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Rationale and impact of vitamin C in clinical nutrition.

PURPOSE OF REVIEW: The impact of vitamin C on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. Parenteral administration can increase the benefit of vitamin C supplementation as is evident in critically ill patients. The aim here is to assess recent evidence of the clinical benefit and underlying effects of parenteral vitamin C in conditions of oxidative stress. RECENT FINDINGS: In critically ill patients and after severe burns, the rapid restoration of depleted ascorbate levels with high-dose parenteral vitamin C may reduce circulatory shock, fluid requirements and oedema. SUMMARY: Oxidative stress is associated with reduced ascorbate levels. Ascorbate is particularly effective in protecting the vascular endothelium, which is especially vulnerable to oxidative stress. The restoration of ascorbate levels may have therapeutic effects in diseases involving oxidative stress. The rapid replenishment of ascorbate is of special clinical significance in critically ill patients who experience drastic reductions in ascorbate levels, which may be a causal factor in the development of circulatory shock. Supraphysiological levels of ascorbate, which can only be achieved by the parenteral and not by the oral administration of vitamin C, may facilitate the restoration of vascular function in the critically ill patient.

Antioxidants↗

Uses of vitamins A, C, and E and related compounds in dermatology: a review.

Vitamins have been increasingly used as prophylactic and therapeutic agents in the management of skin disorders. The current literature is replete with studies that promote the potential benefits of these compounds and attempt to elucidate their mechanisms of action. We review the literature and discuss the roles, safety, and efficacy of vitamins A, C, and E and related compounds in cutaneous health and disease.

Ascorbic Acid↗

Therapy of chronic idiopathic thrombocytopenic purpura in adults.

Chronic ITP is a common hematologic illness. Approximately three fourths of the patients respond to corticosteroids or splenectomy and need no further treatment. Patients refractory to these two therapeutic approaches are relatively resistant to present forms of treatment and are at much greater risk for morbidity and mortality. Future clinical studies evaluating therapy in this refractory group would be best performed in a cooperative group setting in which large numbers of patients could be treated in a prospective randomized manner.

Adrenal Cortex Hormones↗

Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of patients with HCC remain very poor. This study was conducted to evaluate the efficacy and safety of viscum fraxini-2 in patients with chemotherapy-naïve, advanced hepatocellular carcinoma. 23 patients with unrespectable HCC who had received no prior systemic chemotherapy with objectively measurable tumors were enrolled on this study. The mistletoe preparation for the study is an aqueous injectable solution. It contains one milliliter of viscum fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe herb from ash tree, diluted in di-natrium-mono-hydrogen phosphate, ascorbic acid and water) which is equivalent to 10 000 ng/ml injection ampoules. 2 ampoules of viscum fraxini-2 were administered subcutaneously once weekly. As assessed by conventional imaging criteria, 3 (13.1%) patients have achieved complete response, 2 (8.1%) patients have achieved a partial response. 9 (39.1%) had progressive disease while 9 (39.1%) patients didn't have evaluation of response due to early death. The median overall survival time for all patients was 5 months (range 2-38 months), for those who achieved a CR was 29 months (range 12-38 months) and, for those who achieved a PR was 6.5 months (range 6-7 months). The median progression free survival for all patients was 2 months (range 1-38 months), for those who achieved a CR, it was 29 months (range 8-38 months) and for those who achieved a partial response, it was 5 months (range 4-6 months). No hematologic toxicity has been encountered. The spectrum of non-hematologic toxicity was mild. The WHO toxicity criteria grade 3-4 were 34.8% drug related fever, 13.1% erthyma at injection site and 17.4% pain at the site of injection. No drug related discontinuation or toxic deaths have occurred. Viscum fraxini-2 seems to be particularly promising in patients with advanced HCC, it shows antitumor activity and low toxicity profile. Further studies in combination with other active agents are clearly warranted.

Adult↗

Nutraceutics and delivery systems.

