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Absent ileal uptake of IF-bound vitamin B12 in vivo in the Imerslund-Grasbeck syndrome (familial vitamin B12 malabsorption with proteinuria).

A Syrian family is described with three children who had inherited selective vitamin B12 malabsorption associated with proteinuria. (Imerslund-Grasbeck syndrome). Although inherited the defect was apparently not present at birth. A third child had less severe vitamin B12 malabsorption, was not vitamin B12 deficient and had no proteinuria. Studies on two of the affected children with subcellular fractionation of the uptake of radioactive vitamin B12 by ileal tissue in vivo indicate a defect in the ileal receptors for IF-bound vitamin B12. These findings are different from the single in vitro experiment on a patient with this condition that has been previously reported.

Adolescent↗

Is the bioreactivity of vitamin-E-modified dialyzer an expression of increased plasmatic vitamin E concentration?

The present study was designed to test the biocompatibility of a new vitamin E-modified multilayer membrane compared with highly biocompatible polysulphone dialyzer and acrylonitrile dialyzer. Thirty patients (mean age 53.2 +/- 15.3 SD years; dialytic age 36 +/- 5.6 months) were selected for the study. The study was divided into three periods of 6 months (phases A, B and C). In the first phase (from Jan. 1999 to June 1999) patients undergoing maintenance bicarbonate dialysis were randomly divided into three filter groups composed, respectively, of 10 patients: acrylonitrile group, polysulphone group and vitamin E-coated dialyzer group. In the phase B (from July 1999 to Dec. 1999) and in the phase C (from Jan. 2000 to June 2000), all three groups changed their own dialysis membranes. Vitamin E-coated dialyzer causes significant decreases in beta(2)-microglobulin, ferritin and immunoglobulin G, a normalization of complement C3 and an increase of plasmatic vitamin E compared to other filters. In the VE group homocysteine decreases but not in a significant manner. In addition, this dialyzer seems not to influence lipid pattern and protein-energy malnutrition parameters. These results clearly show a positive effect of this new filter in influencing different biochemical parameters, perhaps saving vitamin E and reducing polymorphonuclear cell activation.

Acrylonitrile↗

Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE).

BACKGROUND: Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3x2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients. METHODS AND RESULTS: A total of 732 patients >/=55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-alpha-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (P=0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo. CONCLUSIONS: Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.

Aged↗

Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha-tocopherol (vitamin E).

The premise that oxidative stress, among several other factors, plays an important role in atherogenesis implies that the development and progression of atherosclerosis can be inhibited by antioxidants. In this minireview we discuss several mechanisms by which the antioxidants ascorbate (vitamin C) and alpha-tocopherol (vitamin E) may protect against atherosclerosis. These mechanisms include inhibition of LDL oxidation and inhibition of leukocyte adhesion to the endothelium and vascular endothelial dysfunction. Overall, ascorbate appears to be more effective than alpha-tocopherol in mitigating these pathophysiological processes, most likely as a result of its abilities to effectively scavenge a wide range of reactive oxygen and nitrogen species and to regenerate alpha-tocopherol, and possibly tetrahydrobiopterin, from its radical species. In contrast, alpha-tocopherol can act either as an antioxidant or a pro-oxidant to inhibit or facilitate, respectively, lipid peroxidation in LDL. However, this pro-oxidant activity of alpha-tocopherol is prevented by ascorbate acting as a coantioxidant. Therefore, an optimum vitamin C intake or body status may help protect against atherosclerosis and its clinical sequelae, whereas vitamin E may only be effective in combination with vitamin C.

Animals↗

Serum vitamin E levels in very low-birth weight infants receiving vitamin E in parenteral nutrition solutions.

Serum vitamin E levels were measured in 17 very low-birth weight infants in the first 2 wk of life, before and after the institution of intravenous vitamin E supplementation in a dosage of 4.5 mg/day, as a component of MVI Pediatric multivitamin preparation. Serum vitamin E levels were 0.22 +/- 0.16 (SD) mg/dl before supplementation, and rose to 2.55 +/- 0.65 (SD) mg/dl in nine infants more than 899 g birth weight, and rose to 3.68 +/- 0.70 (SD) mg/dl in six infants less than 900 g at birth. These postsupplementation serum vitamin E levels are in the range in which a reduction of incidence or severity of retinopathy of prematurity and intraventricular cerebral hemorrhage has been reported by others. No toxic effects of the preparation or of the increased vitamin E levels were found.

