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This article was originally published in The Tan Sheet

Executive Summary

BISMUTH SUBSALICYLATE THERAPY STOPPED DIARRHEA IN NEARLY 90% OF INFANTS and young boys also receiving oral rehydration therapy after five days of use, according to a study conducted in Lima, Peru and published in the June 10 issue of The New England Journal of Medicine. The 275 patients in the study received oral rehydration therapy and either 100 mg of bismuth subsalicylate per kg of body weight daily, 150 mg/kg a day of bismuth, or placebo. After five days of treatment, diarrhea had stopped in 89% of those given 100 mg/kg of bismuth, in 88% of those receiving 150 mg/kg of bismuth, and in 74% of the placebo group. The study authors, Dante Figueroa-Quintanilla et al., noted that "the reduction in the duration of diarrhea became evident the third day after treatment in the bismuth groups and was sustained throughout the period of evaluation." The study also found that the length of hospitalization for patients in the bismuth groups was nearly a day shorter on average than for patients in the placebo group. The infants and young children on 100 mg/kg of bismuth were released after 3.3 days on average while those on 150 mg/kg of bismuth were in the hospital an average of 3.4 days. Patients in the placebo group were hospitalized for an average of 4.1 days. The average age of the hospitalized young children participating in the study was 13.5 months, with ages ranging from three months to five years. Bismuth subsalicylate (Procter & Gamble's Pepto-Bismol) also reduced total stool output by approximately 30%, allowed a reduction in intake of rehydration solution by nearly 25%, and limited vomiting. The study points out that the "reduction in the intake of oral rehydration solution and the duration of hospitalization in the patients given bismuth was related to the reduction in stool output and the duration of diarrhea in these groups." The study found "no significant differences" between the effects of the two bismuth doses. "The results of this study show the effectiveness of bismuth subsalicylate as adjunctive therapy to oral rehydration and early continued feeding of children with acute diarrhea," the authors stated. Noting that earlier studies had not specifically addressed use of the drug as an adjunct to oral rehydration therapy, they reported that their study "found that treatment with bismuth significantly improved the clinical course of disease even when the currently recommended oral treatment regimen was followed." In their discussion of the study results, the authors also addressed the safety of bismuth salts, which at high doses have been associated with cases of encephalopathy. The authors noted that "there is no evidence that short-term therapy with bismuth subsalicylate presents a similar hazard if the recommended dose is not exceeded." They pointed out that, in their study, "all the patients who received bismuth subsalicylate had bismuth blood levels well below those considered toxic, and none had adverse reactions." The study concludes that bismuth subsalicylate, "used properly, could be a useful, safe, and cost-effective adjunct to oral rehydration therapy and nutritional therapy in children with acute watery diarrhea." Regarding the added cost of bismuth subsalicylate when used with oral rehydration therapy, the authors suggested that the cost "could be balanced by savings due to shorter hospitalizations." The Lima study -- conducted by the Institute Nacional de Salud del Nino, the Universidad Peruana Cayetano Heredia, and the Johns Hopkins University School of Hygiene and Public Health -- was sponsored by the International Child Health Foundation and Procter & Gamble. In a June 9 press release, ICHF indicated that the researchers chose bismuth subsalicylate because it is "the safest and least expensive medicine likely to reduce severity and shorten diarrheal illness in children." The group estimated that "dangerous dehydration due to diarrhea . . . strikes 20 mil. children annually [in the U.S.(BRACKET), resulting in 209,000 hospitalizations and $ 500 mil. in preventable hospital costs." The doses of bismuth subsalicylate used in the Lima study are higher than the doses recommended for Pepto-Bismol use for children in the U.S. Pepto-Bismol labeling recommends a maximum daily dose of about 700 mg a day for children three-to-six years old. For children under three, labeling recommends that a physician be consulted. P&G currently is conducting a clinical trial to confirm the appropriate dosing levels of Pepto-Bismol in children. Outside of the U.S., P&G sells Pepto-Bismol in Canada, Mexico, Panama, Puerto Rico and the U.K. The company said it is "working with a number of foreign regulatory agencies and governments to expand availability of Pepto-Bismol internationally." Despite the positive data on bismuth subsalicylate, the use of drugs to treat infant and childhood diarrhea can be expected to meet some resistance given the serious mortality and morbidity caused by the condition and the efficacy and cost-effectiveness of oral rehydration therapy. FDA currently is reviewing a petition from Public Citizen's Health Research Group to ban the use of several OTC and prescription antidiarrheal drugs and to encourage use of oral rehydration treatment. Bismuth subsalicylate is not among the drug ingredients HRG seeks to ban. However, the HRG petition cites a 1990 World Health Organization report that concluded that "antidiarrheal drugs should never be used. None has any proven value and some are dangerous." In an editorial in the same issue of the NEJM, John Snyder, MD, University of California-San Francisco, questioned the usefulness of bismuth subsalicylate despite the positive data because of the dosing regimen (six times daily) and the relative cost of the drug for developing countries. Based on the study by Figueroa-Quintanilla et al., he suggested that a one-year-old child weighing 10 kg "would require about 8 oz of bismuth subsalicylate for four days." At a cost in the U.S. of about $ 3.50 for an 8 oz bottle, bismuth subsalicylate therapy costs "several times" the cost in the developing world of treating a child with oral rehydration therapy, Snyder asserted. "If all 1.5 bil. episodes of diarrhea in young children in the developing world were treated [with bismuth subsalicylate(BRACKET), the additional cost would be about $ 5 bil. annually," Snyder added. He maintained that "the cost of adding adjunctive therapy for even a few episodes per child could exceed the annual per capita budget for all health services" in developing countries. Snyder suggested that "emphasizing the use of adjunctive antidiarrheal therapy may divert attention and resources away from the use of oral rehydration therapy and early, appropriate feeding, which are the essential components of effective therapy." Instead of putting money toward bismuth treatment, he argued that the funds "might be better put toward the $ 25 bil. that the United Nations Children's Fund estimates is needed each year to control the major childhood diseases (including diarrhea), halve the rate of childhood malnutrition, bring clean water and sanitation to all communities, make family-planning services universally available, and provide almost every child with a basic education."

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