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Patients with higher inflammation or tumor burdens, as measured by CRP levels or tumor antigen levels, tend to show lower peak plasma ascorbate levels after IVC.

Patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate levels than those with localized tumors.

Meta-analyses of clinical studies involving cancer and vitamins also conclude that antioxidant supplementation does not interfere with the efficacy of chemotherapeutic regiments

Most of the prostate cancer patients studied, 75±19% (95% confidence), showed reductions in PSA levels during the course of their IVC therapy

Laboratory studies suggest that, at high concentrations, ascorbate does not interfere with chemotherapy or irradiation and may enhance efficacy in some situations

Cameron and Pauling observed fourfold survival times in terminal cancer patients treated with intravenous ascorbate infusions followed by oral supplementation

The inflammatory microenvironment of cancer cells leads to increasing oxidative stress, which apparently depletes vitamin C, resulting in lower plasma ascorbate concentrations in blood samples post IVC infusion. Another explanation for this finding may be that cancers are themselves more metabolically active in their uptake of vitamin C, causing subjects to absorb more of the vitamin, and as a results show lower plasma ascorbate concentrations in blood post IVC infusion.

patients with severely elevated CRP levels attain plasma ascorbate concentrations after IVC infusions that are only 65% of those attained for subjects with normal CRP levels

The finding of decreased plasma ascorbate levels in cancer patients may relate to the molecular structure of ascorbic acid; in particular, the similarity of its oxidized form, dihydroascorbic acid, to glucose

Since tumor have increased requirement for glucose [67], transport of dehydroascorbate into the cancer cells via glucose transport molecules and ascorbate through sodium-dependent transporter may be elevated

Increased accumulation of ascorbic acid in the tumor site was supported by measurements of the level of ascorbic acid in tumors in animal experiments

patients with advanced malignancies may have lower level of ascorbic acid in tissue, creating a higher demand for the vitamin C

IVC therapy appears to reduce CRP levels in cancer patients.

CRP concentrations directly correlate with disease activity in many cases and can contribute to disease progression through a range of pro-inflammatory properties.

Being an exquisitely sensitive marker of systemic inflammation and tissue damage, CRP is very useful in screening for organic disease and monitoring treatment responses

ncreases in CRP concentrations have been associated with poorer prognosis of survival in cancer patients, particularly with advance disease independent of tumor stage

Regarding inflammation, 73±13% of subjects (95% confidence) showed a reduction in CRP levels during therapy. This was an even more dramatic 86±13% (95% confidence) in subjects who started therapy with CRP levels above 10 mg/L

patients treated by IVC with follow-up several year showed that suppression of inflammation in cancer patients by high-dose IVC is feasible and potentially beneficial

Inflammation is a marker of high cancer risk, and poor treatment outcome

The subjects with highly elevated CRP concentrations have a three-fold elevation “all-cause” mortality risk and a twenty-eight fold increase in cancer mortality risk

cancer patients may need higher doses to achieve a given plasma concentration.

patients with lower vitamin C levels may see more distribution of intravenously administered ascorbate into tissues and thus attain less in plasma.

When treating patients with IVC, the first treatment likely serves to replenish depleted tissue stores, if those subjects were vitamin C deficient at the beginning of the treatment. Then, in subsequent treatments, with increasing doses, higher plasma concentrations can be attained. On-going treatments serve to progressively reduce oxidative stress in cancer patients.

large doses given intravenously may result in maximum plasma concentrations of roughly 30 mM, a level that has been shown to be sufficient for preferential cytotoxicity against cancer cells

oral intake of vitamin C exceeded 200 mg administered once daily, it was difficult to increase plasma and tissue concentrations above roughly 200 μM.

The CHALICE cohort of 404 individuals aged 50 years had an average vitamin C intake of ~110 mg/day, which should provide adequate plasma concentrations [14]. Despite this, a significant proportion of the participants had inadequate plasma vitamin C status

inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)

adequate plasma levels (i.e., >50 µmol/L)

Higher plasma vitamin C status was associated with lower weight, BMI and waist circumference

plasma vitamin C was negatively associated with blood triglycerides, HbA1c and insulin, and positively associated with HDL levels.