Food, Formulated↗

Survival in septic guinea pigs is influenced by vitamin E, but not by vitamin C in enteral diets.

Oxygen-free radicals are produced during sepsis, and may contribute to cell injury and dysfunction. We studied the effect of different levels of vitamins E and C in the diet fed enterally to septic guinea pigs. Sixty-four female guinea pigs were provided with gastrostomies and allowed to recover. Intraperitoneal osmotic pumps were then implanted that provided effusion of Escherichia coli and Staphylococcus aureus for the next 7 days. Three days after pump implantations, the animals were started on one of nine diets. The diets were isocaloric and isonitrogenous, and differed only in the amounts of vitamins E and C. Three levels of each vitamin were used, based on the Recommended Daily Allowance (RDA). The feedings were continued for 2 weeks, during which time mortality was observed. The amount of vitamin C had no effect on outcome, with mortality rates of 68% (15/22) in the 1 x RDA group, 73% (16/22) in the 5 x RDA group, and 65% (13/20) in the 25 x RDA group. However, vitamin E altered outcome significantly, with mortality rates of 86% (18/21) in the 1 x RDA group, 45% (10/22) in the 3 x RDA group, and 76% (16/21) in the 9 x RDA group. Mortality in the 3 x RDA group was significantly lower than that in the 1 x RDA group and in the 9 x RDA group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Review of vitamin E and selenium in the prevention of prostate cancer: implications of the selenium and vitamin E chemoprevention trial.

The National Cancer Institute in cooperation with the Southwest Oncology Group has begun one of the largest prostate cancer prevention studies to date, the Selenium and Vitamin E Chemoprevention Trial (SELECT). The purpose of this article is to review the evidence and discuss the individual antioxidant compounds under study. The authors comprehensively reviewed the peer-reviewed literature on the chemoprevention of prostate cancer with emphasis on the antioxidants vitamin E and selenium. The credible leads for the primary prevention of prostate cancer using selenium and vitamin E have emerged as secondary findings from randomized controlled trials with corroborative evidence from observational and in vitro studies. Selenium and vitamin E are widely available compounds that are safe if taken in moderation, with relatively few adverse effects. The evidence in support of the antioxidants in the primary prevention of prostate cancer is promising, and the next step in definitively answering the question has been addressed by the investigators of SELECT. The SELECT study will define the role of the antioxidants selenium and vitamin E in the prevention of prostate cancer; complete data from the study will be available in 12 years.

Antioxidants↗

Vitamin D and vitamin D analogs as cancer chemopreventive agents.

Epidemiologic studies have associated vitamin D, attained through nutrition and sun exposure, with reduced cancer risk. Although dose-limiting hypercalcemia has limited the use of natural vitamin D in cancer prevention, several promising new synthetic vitamin D analogs (deltanoids) are under development. Examples are KH-1060, EB-1089, 1alpha-hydroxyvitamin D5, vitamin D2, and QW-1624F2-2. Clinical targets for deltanoids include colon, prostate, and breast. Studies to elucidate the molecular mechanisms underlying the observed efficacy of deltanoids are ongoing. The vitamin D receptor, a steroid/thyroid receptor superfamily member, appears to control most deltanoid effects on proliferation, apoptosis, differentiation, and angiogenesis.

Animals↗

Dementia and Alzheimer's disease in community-dwelling elders taking vitamin C and/or vitamin E.

BACKGROUND: Since increased oxidative stress may impair cognition and be a risk factor for dementia, there has been interest in determining whether use of antioxidants could protect against such events. OBJECTIVE: To determine whether supplement use of vitamins C and/or E in a community-based sample of older African American and white individuals delayed incident dementia or Alzheimer's disease (AD). METHODS: We selected a subgroup from the Duke Established Populations for Epidemiologic Studies of the Elderly, a longitudinal study of community-representative persons aged 65-105 years living in 5 adjacent counties in North Carolina, and followed them for dementia (1986-1987 through June 2000). Information gathered during in-home interviews included sociodemographic characteristics, health status, health service use, and vitamin use. Diagnosis of dementia and AD was based on evaluations using the clinical and neuropsychological batteries of the Consortium to Establish a Registry for Alzheimer's Disease, with final determination by consensus agreement of specialists using Diagnostic and Statistical Manual of Mental Disorders, third revision, and National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders criteria. RESULTS: Of 616 persons initially dementia-free (mean age 73 y; 62% female; 62% African American), 141 developed dementia, of whom 93 developed AD. Increased age and mobility problems were risk factors for dementia (only age for AD), while an increased number of outpatient visits reduced the likelihood of developing dementia. Neither use of any vitamins C and/or E (used by 8% of subjects at baseline) nor high-dose use reduced the time to dementia or AD. CONCLUSIONS: In this community in the southeastern US where vitamin supplement use is low, use of vitamins C and/or E did not delay the incidence of dementia or AD.

