Effectiveness and Efficacy of Zinc for the Treatment of Acute Diarrhea in Young Children

Strand, Tor A.; Chandyo, Ram; Bahl, Rajiv; Sharma, Pushpa Raj; Adhikari, Ramesh; Bhandari, Nita; Ulvik, Rune J.; Mølbak, Kåre; Bhan, M. K.; Sommerfelt, Halvor

doi:10.1542/peds.109.5.898

Cited by 114 publications

(85 citation statements)

References 18 publications

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“…Study characteristics are shown in Table 1 (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). Only three studies had a population of fewer than 100 patients, and all studies were conducted in countries considered to be "emerging and developing economies" (48).…”

Section: Resultsmentioning

confidence: 99%

“…The only relevant adverse reaction reported was vomiting, which had the highest incidence in the zinc-treated group (Figure 4) (29,30,35,37,39).…”

Section: Resultsmentioning

confidence: 99%

“…Five studies evaluated only malnourished children or included an evaluation of this subgroup (31,35,38,41,49). Three of these studies (29,36,37) included children with zinc deficiency, who are labeled as malnourished children in this review.…”

Section: Malnourished Population Analysismentioning

confidence: 99%

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Zinc supplementation for treating diarrhea in children: a systematic review and meta-analysis

Galvão

Silva²,

Pontes³

et al. 2013

Rev Panam Salud Publica

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Galvao TF, Thees MFRS, Pontes RF, Silva MT, Pereira MG. Zinc supplementation for treating diarrhea in children: a systematic review and meta-analysis. Rev Panam Salud Publica. 2013;33(5):370-7. Suggested citationZinc supplementation for treating diarrhea in children: a systematic review and meta-analysis Results. Eighteen of 1 041 studies retrieved were included in the review (n = 7 314 children). Zinc was beneficial for reducing the duration of diarrhea in hours (mean difference [MD] = -20.12, 95% confidence interval [CI] = -29.15 to -11.09, I² = 91%). The effect was greater in malnourished children

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Section: Resultsmentioning

confidence: 99%

“…The only relevant adverse reaction reported was vomiting, which had the highest incidence in the zinc-treated group (Figure 4) (29,30,35,37,39).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Zinc supplementation for treating diarrhea in children: a systematic review and meta-analysis

Galvão

Silva²,

Pontes³

et al. 2013

Rev Panam Salud Publica

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“…Beneficial effects of zinc supplementation have been observed in treatment and prevention studies of diarrhea in many locations around the world (2,3,11,16,25,32). Until recently, these beneficial effects of zinc on the duration and severity of diarrhea were almost always interpreted as the result of correction of a zinc deficiency (11,35).…”