Medical treatment has been shifted to being more prophylactic as a recent trend. Postgenomic research has unveiled the fact that nutritional intervention has been strongly associated with genetic expressions, which are responsible for a variety of biological functions. Based on these findings, the prophylactic effects of dietary supplement and nutrient have been enthusiastically investigated. Preventing or retarding the onset of diseases has become a more attractive and cost effective strategy in the medical arena. Among other approaches to prevent diseases, antioxidants, which are found in many phytochemicals, have received much attention. However, most natural antioxidants such as alpha-tocopherol, ascorbic acid and others are biologically unstable, poorly soluble in water, and poorly distributed to target sites. Because of these shortcomings further prophylactic applications of dietary supplements have stagnated. This is partially due to a lack of basic awareness of drug delivery system for dietary supplements and nutrients. In this article, we strongly advocate serious consideration of the bioavailability of dietary supplements. Currently, there are some challenging works to improve their bioavailability using delivery systems such as liposomal formulations. We will discuss the target molecules of dietary supplements for prevention of diseases and also introduce the pioneering works of delivery systems for dietary supplements to promote their therapeutic value.

Antioxidants↗

Absorption of calcium oxalate does not require dissociation in rats.

Calcium absorption is thought to occur only if calcium is in a soluble or dissociated form, although experimental evidence is lacking. The intestinal absorption of calcium oxalate, a small, neutral and virtually insoluble calcium salt, was elucidated in the whole body of awake rats. Suspensions of 45Ca ascorbate, 14C-oxalic acid and doubly labeled 45Ca-[14C]-oxalate were given by gavage to separate groups of rats. Following dosing, blood samples were drawn for up to 240 min through a previously inserted intravenous catheter. Serum was assayed for radioactive tracers, and data were then plotted as fraction of dose over time. Calcium absorption was 15% [with a loading of 0.3 mmol (15 mg) calcium], oxalic acid absorption was 22% and Ca-oxalate absorption was <2%. Appearance of 45Ca from calcium ascorbate and 14C from oxalic acid differed, whereas 45Ca and 14C from doubly labeled Ca-oxalate had identical serum appearance profiles. Therefore, we conclude that calcium oxalate was absorbed intact. Addition of excess, unlabeled calcium to the doubly-labeled calcium oxalate did not alter the relationship of the serum level of the two tracers, confirming absorption of calcium oxalate as the intact salt. Thus, calcium bound as a small, neutral, calcium salt such as calcium oxalate does not have to be dissociated prior to absorption. Possibly other small compounds would be similarly absorbed. These results alter our current understanding of calcium bioavailability from foods and therapeutic agents.

Absorption↗

A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects.

It is rare to see a day pass in which we are not told through some popular medium that the population is becoming older. Along with this information comes the "new" revelation that as we enter the next millennium there will be increases in age-associated diseases (e.g., cancer, cardiovascular disease) including the most devastating of these, which involve the nervous system (e.g., Alzheimer's disease [AD] and Parkinson's disease [PD]). It is estimated that within the next 50 years approximately 30% of the population will be aged 65 years or older. Of those between 75 and 84 years of age, 6 million will exhibit some form of AD symptoms, and of those older than 85 years, over 12 million will have some form of dementia associated with AD. What appears more ominous is that many cognitive changes occur even in the absence of specific age-related neurodegenerative diseases. Common components thought to contribute to the manifestation of these disorders and normal age-related declines in brain performance are increased susceptibility to long-term effects of oxidative stress (OS) and inflammatory insults. Unless some means is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Thus, it is extremely important to explore methods to retard or reverse age-related neuronal deficits as well as their subsequent, behavioral manifestations. Fortunately, the growth of knowledge in the biochemistry of cell viability has opened new avenues of research focused at identifying new therapeutic agents that could potentially disrupt the perpetual cycle of events involved in the decrements associated with these detrimental processes. In this regard, a new role in which certain dietary components may play important roles in alleviating certain disorders are beginning to receive increased attention, in particular those involving phytochemicals found in fruits and vegetables.

Alzheimer Disease↗

[Vitamin supplements in oncology -- necessary, useful or superfluous?].