No correlation was found between plasma vitamin C and the two indicators of heart health; blood pressure and cardiovascular risk score.

2.4% of 50-year-olds were deficient in vitamin C (i.e., <11 µmol/L)

hypovitaminosis C (i.e., <23 µmol/L)

A high proportion (63%) of our participants had inadequate plasma vitamin C concentrations (i.e., <50 µmol/L)

The association of low vitamin C with obesity in this study replicates results in the literature [35,40,41,42,43,44], and it is apparent that individuals with higher weight require higher intakes of vitamin C to reach adequate vitamin C status

higher plasma vitamin C status is associated with lower circulating levels of blood triglycerides, insulin and HbA1c

A role for vitamin C in the prevention or management of diabetes and/or metabolic syndrome has been suggested

In this study, we also demonstrate lower levels of mild cognitive impairment in those with high vitamin C status

The odds of mild cognitive impairment were twice as high for those below 23 μmol/L plasma vitamin C concentration.

Vitamin C is present at very high concentrations in the brain

animal models have shown that the brain is the last organ to be depleted of the vitamin during prolonged deficiency

A recent animal study has shown that moderate vitamin C deficiency may play a role in accelerating amyloid plaque accumulation in Alzheimer’s disease

related to intracellular hydrogen peroxide generation

only be obtained by intravenous administration of AA

Preferentially kills neoplastic cells

Is virtually non-toxic at any dosage

Does not suppress the immune system, unlike most chemotherapy agents

Increases animal and human resistance to infectious agents by enhancing lymphocyte blastogenesis, enhancing cellular immunity, strengthening the extracellular matrix, and enhancing bactericidal activity of neutrophils and modulation of complement protein

Strengthens the structural integrity of the extracellular matrix which is responsible for stromal resistance to malignant invasiveness

1969, researchers at the NCI reported AA was highly toxic to Ehrlich ascites cells in vitro

In 1977, Bram et al reported preferential AA toxicity for several malignant melanoma cell lines, including four human-derived lines

Noto et al reported that AA plus vitamin K3 had growth inhibiting action against three human tumor cell lines at non-toxic levels

Metabolites of AA have also shown antitumor activity in vitro

The AA begins to reduce cell proliferation in the tumor cell line at the lowest concentration, 1.76 mg/dl, and is completely cytotoxic to the cells at 7.04 mg/dl

the normal cells grew at an enhanced rate at the low dosages (1.76 and 3.52 mg/dl)

preferential toxicity of AA for tumor cells. >95% toxicity to human endometrial adenocarcinoma and pancreatic tumor cells (ATCC AN3-CA and MIA PaCa-2) occurred at 20 and 30 mg/dl, respectively.

No toxicity or inhibition was demonstrated in the normal, human skin fibroblasts (ATCC CCD 25SK) even at the highest concentration of 50 mg/dl.

the use of very high-dose intravenous AA for the treatment of cancer was proposed as early as 1971

Cameron and Pauling have published extensive suggestive evidence for prolonged life in terminal cancer patients orally supplemented (with and without initial intravenous AA therapy) with 10 g/day of AA

AA, plasma levels during infusion were not monitored,

the long-term, oral dosage used in those experiments (10 g/day), while substantial and capable of producing immunostimulatory and extracellular matrix modulation effects, was not high enough to achieve plasma concentrations that are generally cytotoxic to tumor cells in culture

This low cytotoxic level of AA is exceedingly rare

5 — 40 mg/dl of AA is required in vitro to kill 100% of tumor cells within 3 days. The 100% kill levels of 30 mg/dl for the endometrial carcinoma cells and 40 mg/dl for the pancreatic carcinoma cells in Figure 2 are typical

normal range (95% range) of 0.39-1.13 mg/dl

1 h after beginning his first 8-h infusion of 115 g AA (Merit Pharmaceuticals, Los Angeles, CA), the plasma AA was 3.7 mg/dl and at 5 h was 19 mg/dl. During his fourth 8-h infusion, 8 days later, the 1 h plasma level was 158 mg/dl and 5 h was 185 mg/dl

plasma levels of over 100 mg/dl have been maintained in 3 patients for more than 5 h using continuous intravenous infusion