Section: Discussionmentioning

confidence: 99%

Effect of Zinc in Enteropathogenic Escherichia coli Infection

et al. 2007

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Enteropathogenic Escherichia coli (EPEC) infection triggers the release of ATP from host intestinal cells, and the ATP is broken down to ADP, AMP, and adenosine in the lumen of the intestine. Ecto-5-nucleotidase (CD73) is the main enzyme responsible for the conversion of 5-AMP to adenosine, which triggers fluid secretion from host intestinal cells and also has growth-promoting effects on EPEC bacteria. In a recent study, we examined the role of the host enzyme CD73 in EPEC infection by testing the effect of ecto-5-nucleotidase inhibitors. Zinc was a less potent inhibitor of ecto-5-nucleotidase in vitro than the nucleotide analog ␣,␤-methylene-ADP, but in vivo, zinc was much more efficacious in preventing EPEC-induced fluid secretion in rabbit ileal loops than ␣,␤-methylene-ADP. This discrepancy between the in vitro and in vivo potencies of the two inhibitors prompted us to search for potential targets of zinc other than ecto-5-nucleotidase. Zinc, at concentrations that produced little or no inhibition of EPEC growth, caused a decrease in the expression of EPEC protein virulence factors, such as bundle-forming pilus (BFP), EPEC secreted protein A, and other EPEC secreted proteins, and reduced EPEC adherence to cells in tissue culture. The effects of zinc were not mimicked by other transition metals, such as manganese, iron, copper, or nickel, and the effects were not reversed by an excess of iron. Quantitative real-time PCR showed that zinc reduced the abundance of the RNAs encoded by the bfp gene, by the plasmid-encoded regulator (per) gene, by the locus for the enterocyte effacement (LEE)-encoded regulator (ler) gene, and by several of the esp genes. In vivo, zinc reduced EPEC-induced fluid secretion into ligated rabbit ileal loops, decreased the adherence of EPEC to rabbit ileum, and reduced histopathological damage such as villus blunting. Some of the beneficial effects of zinc on EPEC infection appear to be due to the action of the metal on EPEC bacteria as well as on the host.Enteropathogenic Escherichia coli (EPEC) infection is a common cause of watery diarrhea in children in developing countries. The mechanism by which EPEC triggers watery diarrhea is obscure, since unlike several other types of diarrheaproducing E. coli strains, EPEC produces no toxins. We recently theorized that the release of adenine nucleotides from the host intestinal cells, followed by the breakdown to adenosine, could trigger watery diarrhea by the activation of adenosine receptors in the intestine (8).Our interest in zinc was prompted by studies of ecto-5Ј-nucleotidase, a key extracellular enzyme which catalyzes the hydrolysis of extracellular 5Ј-AMP to adenosine. Zinc and the nucleotide analog ␣,␤-methylene-ADP are the classical inhibitors of this enzyme that were tested in vitro and in vivo in a recent study by one of our laboratories (9). Although ␣,␤-methylene-ADP is about eightfold more potent than zinc acetate in the inhibition of ecto-5Ј-nucleotidase, in vivo, zinc acetate was superior to ␣,␤-methylene-ADP in its ability to...

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“…Zinc has been shown to reduce the duration and severity of acute diarrhea in children in field trials on several continents (1,24). In earlier decades, these beneficial effects of zinc were usually attributed to the correction of zinc deficiency (29), which is unfortunately still seen in poor, malnourished children.…”

Section: Shiga-toxigenic Escherichia Coli (Stec) Also Called Enterohmentioning

confidence: 99%

Virulence Inhibition by Zinc in Shiga-Toxigenic Escherichia coli

2011

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Previously, our laboratories reported that zinc inhibited expression of several important virulence factors in enteropathogenic Escherichia coli (EPEC) and reduced EPEC-induced intestinal damage in vivo. Since EPEC is genetically related to Shiga-toxigenic E. coli (STEC), we wondered whether the beneficial effects of zinc extended to STEC as well. Treatment options for STEC infection are very limited, since antibiotics tend to exacerbate disease via enhanced toxin production, so a safe intervention for this infection would be welcome. In this study, we report that in STEC strains zinc inhibits adherence to cultured cells as well as expression of EHEC secreted protein A (EspA). In addition, zinc inhibits the expression of Shiga toxin (Stx) at both the protein and the RNA level. Zinc inhibits basal and antibiotic-induced Stx production and inhibits both Stx1 and Stx2 by >90% at a concentration of 0.4 mM zinc. Rabbit EPEC strains were selected for acquisition of Stx-encoding bacteriophages, and these rabbit STEC strains (designated RDEC-H19A and E22-stx2) were used to test the effects of zinc in vivo in ligated rabbit intestinal loops. In vivo, zinc reduced fluid secretion into loops, inhibited mucosal adherence, reduced the amount of toxin in the loops, and reduced STEC-induced histological damage (villus blunting). Zinc has beneficial inhibitory effects against STEC strains that parallel those observed in EPEC. In addition, zinc strongly inhibits Stx expression; since Stx is responsible for the extraintestinal effects of STEC infection, such as hemolytic-uremic syndrome (HUS), zinc might be capable of preventing severe sequelae of STEC infection.

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Effectiveness and Efficacy of Zinc for the Treatment of Acute Diarrhea in Young Children

Abstract: Three Recommended Daily Allowances of zinc given daily by caretakers or by field workers substantially reduced the duration of diarrhea. The effect of zinc was not dependent on or enhanced by concomitant vitamin A administration.

Cited by 114 publications

References 18 publications

Zinc supplementation for treating diarrhea in children: a systematic review and meta-analysis

Zinc supplementation for treating diarrhea in children: a systematic review and meta-analysis

Effect of Zinc in Enteropathogenic Escherichia coli Infection

Virulence Inhibition by Zinc in Shiga-Toxigenic Escherichia coli

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