Vitamins are essential components of a normal diet, and sufficient amounts are always needed. Occasionally, multivitamin supplements may make sense in cancer patients. However, because of the balance of (antioxidant) vitamins, coenzymes, trace elements and secondary phytochemicals it offers, a varied diet of fresh fruits and vegetables is--wherever possible--to be preferred to supplements of single or combinations of vitamins. Although preclinical studies have confirmed the positive effects of high-dose vitamins on cancer, there is currently no evidence that increased consumption of vitamins benefits cancer patients--nor is the dose necessary to achieve a possible therapeutic impact known. Since a number of clinical and epidemiological studies fail to show any benefit, and adverse effects have even been reported, high-dose vitamins can at present be recommended only for short-term substitution in known vitamin deficiencies. Before a definitive pronouncement can be made, therefore, further clinical studies of megavitamins in cancer patients are needed.

Adult↗

[Diagnosis and therapy of iron deficiency anemia in pregnancy].

39 pregnant women, hemoglobin in serum less than or equal to 6,80 mmol/l were treated with Vitaferro, Folicombin and additional vitamins. Test groups were formed by means of randomisation. Hematological and clinicochemical parameters were measured before, as well as 2 and 6 weeks after starting treatment and the results were evaluated.--In the diagnosis of iron deficiency anemia in pregnancy serum iron concentration and iron-binding capacity are sufficient. The diagnosis is proved by an increase of the serum hemoglobin 2 weeks after starting therapy. For the total number of patients an increase of hemoglobin could be proved 2- and 6 weeks after starting therapy. However, the 3 chosen therapeutic methods did not show any differences in statistically proved values in form of therapeutic results. This is, in our view, due to given deviation and the specific character of the test group. During pregnancy iron deficiency anemia should be treated by doses more than 100 mg iron per day. Normalization of the hemoglobin under iron substitution is no indication for immediate interruption of the treatment.

Anemia, Hypochromic↗

Dietary rescue of fumble--a Drosophila model for pantothenate-kinase-associated neurodegeneration.

Hallervorden-Spatz syndrome (HSS) is a devastating neurological disease, characterized by iron accumulation in the globus pallidus in the basal ganglia. Most HSS cases are caused by mutations in one of the four human pantothenate kinases (PANK2). This PANK2-caused subgroup of HSS is sometimes referred as PKAN (pantothenate-kinase-associated neurodegeneration). No effective treatment for PKAN or HSS is currently available. fumble, a Drosophila mutant that carries a mutation in Drosophila Pank, has many features similar to those of PKAN patients. In this study, we used fumble as a model to evaluate various compounds or nutritional products for their possible therapeutic efficacy. While no product was found to dramatically improve the symptoms, GKE (containing Ginkgo biloba extract and flavone) and vitamin E showed statistically significant beneficial effects. Our studies indicate that pantothenate is of limited value in alleviating fumble phenotypes and also suggest that some compounds might have deleterious effects.

Acetylcysteine↗

Antioxidant properties of bucillamine: possible mode of action.

The antioxidant properties of Bucillamine (BUC), a di-thiol compound used for treatment of rheumatoid arthritis (RA) and its possible mode of action, were investigated. BUC exhibits potent antioxidant activity similar to those of trolox and ascorbic acid. It reduces the stable free radical diphenyl-2-picrylhydrazyl (DPPH) with IC(50) of 18.5+/-0.1 micromol, its relative antioxidant activity by the ferric reducing ability (FRAP) is 2.07+/-0.01 mM and by the trolox equivalent antioxidant capacity (TEAC), 1.46+/-0.05 mM. However, its superoxide and apparent hydroxyl radical scavenging activities are low (IC(50) at millimolar concentrations). We found that BUC is a strong iron (II) and copper (II) chelator. This finding is very important since these metal ions are significantly higher in RA patients and may be involved in oxidative stress-induced damage. Our study suggests that BUC is a potent antioxidant which exerts its beneficial therapeutic activities in RA patients by metal chelation rather than by scavenging free radical species.

Antioxidants↗

Modulation of ochratoxin-produced genotoxicity in mice by vitamin C.

Ochratoxin A (OA), when administered orally daily for 45 days to albino Swiss mice, Mus musculus, at a level equivalent to the human dietary concentration of 1 microgram/kg body weight/day, increased the production of abnormalities in both mitotic and meiotic chromosomes as well as in the gross morphology of the sperm head. The sperm count per unit volume of caput epididymal suspension also decreased. Vitamin C at a concentration equivalent to the human therapeutic dose (10 mg/kg body weight/day), when administered orally concurrently with OA, significantly minimized the incidence of these abnormalities. The protective effect of vitamin C was most marked in mitotic chromosomes followed by that in meiotic chromosomes and sperm head morphology; the improvement in sperm count was least marked. The possible mechanism of this effect is discussed.

