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A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhea OBJECTIVE.

Children in developing countries are at a high risk for zinc deficiency. Supplemental zinc has previously been shown to provide therapeutic benefits in diarrhea. The objective of this study was to examine the efficacy and safety of supplemental oral zinc therapy during recovery from acute or persistent diarrhea. METHODS.We conducted a meta-analysis of randomized, controlled trials to compare the efficacy and safety of supplementary oral zinc with placebo in children with acute and persistent diarrhea. Results were reported using a pooled relative risk or al weighted mean difference. A total of 22 studies were identified for inclusion: 16 examined acute diarrhea (n _ 15 231), and 6 examined persistent diarrhea (n _2968). RESULTS. Mean duration of acute diarrhea and persistent diarrhea was significantly lower for zinc compared with placebo. Presence of diarrhea between zinc and placebo at day 1 was not significantly different in acute diarrhea or persistent diarrhea trials. At day 3, presence was significantly lower for zinc in persistent diarrhea trials (n _ 221) but not in acute diarrhea trials. Vomiting after therapy was significantly higher for zinc in 11 acute diarrhea trials (n _ 4438) and 4 persistent diarrhea trials (n _ 2969). Those who received zinc gluconate in comparison with zinc sulfate/acetate vomited more frequently. Overall, children who received zinc reported an 18.8% and 12.5% reduction in average stool frequency, 15.0% and 15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability of reducing diarrhea over placebo in acute and persistent trials, respectively. CONCLUSIONS. Zinc supplementation reduces the duration and severity of acute and persistent diarrhea; however, the mechanisms by which zinc exerts its antidiarrheal effect have not been fully elucidated. DIARRHEAL DISEASES POSE a significant public health problem on a global scale and especially in developing countries. It is estimated that there are _1.5 billion episodes of diarrhea per year and that diarrheal disease accounted for 21% of all deaths in children who were younger than 5 years. This is equivalent to 2.5 million deaths in the same age group. This compares more favorably with the results of a previous study from 1982 in which on the basis of a review of active surveillance data from studies conducted in the 1950s, 1960s, and 1970s, it was estimated that 4.6 million children died annually from diarrhea.3 Newer data from the World Health Organization (WHO) show that diarrheal disease accounts for 18% of the 10.6 million deaths in children who were younger than 5 years. One of the major advances in the reduction of mortality from diarrhea was the introduction of WHO oral rehydration solution (ORS); however, WHO ORS does not significantly decrease stool output and duration of diarrhea, and therefore other approaches to add to or to enhance the available ORS have been sought. Several newer approaches have included the addition of zinc to the treatment regimen. Zinc is an essential micronutrient and protects cell membranes from

oxidative damage. Zinc is not stored in the body, so the level of zinc is determined by the balance of dietary intake, absorption, and losses. A zinc deficiency state may exist in children with acute diarrhea as a result of intestinal loss. A comprehensive review onthis subject was recently published. An alternative viewis that zinc may be working as a pharmacologic agent at the level of gene expression. The efficacy of zinc in the treatment of diarrhea is supported by several randomized, controlled trials that showed reduction of diarrhea duration, stool output, and stool frequency. Meta-analyses on the therapeutic effects of zinc in acute and persistent diarrhea as well as prevention of diarrhea with zinc supplementation have been previously published. The published data so far have shown the efficacy of zinc in the treatment of acute and chronic diarrhea. Our meta-analysis was performed to include new studies published since the last meta-analysis and to examine the efficacy and safety of zinc therapy during recovery from acute or persistent diarrhea. METHODS Inclusion Criteria Studies that were selected for inclusion tested the same primary hypotheses (average duration of diarrhea and presence of diarrhea at days 1, 3, and 5) using similar patient characteristics (primarily children aged between 1 and 60 months), with either acute or persistent diarrhea, including dysentery. Acute diarrhea was defined as lasting up to 14 days, with persistent diarrhea lasting _14 days. Random allocation to treatment groups and concealment of allocation had to be met to satisfy inclusion because inadequate allocation concealment, despite the use of randomization, allows a risk for selection bias. Intervention with oral zinc salt supplementation, allowing for any zinc salt type or formulation (sulfate, gluconate, or acetate) if applied at _5 mg/day for any length of duration, was examined against a control using a placebo. All comparisons between treatment groups had to be free of confounding by additional agents or co-interventions. Study groups who, after randomization, received zinc supplementation and ORS or zinc supplemented with vitamin A were excluded. Identification of Trials The search strategy used computerized bibliographic searches of Medline (19662006); the Cochrane Central Register of Controlled Trials (2006); Embase (19742006); Lilacs (19822006); CINAHL (19822006); Current Controlled Trials (2006); and abstracts published in Pediatric Research (19912006) and the First (Boston, 2000) and Second (Paris, France, 2004) World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Both published and unpublished trials were included in an effort to control for publication bias. Citations of appropriate studies were verified by reviewing the bibliographies and reference lists of identified trials. Identified titles of abstracts with potential relevance were downloaded, and full manuscripts were then obtained for all abstracts that were deemed relevant on the basis of the inclusion criteria. Twenty-two trials