In rare instances of patients with widely disseminated and rapidly proliferating tumors, intravenous AA administration (10 — 45 g/day) precipitated widespread tumor hemorrhage and necrosis, resulting in death

Although the outcomes were disastrous in these cases, they are similar to the description of tumor-necrosis-factor-induced hemorrhage and necrosis in mice (52) and seem to demonstrate the ability of AA to kill tumor cells in vivo.

toxic effects of AA on one normal cell line were observed at 58.36 mg/dl and the lack of side effects in patients maintaining >100 mg/dl plasma levels

Although it is very rare, tumor necrosis, hemorrhage, and subsequent death should be the highest priority concern for the safety of intravenous AA for cancer patients.

Klenner, who reported no ill effects of dosages as high as 150 g intravenously over a 24-h period

Cathcart (55) who describes no ill effects with doses of up to 200 g/d in patients with various pathological conditions

following circumstances: renal insufficiency, chronic hemodialysis patients, unusual forms of iron overload, and oxalate stone formers

Screening for red cell glucose-6-phosphate dehydrogenase deficiency, which can give rise to hemolysis of red blood cells under oxidative stress (57), should also be performed

any cancer therapy should be started at a low dosage to ensure that tumor hemorrhage does not occur.

patient is orally supplementing between infusions

a scorbutic rebound effect can be avoided with oral supplementation. Because of the possibility of a rebound effect, measurement of plasma levels during the periods between infusions should be performed to ensure that no such effect takes place

Every effort should be made to monitor plasma AA levels when a patient discontinues intravenous AA therapy.

The rate of water loss can be quantified through measurement of sweat rate

Pre- and postexercise body weight measurements are the most common means to estimate overall water loss but are condition specific

It appears that 1% to 2% body weight loss is well tolerated by the exercising athlete

Dehydration, defined as greater than 2% loss of body weight, can negatively affect performance

In highly trained endurance athletes, plasma volume and sodium serum concentration were preserved despite a 5% body weight loss

In Ironman triathletes, dehydration to 5% body weight loss did not correlate with occurrence of medical complications

hydration should begin hours prior to exercise, especially if known deficits are present, and fluids should be consumed at a slow, steady rate, with 5 to 7 mL/kg taken 4 hours prior to exercise

Sodium concentration did not produce significant changes in the rate of absorption but was primarily dependent on carbohydrate concentration

Replacing 150% of body weight loss over 60 minutes has been tolerated without complications

IV treatment of severe dehydration (>7% body weight loss), exertional heat illness, nausea, emesis, or diarrhea, and in those who cannot ingest oral fluids for other reasons, is clinically indicated

A recent survey of the National Football League teams revealed that 75% (24 of 32) of the teams utilized IV infusion of fluids for prehydration in at least some otherwise healthy individuals

In the National Football League, an average of 1.5 L of normal saline was administered approximately 2.5 hours prior to competition

after 2 hours of exercise, the rectal temperature was 0.6° higher in the group not receiving IV infusion. Also, stroke volume and cardiac output were 11% to 16% lower in the control group versus the IV infusion group.

Recent evidence suggests the etiology of EAMC is related to muscle fatigue and neuronal excitability

no correlation between hydration status or electrolyte concentrations with EAMC

there may be a subset of muscle cramping that is associated with a loss of both body fluid and sodium

Glycerol is the primary agent for oral hyperhydration

elevation of plasma volume by 200 to 300 mL via dextran infusion resulted in 15% increase in stroke volume, 4% increase in VO2 max, and an increase in the exercise time to fatigue

Neither the tonicity nor mode of hydration resulted in improved speed of rehydration, greater fluid retention, or improved performance

There are beneficial anecdotal reports of EAMC treatment in elite and professional-level athletes with IV hydration during the course of an event