Administration, Oral↗

Dependence of nucleic acid degradation on in situ free-radical production by adriamycin.

Adriamycin (Adr) is one of the most powerful antitumor drugs. Its therapeutic effect may be due to its cyclic reduction-oxidation and, thus, generation of oxygen radicals. Using the spin-trap 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) and EPR we have demonstrated that in an enzymatic system consisting of NADPH, NADPH-cytochrome P-450 reductase, and Fe(EDTA)2 Adr stimulates formation of .OH radicals in the presence of DNA or RNA with equal efficiency. Incubation of nucleic acids in the Adr-dependent reaction generating .OH radicals resulted in extensive degradation of double- and single-stranded DNA, but did not effect RNA. In contrast, both DNA and RNA were effectively destroyed in a footprinting system, ascorbate-Fe(EDTA)2-H2O2, which generates .OH radicals in massive quantities. Fluorescence assays indicated that Adr forms stable complexes with ds- and ss-DNA but reacts only slightly with RNA. We conclude that the formation of Adr-nucleic acid complex is necessary for .OH radical-mediated cleavage of the latter, and thus, Adr may be regarded as a chemical nuclease acting in situ.

DNA↗

Captopril gastrointestinal therapeutic system coated with cellulose acetate pseudolatex: evaluation of main effects of several formulation variables.

Maintenance of constant drug levels in the body for those drugs that are used in management of hypertension is extremely beneficial. This can be successfully achieved by delivering the antihypertensives as osmotically-controlled drug-delivery system that essentially eliminates the influence of pH on the drug release. The main objective of this study was to evaluate the main effects of the formulation variables on the release of captopril from osmotically-controlled drug-delivery system coated with a custom-made cellulose acetate (CA) pseudolatex reported earlier. A secondary objective was to identify a suitable antioxidant for incorporating in the formulation as the drug undergoes metal-catalyzed oxidative degradation. The drug showed good stability (> or = 90% intact captopril) in solution in the presence of ascorbic acid for a period of 48 h. A seven-factor, 12-run Plackett-Burman screening design was employed to study the main effects of amounts of Polyox(R) N10 and N80, Carbopol(R) 934P and 974P, sodium chloride, orifice size, and % coating weight gain. The response variable was cumulative percent of drug released in 12 h, Y(3), with constraints on lag time Y(1) and time for 50% drug released Y(2)amount of sodium chloride (1.97).

Algorithms↗

Antioxidant status in rheumatoid arthritis and role of antioxidant therapy.

BACKGROUND: Oxygen free radicals have been implicated as mediators of tissue damage in patients of rheumatoid arthritis (RA). This study was designed to elucidate plasma oxidant/antioxidant status in rheumatoid arthritis, with the aim of evaluating the importance of antioxidant therapy in the management of this disease. METHODS: The study included 40 patients of rheumatoid arthritis who were randomly divided into two subgroups of 20 each. One group received conventional treatment for 12 weeks and in the other group conventional treatment was supplemented with antioxidants for the same duration. Twenty age- and sex-matched normal individuals constituted the control group. Blood samples of controls and patients were collected at the time of presentation and analyzed for total thiols, glutathione, vitamin C and malondialdehyde (MDA-marker of oxidative stress). The investigations were repeated in the patients after 12 weeks. RESULTS: The blood concentrations of total thiols, glutathione and vitamin C were found to be significantly lower in rheumatoid arthritis patients as compared to healthy controls, while the concentrations of MDA were much higher. There was a statistically significant increase in the posttreatment concentrations of these antioxidants, along with a decrease in the concentrations of MDA. CONCLUSIONS: The antioxidant defense system is compromised in rheumatoid arthritis patients. There is a shift in the oxidant/antioxidant balance in favor of lipid peroxidation, which could lead to the tissue damage observed in the disease. The results suggest the necessity for therapeutic co-administration of antioxidants along with conventional drugs to such patients. However, due to the limited number of cases included in this study, more studies may be required to substantiate the results and arrive at a definite conclusion, in terms of safety and efficacy of adding on antioxidant therapy for the treatment of RA.