met inclusion criteria: 16 published studies relative to the definition of acute diarrhea and 6 relative to persistent diarrhea. Primary and Secondary Outcomes Data on 8 clinically relevant outcome measures were collected. We held average duration of diarrhea and presence of diarrhea episodes at days 1, 3, and 5 as our primary outcomes. Data on vomiting frequency, vomiting frequency by therapy type, stool frequency reduction, and probability of diarrhea continuation were extracted as secondary outcomes. All 3 authors independently extracted data from the same articles using a data extraction sheet and subsequently compared results for agreement. The data thus obtained were checked for consistency among authors, integrity of randomization, and concealment of allocation. Questions regarding the interpretability of certain data values were resolved by all 3 authors. The final database entries were verified by the statistician (Dr Thomas). Few studies satisfied criteria for inclusion on every datum variable. When necessary, authors of selected studies were contacted to verify extracted data values derived from graphs and/or to provide additional information in a scaling form that could be combined with other studies. Where those instances occurred, they are noted in Tables1 and 2. Definitions Definitions of diarrhea varied somewhat in all included studies. In acute trials, generally, the definitions stated for diarrhea were the passage of _3 loose, watery stools or 1 loose, watery stool with blood within 24 hours for between 3 and 7 days in duration. In persistent diarrhea trials, the definitions were similar, with the exception that they persisted up to 14 days in duration. Definitions for duration of diarrhea varied as well but was defined, generally, from the time of enrollment into the study until the first formed stool. Duration was measured in either days or hours. For the purpose of this meta-analysis, hours were converted to days. After enrollment randomization, either the zinc treatment or the placebo was assigned within 24 hours. Statistical Analyses Comprehensive Meta-Analysis,10 a stand-alone program, was used to synthesize data that were obtained from the 22 trials identified for inclusion: 16 acute and 6 persistent diarrhea trials. Briefly, the analysis software produces a Forrest plot as a schematic description of the meta-analysis results. The program is augmented using accepted computational algorithms. Where appropriate, results were reported using a pooled relative risk (RR). For continuous outcomes, the weighted mean difference (WMD) was calculated. The 95% confidence intervals (CIs) were reported around the weighted effect size. Heterogeneity Given that studies that are selected for inclusion in a meta-analysis will differ, the types of

variability (clinical, methodologic, and/or statistical) that may occur among studies must be investigated. These various types of variability are termed heterogeneity. Meta-analysis should be considered only when a group of trials is sufficiently homogeneous (as indicated in the inclusion criteria) in terms of participants, interventions, and outcomes to provide a meaningful summary. Strict adherence to the inclusion criteria listed, such as blinding and concealment of allocation, help to control for clinical/methodologic heterogeneity. Still, statistical heterogeneity can also occur when variability in the treatment effects being evaluated in the different trials exists. This results when the observed treatment effects are more different from each other than would be expected as a result of random error (chance) alone. Following convention, statistical heterogeneity in the results of this meta-analysis are referred to simply as heterogeneity. Different approaches for identification and measurement of heterogeneity were therefore undertaken to examine the extent to which the results of the studies included were consistent. CIs for the results of individual studies (depicted graphically using horizontal lines) were examined for poor overlap, a general indication of presence of statistical heterogeneity. Variability (heterogeneity) among the obtained effects sizes was formally operationalized using a _2 test of significance. The formula for heterogeneity assesses the dispersion of individual outcomes, vis-a` -vis the combined effect, and denotes this value using a Q statistic.11 A low P value (or a large _2 statistic relative to its degree of freedom) provides evidence of heterogeneity of treatment effects (variation in effect estimates beyond chance). Because some degree of clinical and methodologic diversity always occurs in a meta-analysis, some statistical heterogeneity is inevitable; therefore, the test for heterogeneity is irrelevant to the choice of analysis: heterogeneity will always exist regardless of whether it can be detected using a statistical test. Still, methods have been developed for quantifying inconsistency across studies that move the focus away from testing whether heterogeneity is present to assessing its impact on the meta-analysis. A useful statistic for quantifying inconsistency is I2, the percentage of the variability in effect size estimates that is attributable to heterogeneity rather than sampling error (chance).12 A value _50% may be considered substantial heterogeneity, and that percentage cutoff was adopted and examined also in our analyses. Gravity Another more recent approach13 proposed jackknife resampling to measure a concept termed gravity. In any meta-analysis, arguments have focused on the inclusion or exclusion of some studies, with debate on which ones should be included or excluded because studies are commonly weighted according to their sample size and/or internal variability. Gee13

