Large Doses Of Vitamin Research Articles

Vitamin K metabolism.

The discovery of vitamin K can be largely attributed to the Danish scientist Henrik Dam, whose work on sterol metabolism in chicks required the feeding of carefully controlled diets, some of which were depleted in lipids (Dam, 1929). This often caused internal hemorrhages and other symptoms similar to scurvy, but which Dam showed to be incurable by large doses of vitamin C. The finding of the lack of influence of cod liver oil concentrates (as a source of vitamins A and D), but the protective effect of cereals and seeds, prompted Dam to suggest that the bleeding syndrome was caused by a lack of an essential dietary component that was different from vitamins A, D, and C (Dam and Schoenheyder, 1934; Dam, 1934). Further work by Dam with experimental diets showed the factor was fat soluble, heat stable and occurred in various animal and plant tissues, hog liver fat being one of the best sources. In 1935, after ruling out vitamin E (hog liver fat was many times as active as wheat-germ oil), Dam proposed that the antihemorrhagic factor was a new fat-soluble vitamin that he called “Koagulations vitamin” or vitamin K (Dam, 1935a,b). Other rich sources of vitamin K were found to be green leaves such as alfalfa. Another surprisingly rich souce was bran or fishmeal which had become putrifled by the action of bacteria (Almquist and Stokstad, 1935; Almquist et al., 1938), suggesting that microbial action as well as plant biosynthesis is capable of producing the factor. Improvements in the assay method based on the restoration of normal clotting time in hemorrhagic chicks led to the proposal that a lack of vitamin K caused a deficiency in prothrombin activity and that vitamin K might be some kind of coenzyme or prosthetic group required for active prothrombin (Schoenheyder, 1936). However, subsequent work showed that prothrombin precipitates were active after all lipids had been removed and that vitamin K concentrates could not induce blood to clot (Dam et al., 1936).

Modulation of Kupffer cell and peripheral blood monocyte activity by in vivo treatment of rats with all-trans-retinol.

Previous studies have shown that large doses of vitamin A potentiate chemical-induced liver injury and that the Kupffer cell is directly involved in this potentiation. Therefore, these studies were designed to determine if Kupffer cells isolated from vitamin A treated male Sprague-Dawley rats (75 mg/kg/day for 3-7 days as all- trans-retinol) had altered activity and function. Respiratory activity of Kupffer cells isolated from rats treated with vitamin A for 3 to 7 days markedly increased. Similarly, phagocytic activity was significantly elevated (up to 9-fold) after exposure to vitamin A for 3 to 7 days. Production of reactive oxygen species, measured by luminol-enhanced chemiluminescence of Kupffer cells isolated after 7 days of vitamin A exposure, was significantly higher than that of control cells when stimulated with opsonized zymosan. Also, the release of superoxide anion by individual Kupffer cells isolated from vitamin A treated rats was nearly three times greater than that of control cells. Basal production of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) production were significantly elevated in Kupffer cells isolated from rats treated with vitamin A. Lastly, peripheral blood monocytes (PBMC) isolated from rats treated with vitamin A for 7 days had a significantly greater respiratory activity, as well as TNF-alpha and PGE2 production, than PBMC isolated from control rats. Our data suggest that large doses of vitamin A enhance both Kupffer cell and PBMC function. Upregulation of the activity by these phagocytic cells may play a role in the vitamin A potentiation of chemical-induced liver injury.

Vitamin a megadoses during early infancy on serum retinol concentration and acute side effects and residual effects on 6 month follow-up

We evaluated the safety and efficacy of 3 oral doses of 50,000 IU vitamin A at monthly intervals in predominantly breastfed infants from poor urban Bangladesh aged 6 to 17 weeks along with DPT and oral polio vaccines in a randomised double-masked controlled trial. Ninety-seven infants received vitamin A and 103 received placebo. Initial fasting serum retinol concentrations were very low in most infants (52% < 10 μg/dl and 74% < 15 μg/dl) which improved in both groups but was still less than 15 μg/dl in 30% of those who received vitamin A. Nine infants in the vitamin A group and 2 in the placebo group had bulged fontanelle after the second and/or third dose (RR = 4.78, 95% CI 1.06–21.54, P < 0.025) which resolved in 48 hours. In conclusion young infants from a deprived urban community in Bangladesh were deficient in vitamin A; a large proportion remained deficient even after three large doses of vitamin A. In spite of deficiency, bulged fontanelle, an apparent toxic manifestation, occurred in 9.3% with this dosage schedule of vitamin A. Alternative and/or complementary approaches e.g. maternal supplementation are needed to prevent vitamin A deficiency in under 6 month infants in developing countries.

