L. John Hoffer

Intravenously administered vitamin C as cancer therapy: three cases

Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 μmol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50–100 g) given intravenously may result in plasma concentrations of about 14 000 μmol/L. At concentrations above 1000 μmol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.

Appropriate protein provision in critical illness: a systematic and narrative review

BACKGROUND Widely varying recommendations have been published with regard to the appropriate amount of protein or amino acids to provide in critical illness. OBJECTIVE We carried out a systematic review of clinical trials that compared the metabolic or clinical effects of different protein intakes in adult critical illness and comprehensively reviewed all of the available evidence pertinent to the safe upper limit of protein provision in this setting. DESIGN MEDLINE was searched for clinical trials published in English between 1948 and 2012 that provided original data comparing the effects of different levels of protein intake on clinically relevant outcomes and evidence pertinent to the safe upper limit of protein provision to critically ill adults. RESULTS The limited amount and poor quality of the evidence preclude conclusions or clinical recommendations but strongly suggest that 2.0-2.5 g protein substrate · kg normal body weight⁻¹ · d⁻¹ is safe and could be optimum for most critically ill patients. At the present time, most critically ill adults receive less than half of the most common current recommendation, 1.5 g protein · kg⁻¹ · d⁻¹, for the first week or longer of their stay in an intensive care unit. CONCLUSION There is an urgent need for well-designed clinical trials to identify the appropriate level of protein provision in critical illness.

Effects of dietary protein restriction on glucose and insulin metabolism in normal and diabetic humans

We determined whether the amount of protein in the diet can affect insulin requirements in subjects with diabetes mellitus and glucose metabolism in normal subjects. Seven normal-weight volunteers with uncomplicated, intensively controlled, type I (insulin-dependent) diabetes and 12 similar nondiabetic subjects were studied on a metabolic ward before and after consuming a maintenance-energy but protein-free diet for 10 days. Blood glucose levels of diabetic subjects were measured seven times daily in response to insulin administration by continuous subcutaneous infusion. The plasma glucose appearance rate (Ra) was measured in seven normal subjects and all diabetic subjects using a primed-continuous infusion of D-[6,6-2H2]glucose. After adaptation to the protein-restricted diet, diabetic subjects experienced a 30% decrease in average preprandial and average daily blood glucose concentrations (P < .01); this occurred despite a concurrent 25% decrease in both basal and bolus insulin dosages (P < .001). Protein restriction decreased the postabsorptive glucose Ra (P < .05) and insulin concentrations (P < .01) of normal subjects by 20%, and increased their fasting glucagon concentrations by 24% (P < .01). We conclude that severe protein restriction decreases insulin requirements in type I diabetes and fasting hepatic glucose output and basal insulin levels in normal subjects. This effect appears to be mediated in part by decreased hepatic gluconeogenesis, but a contributory influence of increased insulin sensitivity is not ruled out.

Vitamin C provision improves mood in acutely hospitalized patients

OBJECTIVE Hypovitaminosis C and D are highly prevalent in acutely hospitalized patients, but the clinical significance of these biochemical abnormalities is not known. Because deficiencies of vitamin C and D have been linked to psychologic abnormalities, vitamin C or D provision could improve the mood state of acutely hospitalized patients. METHODS Double-blind clinical trial of the effect of vitamin C (500 mg twice daily) or vitamin D (1000 IU twice daily) on mood, as assessed with a validated instrument, the Profile of Mood States. RESULTS Vitamin C therapy increased plasma (P < 0.0001) and mononuclear leukocyte (P = 0.014) vitamin C concentrations and was associated with a 34% reduction in mood disturbance (P = 0.013). Vitamin D therapy increased plasma 25-hydroxyvitamin D concentrations (P = 0.0004), but had no significant effect on mood. CONCLUSIONS Treatment of hypovitaminosis C improves the mood state of acutely hospitalized patients.

Oxalic acid excretion after intravenous ascorbic acid administration

Ascorbic acid is frequently administered intravenously by alternative health practitioners and, occasionally, by mainstream physicians. Intravenous administration can greatly increase the amount of ascorbic acid that reaches the circulation, potentially increasing the risk of oxalate crystallization in the urinary space. To investigate this possibility, we developed gas chromatography mass spectrometry methodology and sampling and storage procedures for oxalic acid analysis without interference from ascorbic acid and measured urinary oxalic acid excretion in people administered intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight. In vitro oxidation of ascorbic acid to oxalic acid did not occur when urine samples were brought immediately to pH less than 2 and stored at -30 degrees C within 6 hours. Even very high ascorbic acid concentrations did not interfere with the analysis when oxalic acid extraction was carried out at pH 1. As measured during and over the 6 hours after ascorbic acid infusions, urinary oxalic acid excretion increased with increasing doses, reaching approximately 80 mg at a dose of approximately 100 g. We conclude that, when studied using correct procedures for sample handling, storage, and analysis, less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function.

Vitamin C deficiency in a university teaching hospital.

