Zinc Sulfate Acceptability Study in Children With Acute Diarrhea: A Prospective, Open-label, Interventional Study

Background:

Zinc is a metalloprotein. The two important function of zinc are- first, unlike other metals zinc is virtually non-toxic (1). The homeostatic mechanisms that regulate its entrance, allocation, and excretion from cells and tissues are so well-organized that no disorders are known to be associated with its excessive accumulation, in contrast to iron, copper, mercury, and other metals. Second, its physical and chemical properties, including its generally stable relationship with macromolecules and its co-ordination flexibility, make it extremely adaptable in meeting the needs of proteins and enzymes that take diverse biological functions (2-4). Zinc is one of the most common metal ion distributed widely in cytoplasm as well as building blocks for keratin like structures and intracellular organelles like chromosomes(5). Importance of zinc as an essential trace element is well established for its role on growth and development, protection against free radical damage, endocrine, reproductive and cognitive functions(6). Globally, zinc deficiency is associated with 16% of lower respiratory tract infections and 10% of diarrheal diseases respectively with higher attributable fractions in sub-regions(7). Severe zinc deficiency is a rare entity whereas mild to moderate zinc deficiency is quite evident mostly in children living in poverty and associated with approximately 453,000 deaths each year(8, 9). Simultaneously, diarrhoea as the second most prevalent cause of under five deaths and is responsible for 800,000 deaths each year (10). A meta-analysis of 12 studies observed the impact of zinc supplements on the management of acute diarrhea, 11 studies showed a reduction in the duration of the diarrheal episode. In eight of these reported that the reduction of diarrheal episode was statistically significant. Five of these studies also found that zinc supplements reduced stool output and frequency. The data revealed that zinc supplementation had a significant effect on the clinical course of acute diarrhea, reducing its duration as well as severity (11). Another meta-analysis of 18 trials with 6165 enrolled participants observed that in acute diarrhea, zinc reduced duration of diarrhea (MD -- 12.27 hours, 95% CI -23.02 to -1.52 hours; 2741 children, nine trials), and a reduced amount of diarrhea by day three (RR 0.69, 95% CI 0.59 to 0.81; 1073 children, two trials), day five (RR 0.55, 95% CI 0.32 to 0.95; 346 children, two trials), and day seven (RR 0.71, 95% CI 0.52 to 0.98; 4087 children, seven trials). Zinc also reduced the period of persistent diarrhea (MD -15.84 hours, 95% CI -25.43 to - 6.24 hours; 529 children, five trials). In few trials there was report on the severity, but the results were not consistent (12).

Zinc supplementation can significantly reduce diarrheal severity and duration as well as prevents future incidences and reduces use of other medications in diarrhea (13-16). Several studies evaluated the effect of zinc supplementation on diarrhea and found a preventive and long-lasting impact. These showed that 10 mg to 20 mg of zinc per day, for 10 - 14 days, reduced the number of diarrheal episodes in 2 - 3 months after the supplementation (12). For this reason WHO, UNICEF, USAID and experts worldwide jointly recommended zinc supplementation (10 mg for infants less than 6 months old and 20 mg in 6 - 59 months old) combined with reduced osmolarity ORS for clinical management of acute diarrhoea (17).

The physiological effect of zinc on intestinal ion transport has not yet been established thoroughly. In in-vitro studies with rat ileum recently established that zinc inhibits cAMP-induced, chloride-dependent fluid secretion by inhibiting basolateral potassium (K) channels. This study has also observed the specificity of Zn to cAMP-activated K channels, because zinc did not block the calcium (Ca)-mediated pottasium channels. As this study was not done in Zn-deficient animals, it provides support that Zn is probably effective in the absence of Zn deficiency (18, 19). Zinc also improves the absorption of water and electrolytes, improves regeneration of the intestinal epithelium, increases the levels of brush border enzymes, and enhances the immune response, allowing for a better clearance of the pathogens. Another report has recently shown evidence that zinc inhibits toxin-induced cholera, but not Escherichia coli heat-stable, enterotoxin-induced, ion secretion in cultured Caco-2 cells (20). In this way, Zinc plays an important role in modulating the host resistance to infectious agents and decreases the risk, severity, and duration of diarrheal diseases. It also plays an important role in metallo-enzymes, polyribosomes, and the cell membrane and cellular function, giving belief that it plays a central role in cellular growth and in the function of the immune system (21).

The primary site of absorption of exogenous zinc in the human is in the proximal small bowel, either the distal duodenum or proximal jejunum ((22). Factors known to control absorption include the amount of zinc present in the intestinal lumen, the presence of dietary promoters (e.g., human milk, animal proteins) or inhibitors (e.g., phytate, other minerals), zinc "status" especially in relation to chronic zinc intake, and physiologic states (23).