID50 values of 0.7 mg/kg (p.o.) in the females and 10.3 mg/kg (p.o.) in males. In castor oil-induced diarrhea, ZAL also significantly reduced the incidence of diarrhea in female and male rats at doses of 10 and 30 mg/kg (p.o.), respectively. When the same dose of ZAL was given orally to female and male rats, the maximum plasma level of this compound was approximately 3 times higher in female rats than in male rats. In contrast, after intravenous administration of the same dose of ZAL to female and male rats, the total clearance of this compound was similar. In an Ussing chamber experiment, the inhibitory action of ZAL on vasoactive intestinal polypeptide-induced ion secretion in the colon showed no difference between female and male rats. In conclusion, the antidiarrheal effect of ZAL in female rats is more potent than that in males, and could be due to the difference in plasma levels of this compound between female and male rats after oral administration.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antidiarrheals; Benzimidazoles; Castor Oil; Colon; Diarrhea; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Rats; Rats, Sprague-Dawley; Secretory Rate; Sex Characteristics

Zaldaride maleate (ZAL), a calmodulin inhibitor, that ameliorates secretory diarrhea in rodents, has a racemic structure. In this study, we compared the antidiarrheal and antisecretory effects of ZAL and its optical isomers, R(-)-isomer and S(+)-isomer, in rats. In Ussing chamber experiments, the inhibitory action of ZAL on acetylcholine-induced ion transport in the rat colonic mucosa was equipotent for both optical isomers, with IC50 values of approximately 3--4 micromol/l. In castor-oil-induced diarrhea, ZAL and its S(+)-isomer inhibited the incidence of diarrhea, whereas the R(-)-isomer had no effect. In 16,16-dimethyl prostaglandin E2-induced diarrhea, ZAL, the S(+)-isomer and the R(-)-isomer significantly ameliorated diarrhea at doses of 30, 10 and 30 mg/kg (p.o.), respectively; the ED50 values were 25, 10 and above 30 mg/kg (p.o.), respectively. The pharmacokinetic parameters after administration of 30 mg/kg (p.o.) of each compound were as follows: ZAL (Cmax: 378 ng/ml, AUC0-12: 1650 ng-h/ml); S(+)-isomer (Cmax: 565 ng/ml, AUC0-12: 2230 ng-h/ml) and R(-)-isomer (Cmax: 271 ng/ml, AUC0-12: 613 ng-h/ml) (mean, N=4). In conclusion, despite the fact that the antisecretory actions of ZAL and its optical isomers are the same, the antidiarrheal actions of ZAL and its S(+)-isomer are more potent than that of the R(-)-isomer. The antidiarrheal actions of ZAL and its optical isomers may be related to plasma levels.

Topics: Animals; Antidiarrheals; Benzimidazoles; Castor Oil; Diarrhea; Dinoprostone; Male; Rats; Rats, Sprague-Dawley; Stereoisomerism

The effect of zaldaride, a calmodulin inhibitor, on fecal pellet output in rats was compared with that of loperamide, an antidiarrheal drug. 5-Hydroxytryptamine (10 mg/kg, s.c.), neostigmine (0.3 mg/kg, s.c.) and nicotine (1.0 mg/kg, s.c.) increased fecal pellet output. Zaldaride (> or = 30 mg/kg, p.o.) reduced these increases in fecal pellet outputs. Loperamide (10 mg/kg, p.o.) inhibited fecal pellet output induced by 5-hydroxytryptamine and neostigmine but not nicotine. Under normal conditions, zaldaride and loperamide did not affect fecal pellet output at doses used in these studies. In conclusion, zaldaride may inhibit increases in fecal pellet output induced by hyperpropulsion of the gastrointestinal tract without causing constipation as a side effect.

Topics: Animals; Antidiarrheals; Benzimidazoles; Defecation; Diarrhea; Digestive System; Digestive System Physiological Phenomena; Feces; Loperamide; Male; Neostigmine; Nicotine; Nicotinic Agonists; Rats; Rats, Sprague-Dawley; Serotonin

The antidiarrheal action of zaldaride maleate (ZAL) after oral, intravenous and subcutaneous administration was examined to determine whether ZAL acts systemically or locally in the intestine of rats. Oral administration of ZAL inhibited castor oil- and 16,16-dimethyl prostaglandin E2-induced diarrhea; however, intravenous or subcutaneous administration of ZAL was ineffective. When ZAL was orally administered, the area under the plasma concentration time curve of the compound was lower than that of ZAL following intravenous or subcutaneous administration at the maximum doses studied. The antidiarrheal effect of ZAL was not dependent on its plasma concentration level. These results suggest that ZAL acts locally in the intestinal tract in rats.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Oral; Animals; Antidiarrheals; Area Under Curve; Benzimidazoles; Castor Oil; Cathartics; Diarrhea; Injections, Intravenous; Injections, Subcutaneous; Male; Rats; Rats, Sprague-Dawley

KW-5617 (zaldaride maleate), 1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a][4,1]-benzoxazepin -4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one maleate, is a selective calmodulin inhibitor. We studied the effects of KW-5617 on secretory diarrhea and gastrointestinal propulsion in rats, as compared with those of loperamide, a conventional anti-diarrheal drug. Diarrhea was induced in rats either by 16,16-dimethyl prostaglandin E2 (500 microg/kg, i.p.) or by castor oil (1 ml/100 g body weight, p.o.). In the 16,16-dimethyl prostaglandin E2 model, KW-5617 at the doses of 3 mg/kg (p.o.) and higher ameliorated the diarrhea. Similarly, loperamide improved the diarrhea, the activity of loperamide being equivalent to that of KW-5617. In the castor oil model, KW-5617 significantly delayed the onset of diarrhea at the doses of 3 mg/kg (p.o.) and higher, while loperamide delayed the onset of diarrhea at the doses of 0.3 mg/kg (p.o.) and higher. KW-5617 only at the high doses of 30 and 100 mg/kg (p.o.) reduced gastric emptying, small intestinal propulsion, proximal colonic propulsion and distal colonic propulsion. In contrast, loperamide at its anti-diarrheal doses inhibited gastrointestinal propulsion. Our results show that KW-5617, unlike loperamide, at its anti-diarrheal doses does not exert anti-propulsive effects in rats. KW-5617 may be a useful drug for the treatment of diarrhea in terms of less side effects such as constipation.

Topics: Animals; Antidiarrheals; Benzimidazoles; Calmodulin; Diarrhea; Dinoprostone; Gastric Emptying; Loperamide; Male; Peristalsis; Rats; Rats, Sprague-Dawley