proposed that jackknife resampling could be used to examine study influence and detect outlier studies. The technique recomputes the meta-analysis once for each of k studies, where each study is individually excluded. K results are then obtained. The difference between the average of these k results and each studys individual result (when omitted) is taken as an index of raw gravity. This difference, divided by the SD of the k differences, is taken as z score, or standardized gravity, which can be used to establish which studies might be unusually influential. SPSS 15.014 was used to calculate standardized gravity values. Fixed- or Random-Effects Model Choice of whether to interpret a fixed-effects or random- effects model was considered thoroughly. Fixedeffect meta-analyses ignore heterogeneity. The fixedeffect estimate and its CI address the question, What is the best estimate of the treatment effect? The randomeffects estimate and its CI address the question, What is the average treatment effect? The answers to these questions are analogous when no heterogeneity is present or when the distribution of the treatment effects is roughly symmetrical. If they are not, then the random- effects estimate may not reflect the actual effect in any population being studied. In a fixed-effects metaanalysis, a pooled-effect estimate is termed, generally, as the best estimate of the treatment effect. It is for these reasons that we chose a fixed-effects model for our meta-analysis, along with the various stated approaches to examine heterogeneity if found. RESULTS The author, year, country, amount of zinc supplementation and type, sample size, and age for each of the 22 studies selected for inclusion in the meta-analysis are listed in Tables 3 and 4. Although all 22 studies were randomly assigned clinical trials, it seemed that 51519 were not double-blinded. Sixteen of these published studies met the definition for acute diarrhea and 6 for persistent diarrhea. Overall, 56.3% (9 of 16) of acute diarrhea trials were conducted in inpatient hospital settings, and 43.7% (7 of 16) were conducted in outpatient homes and communities. Of the 6 persistent diarrhea trials, 66.7% (4 of 6) were inpatient and 33.3% (2 of 6) were outpatient. Mortality Mortality was originally a primary outcome in this metaanalysis; however, of both acute and persistent trials, only 315,20,21 reported mortality outcome, making it difficult to compare across all included trials. Two of these were acute diarrhea trials,15,20 and 1 was a persistent diarrhea trial.21 In the largest acute diarrhea outpatient trial15 (n _ 8070), 33 children (0.008%; 33 of 3974) died in the zinc-treated group and 37 (0.009%; 37 of 4096) died in the placebo group. Thirty deaths were attributed to drowning, and the remaining were not injury