Aged↗

Low-density lipoprotein receptor-related protein 5 and vitamin D receptor gene polymorphisms in relation to vitamin D levels in menopause.

BACKGROUND: The low-density lipoprotein receptor-related protein 5 (LRP5) gene has been recently identified as a novel candidate for osteoporosis. The c.4037C>T polymorphism in the LRP5 gene has been associated with bone mass variance in general population. In contrast, the IVS8+443G>A polymorphism in the vitamin D receptor gene (VDR) has not been investigated in relation to bone metabolism. The aim of the present study was to determine VDR IVS8+443G>A and LRP5 c.4037C>T polymorphisms in a cohort of 165 perimenopausal women and to associate the genotypes with biochemical and densitometric bone parameters in a subset of 112 postmenopausal women. METHODS: Both polymorphisms were assessed by restriction analysis of the PCR product. Calcium, parathyroid hormone, vitamin D metabolites and bone mineral density (BMD, g/cm(2)) at the hip and in the spine (L(1)-L(4)) were examined. RESULTS: The genotype frequencies of both IVS8+443G>A (UU 75.2%, Uu 23%, uu 1.8%) and c.4037C>T (CC 73.9% TC 23.6%, TT 2.4%) were comparable to other Caucasian female cohorts. Serum 25OH vitamin D levels, assessed in only 63 probands, were significantly associated with VDR genotypes (ANCOVA, p A polymorphism was significantly associated with circulating 25OH vitamin D in postmenopausal Caucasian women. The role of candidate gene polymorphisms in the vitamin D metabolic pathway requires further investigation.

Aged↗

Risk of vitamin A toxicity from candy-like chewable vitamin supplements for children.

Numerous vitamin supplements are available over-the-counter to the general public. Some such supplements are available as candy-like chewable preparations to encourage consumption by children. We report 3 cases of overdose of such preparations. Each patient had taken an estimated 200,000 to 300,000 IU of vitamin A. Their circulating vitamin A (retinol and retinyl palmitate) concentrations were monitored over a 6-month period. There were no clinical or biochemical complications noted. However, there were marked increases in both retinol and retinyl palmitate concentrations above age-related reference ranges. In particular, it took 1 to 3 weeks for the serum retinol concentrations to peak and many months for them to normalize. Parents should be warned about the dangers of excessive vitamin consumption. Clinicians should be aware of the late peak in serum retinol concentrations, which may lead to late complications of vitamin A overdose.

Biotransformation↗

Comparisons between absorption of vitamin E in patients with chronic pancreatitis and healthy controls: the bioavailability of vitamin E.

The fasting serum levels of alpha-tocopherol were determined by high-pressure liquid chromatography in 13 patients with chronic pancreatitis of whom 7 were positive for pancreatic calcification (CCP) and 6, negative (NCP) and 10 healthy subjects. The fasting serum levels of alpha-tocopherol were significantly lower in patients with chronic pancreatitis (7.2 +/- 1.1 micrograms/ml for CCP and 7.9 +/- 0.6 for NCP) than in healthy subjects (11.3 +/- 0.7 micrograms/ml). Vitamin E absorption was determined in those with chronic pancreatitis and in healthy subjects after postprandial oral administration of 400 mg of vitamin E, using soft capsules which contained tocopherol nicotinate along with an appropriate amount of a suspension of an ester of fatty acids with glycerol and middle chain triacylglycerol. The mean absorption of vitamin E was 12.7 +/- 2.0 micrograms/ml X hr for healthy subjects, 9.1 +/- 3.1 micrograms/ml X hr for CCP and 13.0 +/- 2.7 micrograms/ml X hr for NCP, respectively. There was no significant difference in vitamin E absorption between patients with chronic pancreatitis and healthy subjects. Further, the rate of hydrolysis of tocopherol nicotinate did not significantly differ between healthy subjects and patients with chronic pancreatitis. It is of interest to note that vitamin E absorption in patients with chronic pancreatitis was increased by the postprandial use of an oily suspension type preparation of tocopherol nicotinate.