Plasma volume was better restored during rehydration with IV fluids at preexercise and 5 minutes of exercise. At 15 minutes, there was no difference between IV and oral rehydration

More rapid restoration of plasma volume was accomplished in the IV treatment group with no advantages over oral rehydration in physiological strain, heat tolerance, ratings of perceived effort, or thermal sensations

No difference was found in exercise time to exhaustion. IV and oral rehydration methods were equally effective. Heart rates were statistically higher in the oral rehydration group through 75 minutes of exercise, and there were higher increases in norepinephrine plasma concentrations

No significant differences between the groups were found for time to recovery, number of days with pain, number of days with stiffness, sleep disturbance, fatigue, rectal temperature, and loss of appetite

The current data suggest that IV rehydration is faster than oral

There may be physiological benefits of decreased heart rate and norepinephrine in athletes rehydrated via IV route

Postexercise blood 1 hour and 24 hours showed no differences in circulating myoglobin or creatine kinase

The use of IV fluid may be beneficial for a subset of fluid sensitive athletes

this should be reserved for high-level athletes with strong histories of symptoms in well-monitored settings.

Volume expanders may also be beneficial for some athletes

curcumin has potent anti-inflammatory and antioxidant activities that can function to reduce oxidative damage and cognitive deficits associated with neurological disorders

Curcumin provided in the diet before TBI can reduce oxidative damage and counteract TBI-related cognitive dysfunction

Our previous study indicated that n-3 fatty acids supplemented in the diet counteracted learning disability after TBI

curcumin contributes to enhance the effects of DHA on TBI by promoting phosphorylation of the BDNF receptor TrkB in the hippocampus

previous evidence indicates that curcumin10 and DHA5 counteract TBI-related learning disability by involving BDNF

Our findings indicate that curcumin counteracted the TBI-related reduction in n-3 DPA.

curcumin may promote the conversion of n-3 DPA to DHA

the combination of both nutrients has been reported to produce anti-inflammatory action

the enhanced actions of curcumin and DHA in reducing cholesterol levels could be interpreted as preservation of levels of phospholipids in the plasma membrane

curcumin and DHA may contribute to reduce inflammation associated with the action of cholesterol in the pathology of TBI.

Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration

Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid

ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu

H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents

The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.

Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate

Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration

Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations

For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.

It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.

There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.

H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections

Neutrophils generate H2O2 from superoxide,

i.v. ascorbate is effective in some viral infections

H2O2 is toxic to hepatitis C

Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.

Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose

As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,

Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm

Human Burkitt's lymphoma cells

We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines

Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration

plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption

For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion

All tested normal cells were insensitive to 20 mM ascorbate.

Lymphoma cells were selected because of their sensitivity to ascorbate

As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death

Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure

In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate

Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate

Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.

extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.

H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death

Superoxide dismutase was not protective

Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate

For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased

Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes

There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity

H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media

ascorbate radical is a surrogate marker for H2O2 formation.

whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable

The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.

The occurrence of one predicted complication, oxalate kidney stones, is controversial

In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis

ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.

ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation

data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant

More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis

subnormal plasma ascorbic acid levels are a predictable feature in patients with severe sepsis

Ascorbic acid depletion in sepsis results from ascorbic acid consumption by the reduction of plasma free iron, ascorbic acid consumption by the scavenging of aqueous free radicals (peroxyl radicals), and by the destruction of the oxidized form of ascorbic acid dehydroascorbic acid

Sepsis further inhibits intracellular reduction of dehydroascorbic acid, producing acute intracellular ascorbic acid depletion

Ascorbic acid treated patients in this study exhibited rapid and sustained increases in plasma ascorbic acid levels using an intermittent every six hours administration protocol

Septic ascorbic acid-deficient neutrophils fail to undergo normal apoptosis. Rather, they undergo necrosis thereby releasing hydrolytic enzymes in tissue beds, thus contributing to organ injury

We speculate that intravenous ascorbic acid acts to restore neutrophil ascorbic acid levels

Repletion of ascorbic acid in this way allows for normal apoptosis, thus, preventing the release of organ damaging hydrolytic enzymes.