related (ie, not attributable to zinc intervention). When restricted to noninjury deaths, there were 13 in the zinctreated group and 27 in the placebo group. The investigators attributed the lower noninjury death rate in the intervention group almost entirely to fewer deaths from diarrhea and acute lower respiratory infection. Diarrhea and acute lower respiratory infection together accounted for 10 deaths in the zinc intervention group and 20 deaths in the placebo group. In the other acute diarrhea trial,20 2 children in the placebo group died of septicemia. In the persistent diarrhea trial,21 the causes of death were septicemia with diarrhea in 3 children, septicemia in 1 child, bronchopneumonia in 1 child, and continued diarrhea in 1 child. Because acute and persistent diarrhea are, most likely, distinct disease entities, the outcomes obtained are presented initially for acute diarrhea (lasting up to 14 days) and followed by persistent diarrhea (lasting _14 days). Results for Acute Diarrhea Trials Duration of Acute Diarrhea In 16 trials that examined the primary measure of average duration of acute diarrhea 1517,19,20,2232 (n _ 15 231), those who received zinc experienced a significantly lower average duration of diarrhea than those who received a placebo (WMD: 0.24; SE: 0.02; 95% CI: 0.21 0.27; P _ .001; Table 5, Fig 1) but also with the presence of statistically significant heterogeneity (Q _ 95.58, degrees of freedom [df]Q _ 15, P _ .001, I2 _ 84.3%). Figure 1 depicts a Forrest plot for these results, in which every study is displayed as a point estimate with CIs. Examination of significant heterogeneity in the acute diarrhea trials revealed 5 trials17,19,20,25,30 with insignificant differences between zinc and placebo groups in average duration of diarrhea. P values ranged from .478 to nonsignificant in sample sizes that ranged from 50 to 215. Although those who received zinc had a shorter average duration of diarrhea, the difference in 4 trials17,19,20,30 was very small, with an average difference of 0.18 _ 0.18 days ranging from 0.04 to 0.40 days. One trial25 found no difference at all between treatment groups. Participants in all 5 trials had been admitted for dehydration secondary to diarrhea, although the severity of dehydration ranged. Four of the trials17,20,25,30 administered an ORS before treatment assignment. Three trials received zinc sulfate and 2 received acetate. In contrast, all acute diarrhea trials23,31,32 that provided zinc gluconate and not zinc sulfate had a shorter duration of diarrhea than placebo (P _ .08). Two trials17,20 originated from India, 225,30 from Bangladesh, and 119 from Australia. One trial15 in which average duration was significantly lower (1.2 days lower) with zinc use also had a tremendously higher sample size (n _ 8070) than all of the others. Table 6 shows the effect sizes, calculated raw gravity values, standardized gravity values, and sample sizes for each study when removed. It is clear that 1 study15 had a great deal of impact on the strength

and direction of the estimated effect size value found for average duration of acute diarrhea among all studies. When removed, the reaveraged effect size obtained (0.187) and plotted standardized gravity value (3.531; Fig 2) were considered outlying values in comparisons with all others. This is largely attributed to the enormous sample size (n _ 8070) used in the trial, because even very small differences in mean duration of diarrhea would be statistically significant. Occurrence of Diarrhea at Day 1 Five acute diarrhea trials16,19,20,27,32 reported the occurrence of diarrhea at day 1 (n _ 3100). No statistically significant difference in the occurrence of acute diarrhea at day 1 was found (RR: 1.01; 95% CI: 0.991.03; P _ .30). Although the variability in effect sizes ranged from a low of 0.968 to 1.695, significant heterogeneity did occur (Q _ 10.60, dfQ _ 4, P _ .03, I2 _ 62.3%). Occurrence of Diarrhea at Day 3 Six acute diarrhea trials16,19,20,23,27,32 collected data for occurrence of diarrhea at day 3. No statistically significant differences occurred between treatment groups in occurrence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.911.03; P _ .36); however, the occurrence of statistically significant heterogeneity was found (Q _ 10.880, dfQ _ 5, P _ 0.05, I2 _ 54.0%). Only 1 trial30 found a significantly (P _ .01) lower occurrence of diarrhea at day 3 with zinc (27.4%) than placebo (35.4%; effect size: 0.774); however, the occurrence of statistically significant heterogeneity was found (Q _ 10.880, dfQ _ 5, P _ .05, I2 _ 54.0%). Occurrence of Diarrhea at Day 5 Similarly, in the same 6 acute diarrhea trials,16,19,20,23,27,32 no statistically significant differences occurred between treatment groups in occurrence of diarrhea at day 5 (RR: 0.94; 95% CI: 0.841.05; P _ .26). Similar to day 3 results, the occurrence of statistically significant hetero- geneity was found (Q _ 18.957, dfQ _ 5, P _ .002, I2 _ 73.6%). Vomiting In 11 acute diarrhea trials16,17,19,2225,2932 (n _ 4438), the proportion of participants who vomited after the initial dose was significantly higher with zinc (278 [12.7%] of 2196) use than with placebo (171 [7.6%] of 2242; RR: 1.55; 95% CI: 1.301.84; P _ 0.001%; Q _ 25.54, P _.004). Vomiting After Administration of Zinc Sulfate or Gluconate In 3 acute diarrhea trials,23,31,32 a significantly higher proportion of patients who received zinc gluconate vomited (160 [14.6%] of 1095) than zinc sulfate/acetate

