This randomized, double-blind, placebo-controlled trial of 48 hours' duration conducted in 13 primary care ambulatory practices in the United States and Mexico was used to compare the efficacy and safety of loperamide with placebo for the treatment of acute diarrhea in children aged 2 through 11 years. Two hundred fifty-eight children with acute nonspecific diarrhea were enrolled. Children were randomly assigned to treatment with loperamide HCl 0.5 mg/5 mL (n = 130) or placebo (n = 128). The first dose of loperamide consisted of either 1.0 mg (children 2 through 5 years of age) or 2.0 mg (children 6 through 11 years of age) of study medication under the observation of study personnel. This was followed by 1 mg after each unformed stool, with a total daily dose of up to 3.0 mg in the children 2-5 years of age, 4.0 mg in the children 6-8 years of age, and 6.0 mg in the children 9-11 years of age. The primary outcome measures were time to last unformed stool, time to first unformed stool, number of unformed stools during six consecutive 8-hour periods, and overall rating of efficacy/acceptability. Secondary outcomes included abdominal pain/cramping, vomiting, and fever. Children who received loperamide had significantly shorter time to last unformed stool (p = 0.0017) and fewer numbers of unformed stools (p = 0.0237) than children who received placebo. The end-of-study overall efficacy/acceptability rating of loperamide was significantly better than for placebo (p = 0.0107). All other clinically important outcome measures related to diarrhea relief favored loperamide. There was no significant difference in the incidence of drug-related adverse events between treatment groups, although total adverse events were reported more frequently (p = 0.048) by the loperamide group (15%) compared with the placebo group (7%). In conclusion, this controlled study provides data demonstrating that at recommend doses, loperamide is well tolerated and significantly shortens the duration and severity of symptoms of acute nonspecific diarrhea in children 2 through 11 years of age.

The loperamide-simethicone combination chewable product provides faster and more complete relief of acute nonspecific diarrhea and associated gas-related abdominal discomfort (gas pain, cramps, gas pressure, and bloating) than either of its components or placebo. The combination is well tolerated.

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A B S T R A C T The urine of patients with chronic uremia contains a gel filtration fraction that is natriuretic in the rat. The effects of this fraction on the isolated urinary bladder of the toad were examined in the present studies. When added to the serosal surface of the bladder, a significant and substantial fall in short-circuit current and potential difference was observed. The changes began after a lag period of at least 10 min and continued over a period of 60 min. The decrease in short-circuit current at the end of 1 h averaged 44%. The same fraction from the urine of normal subjects produced no significant change in either short-circuit current or potential difference. When the isolated epithelial cells from the toad bladder were incubated in the presence of the inhibitor, intracellular sodium content increased significantly. There was no change in intracellular water content; hence the intracellular concentration of sodium increased by a mean of 7 meq/liter. The changes in intracellular potassium content and concentration were not statistically significant. When the isolated epithelia were incubated with the uremic factor, there was also a significant decrease in pyruvate utilization in relation to cells from paired hemibladders incubated in the absence of the fraction. The fraction from normal subjects pro- INTRODUCTIONThe effector element of the biologic control system which regulates the renal excretion of sodium is believed to be multifaceted and to have several component parts (1-3). Among these is a postulated natriuretic hormone which theoretically could play a central role in modulating the rate of sodium excretion.In previous studies, we have described an inhibitor of sodium transport in the serum of patients with advanced chronic renal disease (4,5). This serum factor was found to inhibit sodium transport by the isolated frog skin and toad bladder (4) and to produce natriuresis in rats with a reduced nephron population (5). More recently, the same gel filtration fraction obtained from urine of patients with chronic uremia has been found to possess natriuretic activity in the rat (6).In the present studies, attempts have been made to derive information about the site and mechanism of action of the urinary inhibitor using the isolated bladder of the toad. The toad bladder lends itself well to this type of study for several reasons. First, the serum factor inhibits transepithelial sodium transport by the anuran bladder, and the urine factor, if it is the same substance, should have similar inhibitory capabilities. Second, isolated epithelial cells removed from the intact toad bladder have been used recently to investigate the site of action of inhibitors of sodium transport (7). Inhibitors that act at the serosal surface of the epithelia (e.g. ouabain) increase intracellular sodium content, while those acting at the mucosal surface (e.g., amiloride) have the opposite effect (7). Third, the isolated The Journal of Clinical Investigation Volume 53 June 1974-1568-1577 1568 epithelial cell prepa...

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