Antioxidants↗

Chemical characterization of iron (III)-hydroxide-dextrin complexes. A comparative study of commercial preparations with alleged reproductions used in the examination of bioavailability.

The iron (III)-hydroxide-dextrin complexes in two commercial preparations were compared with alleged reproduction which have been prepared for bioavailability studies published recently. Precipitation behaviour in chloride media, kinetics of reduction by ascorbic acid, magnetic susceptibility and laser light scattering data reveal that the original preparations and the alleged reproductions are neither identical nor equivalent in chemical properties. The historical controversy about iron(II) versus iron(III) preparations in oral therapy should be dropped because, on chemical grounds, iron(II) salts are sources of iron(III) species appearing in the gastro-intestinal tract.

Biological Availability↗

Therapeutic trials in 200 patients with HTLV-I-associated myelopathy/ tropical spastic paraparesis.

We report here the results of therapeutic trials in 200 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) conducted in our department between 1986 and 1993. Motor disability grades were improved by more than one grade in 69.5% (91/131) of patients by oral administration of prednisolone, 50% (3/6) by eperisone hydrochloride only, 43.8% (7/16) by blood purification (lymphocytapheresis and plasmapheresis), 40.0% (2/5) by intrathecal injection of hydrocortisone, 30.0% (3/10) by intravenous injection of high-dose methylprednisolone, 23.3% (10/43) by interferon-alpha (intramuscular injection and inhalation), 22.2% (2/9) by azathioprine, 20.0% (4/20) by high-dose vitamin C, 16.0% (4/25) by erythromycin, 12.5% (3/24) by salazosulfapyridine, 11.8% (2/17) by mizoribine, 7.1% (1/14) by fosfomycin, and 6.3% (1/16) by thyrotropin releasing hormone. No critical side effects of these therapies were seen with the exceptions of one patient with adult respiratory distress syndrome due to cytomegalovirus infection and one patient with drug-induced hepatitis/hepatic failure. Selection of these treatments for patients with HAM/ TSP must be considered on the basis of age, sex, disease severity and complications to reduce adverse events and to improve quality of life. Although the results were a synopsis of different treatments given to 200 patients with HAM/ TSP as an open trial, we consider this the first report of a large-scale therapeutic trial in patients with HAM/TSP. The results of this study indicate that immunomodulatory therapies have some beneficial effects in HAM/TSP, and the functions of these agents are related to the pathophysiology of this disease.

Administration, Oral↗

Free radicals in antigen formation: reduction of contact allergic response to hydroperoxides by epidermal treatment with antioxidants.

BACKGROUND: For patients with allergic contact dermatitis, the main therapy is anti-inflammatory steroids, a non-specific and symptomatic treatment. In contact allergy, the antigen formation is considered to be the binding of a chemical (hapten) to a biological macromolecule, e.g. a protein. Limonene-2-hydroperoxide (Lim-OOH) is a hapten with a known allergenic effect. It is likely to bind to proteins in the skin via a radical mechanism. It might be possible to inhibit the allergic reaction by epidermal application of substances that can trap free radicals, e.g. antioxidants such as ascorbic acid or alpha-tocopherol, prior to the application of the hapten. OBJECTIVES: To study the influence of antioxidants on the allergenic effect of Lim-OOH in sensitization experiments on guinea pigs. METHODS: Pretreatment with the antioxidants was performed before induction to study the effect on sensitization as well as before challenge testing to study the effect on elicitation. RESULTS: A reduction in the response rate was found both at sensitization and at elicitation. The antioxidants had no effect on cobalt allergy or on the allergenic effect of haptens that form antigens via nucleophilic-electrophilic reactions. No reduction of the effect was seen for irritants. CONCLUSIONS: The protective effect of antioxidants in elicitation could be of practical therapeutic value, as it indicates a possibility for the treatment of patients who have become sensitized to haptens that form full antigens via a radical mechanism.

Allergens↗