Administration, Oral↗

What we learnt from randomized clinical trials and cohort studies of antioxidant vitamin? Focus on vitamin E and cardiovascular disease.

There is no doubt that oxidative stress is pivotally involved in the process of atherosclerosis. Thus antioxidants, particularly vitamin E, have been expected to retard the development of atherosclerosis. In fact, several cohort studies suggested reduced cardiovascular risk in persons taking vitamin E supplements. However, randomized clinical trials of vitamin E did not show any benefit of vitamin E supplementation in terms of prevention of coronary heart disease and death. Discrepancy between cohort studies and randomized clinical trials may be partly explained by difference in coronary risk in study participant. However, use of vitamin E supplementation in low risk population has not been justified yet.

Antioxidants↗

Vitamin D analogs as modulators of vitamin D receptor action.

The natural calcium-regulating hormone 1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) is a secosteroid that offers organic chemists many sites for modifying structural and/or functional groups. Such modifications alter the chemistry, stereochemistry, and biological properties of the natural hormone. The resulting deltanoids (vitamin D analogs) have been used in the past two decades as molecular probes to investigate structure-function relationships based on their interactions with proteins that regulate deltanoid biostability (catabolic enzymes of the vitamin D endocrine system and vitamin D binding protein) and deltanoid transduction of biological activities (nuclear and membrane receptors). In this review we will focus on structural modifications of 1,25D(3) that selectively modulate the nuclear vitamin D receptor (VDR). We will discuss the structural requirements and modifications that create analogs with greater potency and efficacy than the natural hormone (superagonists). We will also identify the structural features of an emerging group of noncalcemic selective agonists and describe the pharmacokinetic properties and VDR-mediated actions that promote their tissue- and gene-selective responses. In addition, we will speculate on the possible structural requirements for vitamin D antagonists. We will also examine the evidence from studies in cell-free systems, in culture and in vivo that explain the mechanisms for the distinct actions of each group of analogs, with special emphasis on the relationship between their mode of interaction with the VDR and the molecular and cellular outcome of these interactions. Finally, we will describe the current and potential use of these selective modulators of the VDR for treatment of human diseases such as osteoporosis, cancer, and secondary hyperparathyroidism.

Animals↗

Ultraviolet light-induced generation of vitamin E radicals and their recycling. A possible photosensitizing effect of vitamin E in skin.

Vitamin E (alpha-tocopherol) is the major lipid-soluble chain-breaking antioxidant of membranes. Its UV-absorbance spectrum (lambda max 295 nm) extends well into the solar spectrum. We hypothesize that in skin alpha-tocopherol may absorb solar UV light and generate tocopheroxyl radicals. Reduction of tocopheroxyl radicals by other antioxidants (e.g. ascorbate, thiols) will regenerate (recycle) vitamin E at the expense of their own depletion. Hence, vitamin E in skin may act in two conflicting manners upon solar illumination: in addition to its antioxidant function as a peroxyl radical scavenger, it may act as an endogenous photosensitizer, enhancing light-induced oxidative damage. To test this hypothesis, we have illuminated various systems (methanol-buffer dispersions, liposomes and skin homogenates) containing alpha-tocopherol or its homologue with a shorter 6-carbon side chain, chromanol-alpha-C6 with UV light closely matching solar UV light, in the presence or absence of endogenous or exogenous reductants. We found that: (i) alpha-tocopheroxyl (chromanoxyl) radicals are directly generated by solar UV light in model systems (methanol-water dispersions, liposomes) and in skin homogenates; (ii) reducing antioxidants (ascorbate, ascorbate+dihydrolipoic acid) can donate electrons to alpha-tocopheroxyl (chromanoxyl) radicals providing for vitamin E (chromanol-alpha-C6) recycling; (iii) recycling of UV-induced alpha-tocopheroxyl radicals depletes endogenous antioxidant pools (accelerates ascorbate oxidation); (iv) beta-carotene, a non-reducing antioxidant, is not active in alpha-tocopherol recycling, and its UV-dependent depletion is unaffected by vitamin E.

