The Science of Vitamin C
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component.
In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function and improves the absorption of nonheme iron, the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility.
However, in trials involving marathon runners, skiers, and soldiers exposed to extreme physical exercise and/or cold environments, prophylactic use of vitamin C in doses ranging from 250 mg/day to 1 g/day reduced cold incidence by 50%. In the general population, use of prophylactic vitamin C modestly reduced cold duration by 8% in adults and 14% in children.
Why Vitamin C IV?
Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects.
Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100–200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.
Due to the low storage capacity of the body for the water-soluble vitamin, a regular and adequate intake is required to prevent hypovitaminosis C. Epidemiological studies have indicated that hypovitaminosis C (plasma vitamin C < 23 μmol/L) is relatively common in Western populations, and vitamin C deficiency (<11 μmol/L) is the fourth leading nutrient deficiency in the United States [13,14].
Vitamin C has a number of activities that could conceivably contribute to its immune-modulating effects. It is a highly effective antioxidant, due to its ability to readily donate electrons, thus protecting important biomolecules (proteins, lipids, carbohydrates, and nucleic acids) from damage by oxidants generated during normal cell metabolism and through exposure to toxins and pollutants (e.g., cigarette smoke) .
Leukocytes, such as neutrophils and monocytes, actively accumulate vitamin C against a concentration gradient, resulting in values that are 50- to 100-fold higher than plasma concentrations. These cells accumulate maximal vitamin C concentrations at dietary intakes of ~100 mg/day, although other body tissues likely require higher intakes for saturation. Neutrophils accumulate vitamin C via SVCT2 and typically contain intracellular levels of at least 1 mM. Following stimulation of their oxidative burst neutrophils can further increase their intracellular concentration of vitamin C through the non-specific uptake of the oxidized form, dehydroascorbate (DHA), via glucose transporters (GLUT). DHA is then rapidly reduced to ascorbate intracellularly, to give levels of about 10 mM. It is believed that the accumulation of such high vitamin C concentrations indicates important functions within these cells.
Accumulation of millimolar concentrations of vitamin C into neutrophils, particularly following activation of their oxidative burst, is thought to protect these cells from oxidative damage . Vitamin C is a potent water-soluble antioxidant that can scavenge numerous reactive oxidants and can also regenerate the important cellular and membrane antioxidants glutathione and vitamin E . Upon phagocytosis or activation with soluble stimulants, vitamin C is depleted from neutrophils in an oxidant-dependent manner [50,51,52,53].
Patients with severe infection exhibit compromised neutrophil chemotactic ability [129,130,131,132]. This neutrophil ‘paralysis’ is believed to be partly due to enhanced levels of anti-inflammatory and immune-suppressive mediators (e.g., IL-4 and IL-10) during the compensatory anti-inflammatory response observed following initial hyper-stimulation of the immune system . However, it is also possible that vitamin C depletion, which is prevalent during severe infection , may contribute. Studies in the 1980s and 1990s indicated that patients with recurrent infections had impaired leukocyte chemotaxis, which could be restored in response to supplementation with gram doses of vitamin C [57,58,59,60,65,66,67]. Furthermore, supplementation of neonates with suspected sepsis with 400 mg/day vitamin C dramatically improved neutrophil chemotaxis .
Preclinical studies using Gluo knockout mice have highlighted the cytokine-modulating effects of vitamin C. Vitamin C-deficient Gulo knockout mice infected with influenza virus showed enhanced synthesis of the pro-inflammatory cytokines TNF-α and IL-1α/β in their lungs, and decreased production of the anti-viral cytokine IFN-α/β . Administration of vitamin C to Gulo mice with polymicrobial peritonitis resulted in decreased synthesis of the pro-inflammatory cytokines TNF-α and IL-1β by isolated neutrophils . Another study in septic Gulo mice administered 200 mg/kg parenteral vitamin C has shown decreased secretion of the inhibitory cytokines TGF-β and IL-10 by Tregs . In this study, attenuated IL-4 secretion and augmented IFN-γ secretion was also observed, suggesting immune-modulating effects of vitamin C in sepsis. Overall, vitamin C appears to normalize cytokine generation, likely through its gene-regulating effects.
Studies using guinea pigs, a vitamin C-requiring animal model, have indicated that vitamin C depletion is associated with enhanced circulating histamine levels, and that supplementation of the animals with vitamin C resulted in decreased histamine levels [56,95,96,97,98]. Enhanced histamine generation was found to increase the utilization of vitamin C in these animals . Consistent with the animal studies, human intervention studies with oral vitamin C (125 mg/day to 2 g/day) and intravenous vitamin C (7.5 g infusion) have reported decreased histamine levels [61,99,100,101], which was more apparent in patients with allergic compared with infectious diseases .
Administration of vitamin C to patients with acute respiratory infections returns their plasma vitamin C levels to normal and ameliorates the severity of the respiratory symptoms . Cases of acute lung infections have shown rapid clearance of chest X-rays following administration of intravenous vitamin C [247,248]. This vitamin C-dependent clearance of neutrophils from infected lungs could conceivably be due to enhanced apoptosis and subsequent phagocytosis and clearance of the spent neutrophils by macrophages . Pre-clinical studies of animals with sepsis-induced lung injury have indicated that vitamin C administration can increase alveolar fluid clearance, enhance bronchoalveolar epithelial barrier function, and attenuate sequestration of neutrophils , all essential factors for normal lung function.
Meta-analysis has indicated that vitamin C supplementation with doses of 200 mg or more daily is effective in ameliorating the severity and duration of the common cold, and the incidence of the common cold if also exposed to physical stress . Supplementation of individuals who had an inadequate vitamin C status (i.e., <45 μmol/L) also decreased the incidence of the common cold .
Vitamin C IV Treatments
Ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H(2)O(2), and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections [such as viral or bacterial infections] where H(2)O(2) may be beneficial.
In sensitive but not resistant cancer cells, intracellular H2O2 could target DNA, DNA repair proteins, or mitochondria because of diminished superoxide dismutase activity (53). New insights may follow from future studies of a very broad range of tumor cells or from microarray analysis of resistant and sensitive cells derived from the same genetic lineage.
H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections. H2O2 is a potent mammalian antimicrobial defense mechanism (54). Neutrophils generate H2O2 from super-oxide, in turn formed by NADPH oxidase-catalyzed reduction of molecular oxygen. There may be particular therapeutic application in patients with chronic granulomatous disease who have dimin-ished superoxide production (55). Old observational animal exper-iments, although uncontrolled, suggest that i.v. ascorbate is effective in some viral infections (56, 57). This finding is also consistent with in vitro experiments, in which H2O2 is toxic to hepatitis C (58). Use of ascorbate as an H2O2-delivery system against sensitive patho-gens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.
More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase defi-iency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis (3, 4, 15, 59). …Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in doses as high as 70 g over several hours (14, 15, 59). Because i.v. ascorbate is easily available to people who seek it, a phase I safety trial in patients with advanced cancer is justified and underway.