therapy16,17,19,22,24,25,29,30 (118 [10.7%] of 1101; RR: 1.18; 95% CI: 1.051.31; P _ .006). Shortening of Diarrhea Duration Eight trials of acute diarrhea1517,20,25,26,29,31 found an average shortening of diarrhea duration of 15.0% for those who received zinc in comparison with placebo (Table 7). Reduction in Stool Frequency Seven trials of acute diarrhea17,22,23,25,29,31,32 found an average reduction in stool frequency of 22.1% with zinc therapy in comparison with placebo. One single trial16 found a 5.0% higher stool frequency using zinc than placebo. Stool Output Three trials of acute diarrhea24,26,30 found an average lowering of stool output of 30.3%. Probability of Diarrhea Reduction Eight acute diarrhea trials20,2325,27,28,30,32 measured the probability of diarrhea reduction and found a 17.9% reduction using zinc compared with placebo. Results for Persistent Diarrhea Trials Duration of Persistent Diarrhea In 5 persistent diarrhea trials18,21,3335 (n _ 489), those who received zinc also experienced a significantly lower average duration of diarrhea than the placebo group (WMD: 0.30; SE: 0.09; 95% CI: 0.120.48; P _ .001; Table 8) but without significant heterogeneity (Q _ 3.08, Forrest plot for these results. Occurrence of Diarrhea at Day 1 In 2 trials of persistent diarrhea34,35 (n _ 221), no statistically significant differences occurred between treatment groups in occurrence of diarrhea at day 1 (RR: 1.00; 95% CI: 0.931.08; P _ .98), and no statistically significant variability occurred among the effect sizes (Q _ 0.01, dfQ _ 1, P _ .93). Occurrence of Diarrhea at Day 3 In 2 trials of persistent diarrhea34,35 (n _ 221), a significantly lower occurrence of diarrhea at day 3 occurred in those who were treated with zinc in comparison with placebo (RR: 0.70; 95% CI: 0.510.94; P _ .02). No statistically significant variability occurred among the effect sizes (Q _ 0.33, dfQ _ 1, P _ .56).

Occurrence of Diarrhea at Day 5 This was not examined; fewer than 2 studies reported. Vomiting In 4 persistent diarrhea trials18,21,35,36 (n _ 2969), a significantly higher proportion vomited on zinc (41 [2.8%] of 1482) than with placebo (2 [0.001%] of 1487; RR: 3.64; 95% CI: 1.0213.02; P _ .047; Q _ 5.91, P _ .116). Vomiting After Zinc Sulfate or Gluconate In 4 persistent diarrhea trials,18,21,35,36 those who received zinc gluconate35,36 vomited more frequently (41 [3%] of 1367) than did those who received zinc sulfate/acetate (0 [0%] of 115; RR: 1.09; 95% CI: 0.941.09; P _ .07). Shortening of Diarrhea Duration In 4 persistent diarrhea trials,18,21,34,35 those who received zinc experienced a 15.5% average shortening of diarrhea duration than those who got a placebo (Table 9). Reduction in Stool Frequency Four trials of persistent diarrhea found that those who received zinc also experienced an average of 9.8% reduction in frequency. Stool Output Stool output was not measured in the persistent trials. Probability of Diarrhea Reduction Two persistent diarrhea trials33,36 that measured the probability of diarrhea reduction found an 18.0% reduction when zinc was used over placebo. DISCUSSION On the basis of these findings, which now add to the large body of previously published clinical data and update previous meta-analyses and systematic reviews,8,37 zinc therapy is useful for treating both acute and persistent diarrhea and for their prophylaxis. Still, as extensively addressed in a recent systematic review,6 much information is lacking relative to the mechanisms by which zinc physiologically exerts its antidiarrheal effect. In this meta-analysis, 5 (31.3%) of 16 acute diarrhea studies17,19,20,25,30 found no statistically significant differences between zinc and placebo on the average duration of diarrhea (at least a P _ .48). Similarly, 2 (40.0%) of 5 persistent diarrhea studies21,33 also found no statistically significant differences in average duration of diarrhea between treatments (at