Preoperative and Postoperative Management of the Body Contour Patient

Rod Rohrich, MD Peter B. Fodor, MD Judith J. Petry, MD, FACS Peter Vash, MD Dr. Rohrich: The first patient (Figure 1) has minimal fat deposits in her hips and thighs and wants liposuction of her lateral thighs. Dr. Fodor, how would you evaluate this patient? Figure 1 Patient has minimal fat deposits in her lips and thighs and wants liposuction of her lateral thighs. Dr. Fodor: This patient appears to be an ideal candidate for lipoplasty. She certainly is not obese, but she has localized fat deposits, and her skin tone is good. As with all of my prospective lipoplasty patients, this patient's lifestyle; “aerobic shape”; body weight fluctuations; and intake of vitamins, Chinese herbs, and other remedies would be evaluated preoperatively. A number of potentially harmful nutritional restriction regimens and dietary supplements are currently “in vogue.” Some of my liposuction and face lift patients who had been taking herbs, Chinese medications, and megadoses of vitamins had intraoperative bleeding and postoperative ecchymosis in excess of what one would ordinarily see. So I check medical histories very carefully to make sure patients are not taking any of these medications or large doses of vitamins. Based on these findings, I sometimes postpone surgery until the proper preoperative nutritional balance and aerobic shape are achieved. Dr. Rohrich: Dr. Vash, as an endocrinologist who has vast experience with diet regimens, how do you approach patients like this, who have a minimal amount of generalized fat deposits? Which patients, in terms of their nutrition, diet medications, and weight loss or gain regimens are ideally suited for liposuction? Dr. Vash: First one needs to be certain that the patient does not have a history of any eating disorder, such as bulimia or binge eating. If the patient's stable body weight fluctuates by more than 5%, this might …

Ataxia with isolated vitamin E deficiency in four siblings

We describe 4 siblings of a consanguineous Bedouin family with Friedreich ataxia phenotype in whom low serum vitamin E levels without other indicators of fat malabsorption were detected. Although age of onset and some of the clinical features were alike in all 4 patients, the electrophysiological parameters were markedly abnormal in 2, but normal in the other 2. Erythrocytes revealed both membranous and intracellular evidence of oxidative damage. The mutations described in other families with ataxia with isolated vitamin E deficiency were not detectable, nor was an abnormal single-stranded conformation polymorphism pattern apparent in the three exons at the 3′ region of the gene. Vitamin E administration in pharmacological doses improved the neurological condition in 2 patients and also corrected some of the patients' erythrocyte cell abnormalities. The finding of vitamin E deficiency in other cases of Friedreich ataxia phenotype may allow treatment at an early stage of the disease, when large dose Vitamin E therapy may reverse the neurological lesions.

Benefits and Liabilities of Vitamin A and Carotenoids

Vitamin A and carotenoids are often cited as members of a family of antioxidant vitamins that can show protective effects against oxidative stress and some chronic diseases. The great advantages of aerobic metabolism are offset in part by adverse physiological effects that can be caused by highly reactive forms of oxygen and its reduction products. Nature has developed a variety of sophisticated defenses against these undesirable side effects of oxygen. Vitamin A and carotenoids can serve chemically both as electron acceptors and donors (i.e., as oxidants and reductants), although in nature vitamin A seems to be protected from oxidation by other physiological antioxidants rather than serving a protective role itself. Furthermore, large doses of vitamin A are toxic. Carotenoids may serve a broader protective role in humans as they do in plants and microorganisms, but the evidence supporting such a role in humans is mixed. The widely used term antioxidant vitamins is too narrow in scope for the properties attributed to them. A much better term is physiological modulators, which broadens both the set of compounds that are included and the possible nature of their actions, whether beneficial or adverse.