Animals↗

[Serum bone Gla-protein increases following short-term oral administration of active vitamin D3 in the elderly with vitamin D deficiency].

Serum bone Gla-protein (BGP) is produced by osteoblasts in a vitamin K-dependent process. It is well known that serum BGP levels increase after oral administration of active vitamin D3 in postmenopausal women and patients with chronic renal failure before dialysis. These findings indicate that active vitamin D3 increases the BGP production by osteoblasts. In the present study, a daily oral dose of 2 micrograms of 1 alpha (OH)D3 was administered to 10 elderly males (age, 75.0 +/- 10.9 years) and 8 young males (age, 29.0 +/- 3.2 years) to compare the changes in serum BGP levels between the two groups. None of the subjects had severe renal or hepatic dysfunction or abnormalities in calcium (Ca) metabolism. Serum BGP and 1,25(OH)2D levels in both groups were measured before the initial administration, at 24 h and at 1, 2 and 3 weeks after the start of administration. Serum parathyroid hormone (m-PTH), alkaline phosphatase (ALP), Ca and phosphorus levels were also measured in the elderly group. Serum BGP levels before the initial administration were 4.63 +/- 1.8 ng/ml in the elderly group and 4.33 +/- 0.92 ng/ml in the young group, with no significant difference between the two groups. In both group serum 1,25(OH)2D levels were slightly increased at 24 h after administration. In the elderly group serum BGP levels increased significantly to 11.5 +/- 3.0 ng/ml, an increase of approximately 250%, 1 week after the initial administration and the increase was maintained for up to 3 weeks after the administration commenced. However, no changes in serum BGP levels were noted in the young group. In the elderly group serum m-PTH levels were 544 +/- 257 pg/ml, almost the upper normal limit, before, and decreased slightly after, the administration of 1 alpha (OH)D3. Serum ALP levels also decreased slightly after the administration and serum Ca levels were slightly increased, however, the changes were within normal limits. We conclude that osteoblastic function is activated after short-term administration of active vitamin D3 in vitamin D deficient elderly subjects.

Administration, Oral↗

Influence of vitamin D status and chronic administration on the renal tubular effects of 1,25-dihydroxy vitamin D3.

Previous studies from this laboratory have demonstrated that the acute infusion of the vitamin D3 derivative, 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) is antiphosphaturic when administered with small "permissive" amounts of parathyroid hormone (PTH). To determine the effect of chronic administration of this metabolite, studies were performed in both vitamin D-deficient (-D) and vitamin D-fed (+D) rats which had been pretreated with 1,25(OH)2D3 for 6 days and then infused with either the metabolite alone, the metabolite with a small "permissive" dose of parathyroid hormone (PTH) or neither. The results indicate that in the -D animals, 1,25(OH)2D3 infusion alone results in antiphosphaturia without the presence of PTH. However, in the +D rats, PTH was required, despite 1,25(OH)2D3 pretreatment, for the acute infusion of the metabolite to enhance phosphate reabsorption. Thus, both vitamin D and parathyroid status are important in determining the effect of 1,25(OH)2D3 on the renal tubular transport of phosphate.

Animals↗

[Therapy of osteoporosis: native vitamin D or as hormone? Advantages of activated vitamin D in secondary osteoporosis].

Vitamin D and its active metabolite (D-Hormone) are major weapons in the therapeutic arsenal available for the treatment of osteoporosis. With regard to native vitamin D, controlled studies have confirmed the prophylactic effect of treatment with vitamin D (+ calcium) in the area of nonvertebral fractures, in particular in elderly women with vitamin D deficiency. The widespread prophylactic use of this form of treatment, which is both inexpensive and largely free of side effects, would presumably save costs by greatly reducing the incidence of fractures of the femur. Treatment with D-hormone (calcitriol) or the pro-hormone 1 alpha-hydroxy-vitamin D (alfacalcidol) is a specific form of treatment of osteoporosis that has been shown to prevent fractures, in particular of the vertebrae, in a number of controlled prospective studies. The D-hormone is of particular value in the treatment of secondary forms of osteoporosis (induced by glucocorticoids or chronic inflammatory disease). Although the incidence of severe side effects is low, monitoring of serum calcium ist nevertheless recommended.

Aged↗