Probiotics: The mechanisms by which the probiotics helps in diarrhea are still not very well understood. The competitive blockage of receptors thereby preventing the adhesion & invasion of the virus, enhanced immune response, down regulation of the host's secretory & motility defenses and /or inactivation of the virus particles by substances produced by the lactobacilli could be the possible mechanisms. A meta-analysis 84 published in 2006 concluded that there is insufficient evidence about the prophylactic or therapeutic role of probiotics in acute childhood diarrhea in the developing world where the main burden of the disease lies. More recently the LGG was not found to be effective in severe dehydrating diarrhea in at least 2 studies done in the developing world 85,86 . In a recently published study from our centre we did not see any significant beneficial effect of the tyndallized Lactobacillus acidophilus on acute childhood diarrhea 87 . At least three meta-analyses have earlier concluded that probiotics could shorten duration of acute diarrhea, especially due to rotavirus in children 88-90 . Among the lactobacilli, the live strain Lactobacillus rhamnosus GGwas found most effective. Almost all of the studies included in the meta-analysis were from the developed world except for a study from Pakistan where earlier recovery from acute non-bloody diarrhea was seen with Lactobacillus rhamnosus GGbut the study included a very small sample size 91 . Most of the RCT's to evaluate the role of Lactobacillus rhamnosus GG in acute childhood diarrhea has been done in rotaviral predominant diarrhea. The efficacy of the lactobacilli needs to be studied in the developing world, where the etiologic profile is different.

Racecadotril : Another antisecretory drug, an d opiate receptor agonist, called Racecadotril is much in the news nowadays. The enkephalins, endogenous opiate substances, act as neurotransmitters of digestive tract where they cause antisecretory activity without affecting intestinal transit time or motility. Enkephalins after release are rapidly inactivated by enzyme enkephalinase. Racecadotril, an enkephalinase inhibitor, reinforces the physiological activity of endogenous enkephalins. The antisecretory mechanism involves activation of d opiate receptor leading to reduction in secretion of intracellular CAMP.

Two RCTs (both funded by the manufacturer's of the drug) have studied the efficacy of Racecadotril in acute childhood diarrhea. In 135 Peruvian boys (3-35 months), 46% reduction in 48 hours stool output was seen in the Racecadotril group as compared to the placebo group 92 . Similar results have been reported by Cezard et al 93 in 172 boys and girls less than 4 years of age. Addition of the girls in the one of the study group makes the primary outcome questionable because urine separation from stool output would be difficult in girls. Moreover 9 cases from the racecadotril and 4 from placebo group were withdrawn during the study. Five cases from the racecadotril and 1 from the placebo group were withdrawn because of adverse events like vomiting or dehydration. In adults with severe cholera comparable total stool output, total ORS intake or duration of diarrhea between the racecadotril and loperamide groups has been recently reported 94 . The results of this trial further strengthen the role of standard management of cholera with ORS, feeding and doxycycline. A recent RCT 95 comparing racecadotril and loperamide for stopping acute diarrhea in adults found comparable clinical success rates and mean duration of diarrhea. More patients on loperamide had reactive constipation and itching was notably higher in the racecadotril group. Well designed RCTs with adequate sample size and independent of any competitive interest, studying the efficacy and safety of racecadotril in acute childhood diarrhea, are needed before we reach any conclusion regarding the role of the drug in the management of acute diarrhea.

Nitazoxanide(2-acetyloxy-N-benzamide), is a synthetic oral antiprotozoal agent which has been approved by Drug Controller General of India (100mg in 1-3 years and 200mg in 4-11 years: bd. for 3 days respectively) for treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia ( http://cdsco.nic.in/DRUGSAPRVD.htm ). The efficacy of single treatment with nitazoxanide is 100% against cryptosporidial diarrhea 98-100 but even third treatment with nitazoxanide could achieve only 80% eradication rate of Giardia lamblia99 . In a double blind randomized controlled trial nitazoxanide had equivalent efficacy to metronidazole in children with giardiasis 101 . Moreover nitazoxanide did not show improvement in the resolution of diarrhea, eradication rate and mortality among HIV- seropositive children with cryptosporidial diarrhea 100 . Therefore relatively costly nitazoxanide has an established role against cryptosporidial diarrhea in immuno-competent children but no added benefits are seen over metronidazole in Giardia lamblia infection in children.

Conclusion: It is important to follow the recommendations in the management of acute diarrhea strictly, since indiscriminate usage of drugs results in development of resistance. Addition of so called harmless but unnecessary drugs shifts the emphasis from the standard management (oral rehydration solution, feeding and zinc supplementation) of acute childhood diarrhea. Not to forget that such additions also bring unnecessary financial burden on the community.

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