Acute Respiratory Infections Prevent Improvement of Vitamin A Status in Young Infants Supplemented with Vitamin A

At immunization contact, 165 infants 2.5 mo old were randomly assigned to receive either 15 mg vitamin A (retinyl palmitate) or placebo. Three doses were given at monthly intervals with each diptheria, pertussis, tetanus and oral polio (DPT/OPV) immunization dose. The diarrhea and acute respiratory infection (ARI) morbidity was similar in the vitamin A and placebo groups. However, the duration (days per child-year, mean ± SD) of ARI was less in the vitamin A group compared with placebo group (27.6 ± 17.1 vs. 40.8 ± 22.7; P = 0.005). Fasting retinol concentrations were measured at entry and in 61 infants, the relative dose response (RDR) test was done 1 mo after the third dose of vitamin A. Eighty-five percent of the infants had serum retinol concentration < 0.70 mol/L at entry. After 3 mo the serum retinol levels improved significantly in both groups, and in the vitamin A-supplemented group the serum retinol concentration was significantly better than that in the placebo group (P = 0.02). However, 61% of the infants remained deficient despite vitamin A supplementation. Among vitamin A-supplemented infants only, diarrhea and ARI morbidity during the 3-mo period were compared in children with normal versus children with abnormal RDR at the end of the supplementation period. The ARI episodes were more frequent in the supplemented infants who remained vitamin A deficient at the end of the 3 mo (P = 0.027). Also, the cumulative duration (days, mean ± SD) of fever and cough was 5.0 ± 2.8 in the normal versus 11.2 ± 6.0 in the deficient group (P = 0.04). The results of this study suggest that a large proportion of infants remain vitamin A deficient even after large dose vitamin A supplementation because of frequent respiratory infections, particularly those accompanied by fever.

Vitamin A Potentiation of Vinylidene Chloride Hepatotoxicity in Rats and Precision-Cut Rat Liver Slices

Pretreatment of large doses of vitamin A (VA) is known to potentiate the hepatotoxicity of carbon tetrachloride. Therefore the effects of 1-day VA pretreatment on VDC hepatotoxicity was examined both in vivo and in an in vitro system of precision-cut rat liver slices. Male Sprague-Dawley rats were pretreated with 250,000 IU/kg VA by oral gavage. After 24 hr rats were administered 50, 100, or 200 mg/kg VDC ip. Precision-cut liver slices were prepared from VA pretreated rats 24 hr later and the liver slices were exposed for 2-8 hr to 0.025-1.0 microliter VDC evaporated into the gas phase of the incubation vials. VA pretreatment resulted in an enhancement of VDC toxicity, both in vivo and in vitro. There was a dose-dependent increase in plasma ALT 24 hr after VDC treatment of rats and an increase in K+ leakage from liver slices after VDC exposure. Histological analysis of the liver or the liver slices revealed that VA + VDC treatment resulted in centrilobular necrosis of the liver. When GdCl3 (10 mg/kg iv) was administered just before VA pretreatment of rats, VDC toxicity was partially reversed as observed by a decrease in ALT in vivo and a decrease in the loss of K+ in vitro. These results indicated that Kupffer cells, the resident macrophages of the liver, were partially responsible for the VA-potentiated VDC hepatotoxicity. One-day pretreatment of VA induced cytochrome P450IIE1 protein content as well as its enzymatic activity as measured by pnitrophenol hydroxylation. Because VDC is bioactivated by cytochrome P450IIE1, the increase in VDC hepatotoxicity after VA may be due to an increased bioactivation of VDC in the liver and in precision-cut liver slices. Thus, more than one mechanism may be involved in the VA enhancement of VDC hepatotoxicity.

Combined Superwarfarin and Ethylene Glycol Ingestion:A Unique Case Report With Misleading Clinical History

A markedly elevated prothrombin time (PT) and activated partial thromboplastin time (APTT) were observed in a 24-year-old man who was admitted with a history of ethylene glycol ingestion. Further laboratory evaluation suggested that the coagulopathy was related to acquired factor deficiencies. The PT and APTT improved transiently on usual doses of vitamin K, but rapidly became abnormal again. The coagulopathy was controlled only after large doses of vitamin K for at least 37 days. On further questioning, the patient admitted to consuming a large quantity of a rodenticide. The second generation anticoagulant rodenticides (superwarfarins) result in a potent and prolonged anticoagulant effect by reducing the activity of the vitamin K dependent factors (II, XII, IX, and X). To our knowledge, this is the first reported concomitant ingestion of both ethylene glycol and a superwarfarin compound. This case serves to illustrate how a logical laboratory evaluation can lead to the proper diagnosis, despite a misleading clinical history.

Vitamin A for common cause of blindness?

Large doses of vitamin A might help prevent age related macular degeneration (ARMD) and blindness, American researchers think.