Objectives: There is almost no information regarding the vitamin C status of patients treated in Canadian and American hospitals. We determined the prevalence and predictors of vitamin C deficiency in patients hospitalized on the acute-care wards of a Canadian teaching hospital, and tracked their plasma vitamin C concentrations while they were there. Methods: This was a population-based cross-sectional and time course survey of 149 medical patients shortly after admission to a university teaching hospital. The procedure for sample handling, storage and analysis was validated by measuring the vitamin C concentrations of a reference sample of 141 presumably well nourished people and comparing the results with published norms. Results: In keeping with published norms, 13% of people in the reference group had a subnormal vitamin C concentration (<28.4 μmol/L) and 3% were vitamin C deficient (<11.4 μmol/L). By contrast, 60% of hospitalized patients had a subnormal vitamin C concentration and 19% were deficient. A history of inadequate nutrition or failure to use a vitamin supplement prior to admission, low serum albumin, and male sex predicted plasma vitamin C deficiency, whereas use of a vitamin supplement prior to admission was associated with adequate vitamin C status in hospital. In a second measurement, obtained in 52 patients after an average of 17 days in hospital, vitamin C status had not improved. Conclusions: Vitamin C deficiency is prevalent and sustained in patients in a Canadian teaching hospital. The abnormality can be prevented by providing a diet sufficient in vitamin C or by prescribing a multiple vitamin tablet.

High-Dose Intravenous Vitamin C Combined with Cytotoxic Chemotherapy in Patients with Advanced Cancer: A Phase I-II Clinical Trial

Background Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. Methods and Findings We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. Conclusions Despite IVC’s biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC’s value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy regimen and IVC in which exceptional responses occur frequently enough to justify appropriately focused clinical trials. Trial Registration ClinicalTrials.gov NCT01050621

How much protein do parenteral amino acid mixtures provide

It is commonly assumed that the weight of the amino acids in a parenteral amino acid mixture equals the amount of protein they provide. This assumption ignores the fact that the molecular weight of free amino acids is 18 mass units greater than when they are protein bound. The actual amount of protein substrate provided by commonly used free amino acid mixtures was determined by analyzing the amino acid composition of 3 commonly used parenteral amino acid solutions and the proteins that would be formed from them, and comparing the results with similar data from 3 nutritionally important proteins. After correction for hydration status, the ratio of essential amino acid mass to total mass of the amino acid mixtures was similar to albumin, myosin, and actin. However, all of the amino acid mixtures provided 17% less protein and energy than is now widely assumed. Current parenteral nutrition guidelines recommend 0.8-1.5 g mixed amino acids/kg normal weight per day, on the assumption that they are equivalent to formed proteins, but they are not equivalent. Clinicians who aim to provide 0.8-1.5 g protein/kg must administer 1.0-1.8 g mixed amino acids/kg.

Metabolic origin of hypovitaminosis C in acutely hospitalized patients

OBJECTIVE Recent studies have indicated a high prevalence of hypovitaminosis C in acutely hospitalized patients. It is unclear whether hypovitaminosis C in this setting represents deficiency or tissue redistribution of the vitamin as part of the acute-phase response. METHODS We administered vitamin C for 1 wk to acutely hospitalized, but not critically ill patients with hypovitaminosis C, on the assumption that a large increase in plasma and mononuclear leukocyte vitamin C concentrations, a decrease in metabolic markers of oxidative stress, or an improvement in psychologic mood state would implicate the initial condition as nutritional deficiency rather than tissue redistribution. RESULTS Vitamin C administration increased plasma and mononuclear leukocyte vitamin C concentrations from subnormal (16.3 ± 12.4 μmol/L and 6.5 ± 5.5 mmol/L, respectively) to normal (71.0 ± 30.9 μmol/L, P < 0.0001, and 8.2 ± 6.8 mmol/L, P < 0.015); the mood disturbance score improved by 33% (P < 0.008). There was no increase in plasma glutathione concentrations or a reduction in plasma or mononuclear leukocyte malondialdehyde concentrations. An inverse relation was observed between plasma C-reactive protein and plasma vitamin C concentrations (P = 0.006). CONCLUSION Although associated with systemic inflammation, the metabolic features of hypovitaminosis C in acutely hospitalized, non-critically ill patients are more consistent with deficiency than with tissue redistribution.

Effects of vitamin C and vitamin D administration on mood and distress in acutely hospitalized patients

BACKGROUND Hypovitaminosis C and D are highly prevalent in acute-care hospitals. Malnutrition with regard to these vitamins has been linked to mood disturbance and cognitive dysfunction. OBJECTIVE The objective was to determine whether vitamin C or D supplementation improves mood state or reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. DESIGN A randomized, double-blind, active-control clinical trial compared the effects of vitamin C (500 mg twice daily) with those of high-dose vitamin D (5000 IU/d) on mood (Profile of Mood States) and psychological distress (Distress Thermometer). RESULTS Vitamin C provided for a mean of 8.2 d increased plasma vitamin C concentrations to normal (P < 0.0001) and was associated with a 71% reduction in mood disturbance (P = 0.0002) and a 51% reduction in psychological distress (P = 0.0002). High-dose vitamin D provided for a mean of 8.1 d increased plasma 25-hydroxyvitamin D [25(OH)D] concentrations (P < 0.0001), but not into the normal range, and had insignificant effects on mood (P = 0.067) and distress (P = 0.45). The changes in mood and distress in the vitamin C group were greater than those in the vitamin D group (P = 0.045 for mood; P = 0.009 for distress). CONCLUSIONS Short-term therapy with vitamin C improves mood and reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. No conclusion is possible regarding the effects of vitamin D because the dose and duration of therapy were insufficient to raise 25(OH)D concentrations into the normal range. This trial was registered at clinicaltrials.gov as NCT01630720.