least a P _ .43). Still, the average stool frequency reductions, shortening of diarrhea durations, and probabilities of a shortening of diarrhea duration reported were higher in studies with zinc therapy in comparison with placebo. To the majority of individuals, diarrhea means an increased frequency or decreased consistency of bowel movements. In many developed countries, the average number of bowel movements is 3 per day; however, diarrhea is associated with an increase in stool weight, mainly as a result of excess water, which normally makes up a large percentage of fecal matter. Given this, diarrhea is distinguished from diseases that cause only an increase in the number of bowel movements or fecal incontinence. Determining the exact causes of diarrhea can be difficult because there are many different diarrheal agents, with such a variety of infectious agents, including bacteria, parasites, and viruses. Identification of specific diarrheal agents is complicated by the lack of access to laboratory tests in many developing countries. Viral gastroenteritis caused by rotavirus is the primary cause of diarrhea among infants worldwide. Other causes include bacterial pathogens such as Vibrio cholerae, Shigella, and Salmonella. Protozoa such as Cryptosporidium parvum and Giardia lamblia are 2 of the most common protozoan diarrheal agents. The primary symptoms of rotavirus infection are fever and vomiting for several days, followed by nonbloody diarrhea. Although not normally fatal, the diarrhea caused by the virus can be quite severe, leading to potentially life-threatening dehydration. Although easily treated with intravenous fluids in developed nations, these supplies are often unavailable in the developing world, and the dehydration that is caused by rotavirus is a significant cause of mortality. In fact, conclusions from these randomized trials for the efficacy of zinc treatment on diarrhea duration included an improved absorption of water and electrolytes by the intestine and quicker regeneration of gut epithelium. 38 Increased levels of brush border (apical) enzymes suggesting a zinc transporter for enterocytes39 and a stronger immune response that increased clearance of pathogens from the intestine40 were also described. Efficacy of oral rehydration therapy in correcting dehydration and reducing mortality led to treatment modifications of ORS with zinc therapy. Success with zinc therapy has generally been attributed to a decrease in the volume of small intestinal fluid and sodium absorption triggered by zinc delivery. Still, the mechanisms by which zinc improves fluid and electrolyte transportation have not been elucidated fully. This includes the effect of zinc on intestinal ion transport, whether zinc initiates or increases cation absorption and/or suppresses anion secretion, and whether deficiency enhances the likelihood of secretory diarrhea. Most likely, the location of the effect of zinc is in the small intestine, given its inhibition of adenosine 3_,5_- cyclic monophosphate (cAMP)-induced chloride-dependent fluid secretion. Treatment with ORS would have its greatest effect on

reducing fluid loss by increasing small intestine absorption. Thus, zinc therapy after pretreatment with ORS may not have shown a beneficial effect (reduced average duration of diarrhea) over placebo in 5 trials17,19,20,25,30 of this meta-analysis simply because pretreatment with ORS had already maximized the small intestine absorption rate. Zinc inhibits cAMP-induced chloride secretion by specifically inhibiting basolateral potassium (K) channels with no blockage effect on calcium (Ca)-mediated K channels in in vitro studies with the rat ileum.41 Zinc also inhibits cholera toxininduced but not Escherichia coli heat-stable enterotoxin-induced ion secretion in cultured Caco-2 cells. One study42 showed that cAMP acted as the intracellular effector of heat-labile enterotoxininduced fluid secretion. Guanosine 3_,5_-cyclic monophosphate mediates heat-stableinduced fluid secretion. If substantiated, then the effectiveness of zinc would be limited to heat-labileinduced diarrhea or to diarrhea mediated by cAMP but not either 3_,5_-cyclic monophosphate or intracellular Ca. It has been reported also43 that a zinc-sensing receptor triggers the release of intracellular Ca2_ and regulates ion transport. A micromolar concentration of extracellular zinc set off a massive release of calcium from intracellular pools in the colonocytic cell line. A sustained increase in intracellular Ca level may augment K efflux and a hyperpolarization of cell membrane potential, leading to an advantageous electrical gradient for chloride secretion. Although the alternative treatment of oral rehydration therapy is more available, there are still significant setbacks in distributing the therapy. An antisecretory drug vaccine would be a much more cost-effective solution. An antisecretory drug vaccine could induce immunity without the childrens needing to go through multiple infections and the risks associated with infections. By preventing children from acquiring infection, a drug vaccine could greatly reduce the number of deaths as a result of diarrheal diseases and greatly reduce the burden on the health system. The model for an antisecretory drug should perform by inhibiting intestinal chloride and HCO3 secretion6 in contrast to focusing on decreasing gastrointestinal motility and regeneration and/or restoration of gut epithelium. Accelerated research directed to achieving a clearer understanding of the biology, chemistry, and pathobiology of zinc in the gastrointestinal system is necessary. Does zinc maintain intestinal defense systems? What is the relationship of zinc to intestinal fluid balance? Definitively what are the linkages of intestinal zinc transporters to body zinc status? Is there a brush border (apical) membrane zinc transporter for enterocytes? Answers to these and other questions will hopefully drive the creation of a treatment drug that collectively induces cation absorption; inhibits anion secretion; reduces stool frequency and output; reduces diarrhea duration; and is safe, tolerable,

and inexpensive.

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