Child morbidity and mortality following vitamin A supplementation in Ghana: time since dosing, number of doses, and time of year.

The impact of large-dose vitamin A supplementation given at intervals of 4 months on child mortality and morbidity was examined according to the time interval since dosing, number of doses received previously, and time of year. Two double-blind, randomized, placebo-controlled trials of large doses of vitamin A administered at intervals of 4 months were conducted in adjacent populations in northern Ghana. While vitamin A supplementation significantly reduced the overall incidence of severe illnesses (especially diarrhea with dehydration), clinic attendances, hospital admissions, and mortality, there was no evidence that the impact of each dose of vitamin A was related to the number of doses the child had received previously. There was no evidence that the effectiveness of the supplement waned over the 3 to 5 months between doses. The impact on mortality did not differ significantly by the month in which the supplement had been given. In the study population, there was no evidence that an interval between doses of less than 4 months would have had a greater impact on severe morbidity or mortality, and the effectiveness of supplementation did not vary by time of year.

Metabolism of vitamin B 6 by human kidney

A continuous intravenous pyridoxine-infusion (dose = 100 mg PN·HCl τ = 6 h) was given to 10 healthy male volunteers (aged between 23 and 32). Concentration-time curves of B 6-metabolites in urine and blood plasma were observed over a period of 240 hours. From these curves biokinetic parameters were calculated. Renal clearances (ml/min/1.73 m 2) were 257.5 ± 92.1 (pyridoxine), 249.8 ± 48.2 (4-pyridoxic acid), and 20.1 ± 6.0 (pyridoxal). Rate constants of elimination (h −1) obtained by non-linear regression of the excretion curves were 1.231 ± 0.877 (pyridoxine), 0.314 ± 0.118 (k α) and 0.048 ± 0.070 (k β) (4-pyridoxic acid), and 0.653 ± 0.360 (pyridoxal). The main part of the infused pyridoxine was eliminated in the form of metabolites (63.7 ± 6.4% for 4-pyridoxic acid, 3.3 ± 0.9% for pyridoxal); only 6.7 ± 1.8% was excreted unchanged. The proportion of 4-pyridoxic acid within each miction increased from 53.0 to 100.0%. Our data indicate a very effective metabolism of the physiologically inactive pyridoxine. An enzyme induction suggested by the increasing proportion of 4-pyridoxic acid cannot be excluded. Large doses of vitamin B 6 are excreted rapidly via the kidney, with the excretion of pyridoxine and 4-pyridoxic acid being enhanced by tubular secretion.

Administration of large doses of vitamin C does not decrease oxidant-induced lung lipid peroxidation caused by bacterial-independent acute peritonitis.

Acute zymosan-induced peritonitis in rats produces lung inflammation and lipid peroxidation. The effect of this process on plasma and lung tissue ascorbic acid was determined, as was the effect of infusing 150 mg/kg of ascorbic acid immediately after zymosan on the degree of lung insult. Ascorbic acid levels were significantly decreased in plasma and lung tissue at 24 h after zymosan, and lung tissue conjugated diene and neutrophil content was also significantly increased. Vitamin C infusion increased postzymosan plasma levels by 50% over normal control levels. However, lung tissue ascorbic acid was still decreased, and no decrease in the lung injury process was noted. Added ascorbic acid also did not prevent a decrease in plasma vitamin E with the peritonitis. We conclude that the amount of ascorbic acid given in this study did not diminish the lung oxidant inflammatory changes. An insufficient dose or inadequate time for plasma ascorbic acid to equilibrate with the lung cytosol are possible explanations for the lack of attenuation of lung oxidant stress.

A 210-µmol Dose of Vitamin A Provides More Prolonged Impact on Vitamin A Status than 105 µmol among Preschool Children

AbstractA randomized controlled clinical trial was conducted to determine the relative protection afforded by two large doses of vitamin A against subclinical vitamin A deficiency among 345 preschool children. At baseline, children either had or were at high risk of developing non-corneal xerophthalmia. Vitamin A status was assessed by the relative dose response (RDR) test, serum retinol concentration, and ocular examination before and 3 and 6 mo following one oral dose of 105 µmol or 210 µmol of vitamin A. At 3 and 6 mo, mean serum retinol concentration was significantly higher in the 210-µmol group than in the 105-µmol group. The proportion of children with a positive RDR did not differ between groups at 3 mo, but by 6 mo there were three times more children positive in the 105-µmol group. Most of the observed difference was confined to children with xerophthalmia at baseline. The relative benefit of the 210-µmol dose was related to baseline vitamin A status. The current World Health Organization recommended prophylactic dose of 210 µmol seems appropriate

Vitamin A supplementation and dietary vitamin A in relation to the risk of xerophthalmia

We examined the effect of 60-mg (200,000-IU) supplements of vitamin A administered every 6 mo on the incidence of xerophthalmia among preschool children who were free of eye symptoms and signs of vitamin A deficiency. We also prospectively studied the relationship of dietary vitamin A intake with the same endpoint. After 18 mo of follow-up, 400 children developed xerophthalmia during 80,104 child-periods of follow-up. Vitamin A supplementation only modestly reduced the risk of xerophthalmia (relative risk 0.88, 95% confidence interval 0.72-1.07, P = 0.19). On the other hand, total dietary vitamin A intake was strongly associated with reduced risk of xerophthalmia; the multivariate relative risk when children in extreme quintiles were compared was 0.38 (95% confidence interval 0.19-0.74; P for trend over quintiles = 0.002). These results emphasize the need for further data on factors that modify the bioavailability of large-dose vitamin A supplements. Increased consumption of inexpensive vegetables and fruits is highly likely to reduce significantly the risks of vitamin A deficiency, including nutritional blindness in developing countries.

Characterization of Vitamin A Potentiation of Carbon Tetrachloride-Induced Liver Injury

Pretreatment of rats with large doses of vitamin A (VA, retinol) has been shown to potentiate carbon tetrachloride hepatotoxicity. The relationship between VA dose or pretreatment duration with VA and the extent of potentiation of CCl 4 hepatotoxicity is unknown. Therefore, VA was administered to male SD rats (180-200 g) by oral gavage in daily doses of 100,000, 150,000, 200,000, or 250,000 IU/kg for 3 weeks. In another experiment, rats were given VA in a daily dose of 250,000 IU/kg for 1 day, 1, 2, 3, or 5 weeks. At 24 hr after the last VA dose, CCl 4 (0.15 ml/kg, ip) was administered. Hepatotoxicity was assessed by increases in plasma alanine aminotransferase activity and by histological evaluation of the liver. Additionally, the correlation between the hepatic concentration of retinol and retinyl palmitate after VA treatment and the extent of potentiation of CCl 4-induced liver injury was studied. In the initial 3-week dose-response study, as the daily dose of VA increased so did the degree of potentiation of CCl 4 hepatotoxicity. All treatment durations with VA (250,000 IU/kg per day), except 1 day, resulted in equivalent potentiation of CCl 4 hepatotoxicity. VA treatment did not result in elevated hepatic concentration of retinol. However, VA treatment did increase the concentration of retinyl palmitate in the liver (except for the 1-day treatment). No linear correlation could be seen between the hepatic concentration of retinyl palmitate and the extent of VA potentiation of CCl 4 hepatotoxicity. VA treatment also potentiated to hepatotoxicity of minimally hepatotoxic doses of acetaminophen, allyl alcohol, and endotoxin. Because these chemicals produce hepatic injury by diverse mechanisms it is concluded that VA potentiates hepatic injury by altering a process involved in the progression of cell injury.

Vitamin A Potentiation of Carbon Tetrachloride Hepatotoxicity: Role of Liver Macrophages and Active Oxygen Species

Pretreatment of rats with large doses of vitamin A (VA) potentiates the hepatotoxicity of CCl 4. Because our previous studies indicate that VA treatment does not enhance CCl 4, metabolism but does enhance CCl 4-induced lipid peroxidation and activates liver Kupffer cells to release increased amounts of oxygen-centered free radicals, the current studies were designed to determine if VA treatment potentiates CCl 4-induced liver injury through increased release of reactive oxygen species. Plasma clearance of colloidal carbon, an index of Kupffer cell phagocytic activity, was enhanced two- to threefold in rats treated for 7 days with VA (retinol, 250,000 IU/kg per day). Accordingly, VA treatment alone caused Kupffer cell activation. To determine if these activated Kupffer cells could potentiate hepatic injury through release of reactive oxygen species upon Cd4 challenge, polyethylene glycol coupled-superoxide dismutase (PEG-SOD, 10,000 IU/kg) or -catalase (PEG-CAT, 40,000 IU/kg) was given iv 2 hr after CCl 4, (0.15 ml/kg, ip) to control or VA-pretreated rats to quench any released reactive oxygen. PEG-SOD and PEG-CAT effectively blocked VA potentiation of CCl 4, liver injury as assessed at 24 hr by change in plasma ALT. Methylpalmitate (MP, 2 g/kg), an inhibitor of Kupffer cell phagocytosis and related oxygen burst, also blocked the potentiation of liver injury when given iv 24 hr before CCI4 to VA-pretreated rats. At the doses used, PEG-SOD or PEG-CAT did not influence CCl 4 toxicity in control rats (at 0.15 or 2 ml CCl 4/kg). Importantly, SOD, CAT, and MP blocked the enhanced lipid peroxidation induced by CCl 4, in VA-pretreated rats. From these findings we conclude that the potentiation of CCl 4, liver injury by VA pretreatment is mediated, at least in part, by active oxygen species released from Kupffer cells and possibly other macrophages that are activated by VA. Supporting this conclusion is the failure of VA pretreatment to increase the release of LDH from suspension of hepatocytes incubated with CCl 4,.

Effect of dietary antioxidant combinations in humans. Protection of LDL by vitamin E but not by beta-carotene.

Experimental and epidemiological evidence supports the hypothesis that oxidation of low density lipoprotein (LDL) appears to be important in mediating the atherogenicity of LDL. To test this hypothesis in humans, it will be necessary to perform intervention studies in large populations. We performed two studies to assess the effectiveness of supplementation with beta-carotene and vitamin E, used alone and in combination with each other, and with vitamin C, to protect LDL from oxidation. In phase 1, after a placebo period, eight subjects were given beta-carotene (60 mg/day) for 3 months, then beta-carotene plus vitamin E (1,600 mg/day) for another 3 months, and then beta-carotene plus vitamin E plus vitamin C (2 g/day) for 3 months. During phase 2, beta-carotene and vitamin C were discontinued, and subjects took only vitamin E for 5 months. During each period, LDL samples were isolated, and measurements of susceptibility to oxidation were performed. beta-Carotene levels in LDL increased nearly 20-fold, but LDL susceptibility to oxidation did not change. Addition of vitamin E increased LDL vitamin E levels nearly 2.5-fold, and this decreased LDL oxidation 30-40%. During the vitamin C supplementation period, plasma levels of beta-carotene and vitamin E rose, but only beta-carotene increased in LDL. However, the susceptibility of LDL to oxidation in this period was not decreased further. During phase 2, when subjects took only vitamin E, LDL susceptibility to oxidation was decreased by 50% as measured by thiobarbituric acid-reactive substances, conjugated dienes, and lipid peroxide formation as well as by macrophage degradation. Thus, long-term supplementation with large doses of vitamin E alone, but not beta-carotene, conferred increased protection to LDL in in vitro assays of oxidation. These data should be useful in planning therapeutic strategies to test the antioxidant hypothesis in humans.

Effects of large doses of vitamin D on calcium, magnesium and phosphate metabolism in horses – clinical and post mortem findings

Effects of large doses of vitamin D on calcium, magnesium and phosphate metabolism in horses – clinical and post mortem findings

Vitamin A supplementation and child survival

Previous studies of the effect of 6-monthly vitamin A supplementation on child mortality have given conflicting results. In other trials, more frequent doses of vitamin A have significantly reduced mortality among children at risk of vitamin A deficiency. We have done a double-blind, placebo-controlled trial of vitamin A supplementation in the Sudan among 28 753 children aged 9-72 months at risk of vitamin A deficiency. Children were assigned to receive either 200 000 IU vitamin A and 40 IU vitamin E every 6 months (vitamin A group) or 40 I U vitamin E alone (placebo group). During the 18 months of follow-up, there were 120 deaths (8·4/1000) in the vitamin A group and 112 (7·9/1000) in the placebo group (relative risk 1·06, 95% confidence interval 0·82-1·37). Controlling for geographic site, round of observation, anthropometry, morbidity, dietary intake of vitamin A, sex, and all baseline differences between the two groups did not change the results. Children living in poor and unsanitary environments, younger children, and those sick, stunted, wasted, or consuming diets low in vitamin A were at a significantly higher risk of dying. The lack of an effect of large-dose vitamin A supplementation on mortality, despite a clear association between dietary vitamin A and mortality, underscores the need to identify factors that modify the efficacy of vitamin A supplements as a public-health measure. Reducing poverty, improvements in sanitation, and access to adequate diets should remain the main goals to improve child survival.