title: Mega-dose vitamin C in treatment of the common cold: a randomised controlled trial. The effects of ascorbic acid and flavonoids on the occurrence of symptoms normally associated with the common cold. Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use
abstract: OBJECTIVE To determine the effect of large doses of vitamin C in the treatment of the common cold . STUDY DESIGN Double-blind , r and omised clinical trial with four intervention arms : vitamin C at daily doses of 0.03 g ( " placebo " ) , 1 g , 3 g , or 3 g with additives ( " Bio-C " ) taken at onset of a cold and for the following two days . PARTICIPANTS AND SETTING 400 healthy volunteers were recruited from staff and students of the Australian National University , Canberra , ACT , between May 1998 and November 1999 . The trial continued for 18 months . INTERVENTIONS Participants were instructed to commence medication when they had experienced early symptoms of a cold for four hours , and to record daily their symptoms , severity , doctor visits and use of other medications . MAIN OUTCOME MEASURES Duration of symptoms and cold episodes ; cumulative symptom severity scores after 7 , 14 and 28 days ; doctor visits ; and whether participants guessed which medication they were taking . RESULTS 149 participants returned records for 184 cold episodes . No significant differences were observed in any measure of cold duration or severity between the four medication groups . Although differences were not significant , the placebo group had the shortest duration of nasal , systemic and overall symptoms , and the lowest mean severity score at 14 days , and the second lowest at 7 and 28 days . CONCLUSIONS Doses of vitamin C in excess of 1 g daily taken shortly after onset of a cold did not reduce the duration or severity of cold symptoms in healthy adult volunteers when compared with a vitamin C dose less than the minimum recommended daily intake A controlled study was made of the effects of natural orange juice , synthetic orange juice , and placebo in the prevention of the common cold ; both natural and synthetic orange juices contained 80 mg of ascorbic acid daily . Three-hundred sixty-two healthy normal young adult volunteers , ages 17 to 25 years , were studied for 72 days with 97 % of participants completing the trial . There was a 14 to 21 % reduction in total symptoms due to the common cold in the supplemented groups that was statistically significant ( P less than 0.05 ) . Ascorbic acid supplementation also increased the number of " episode-free " subjects . However , the clinical usefulness of the results does not support prophylactic ascorbic acid supplements in the well-nourished adult . The results in this study with both natural and synthetic orange juice of physiological content of ascorbic acid , are similar to those obtained using a " megadose " of ascorbic acid Context Clinical studies of vitamin C as a potential anticancer agent have produced inconsistent results despite in vitro evidence that high concentrations kill cancer cells . Contribution Pharmacokinetic studies in healthy persons , using a depletion-repletion design , show that intravenous administration can achieve 70-fold higher blood levels of vitamin C than the highest tolerated oral dose . Caution s Although this study provides better underst and ing of the pharmacokinetic issues involved in research on vitamin C , it provides no evidence that vitamin C has any effect on cancer cells and can not be used to support its clinical use for therapeutic purpose s. The Editors Vitamin C in gram doses is taken orally by many people and administered intravenously by complementary and alternative medicine practitioners to treat patients with advanced cancer ( 1 , 2 ) . After oral intake ,  vitamin C plasma concentrations are tightly controlled at 70 to 85 mol/L for amounts ( as much as 300 mg daily ) that can be obtained from food ( 3 , 4 ) . However , concentrations achieved by higher pharmacologic doses are uncertain . Despite poor rationale , vitamin C in gram doses was proposed as an anticancer agent decades ago ( 5 ) . Unblinded studies with retrospective or nonr and om controls reported clinical benefit from oral and intravenous vitamin C administered to patients with terminal cancer at a dosage of 10 g daily ( 1 , 6 , 7 ) . Placebo-controlled trials in patients with cancer reported no benefit from oral vitamin C at a dosage of 10 g daily ( 8 , 9 ) , and vitamin C treatment was judged ineffective ( 10 ) . However , in vitro evidence showed that vitamin C  killed cancer cells at extracellular concentrations higher than 1000 mol/L ( 11 , 12 ) , and its clinical use by some practitioners continues . We recognized that oral or intravenous routes could produce substantially different vitamin C concentrations ( 13 ) . We report here that intravenous doses can produce plasma concentrations 30- to 70-fold higher than the maximum tolerated oral doses . These data suggest that the role of vitamin C in cancer treatment should be reexamined , and insights from vitamin C pharmacokinetics can guide its clinical use . Methods Pharmacokinetic Studies in Healthy Persons The study was approved by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases , National Institutes of Health . After we obtained written informed consent , 17 healthy volunteers ( 7 men , 10 women ; age , 19 to 27 years ) were studied as in patients by using a depletion-repletion study design ( 3 , 4 ) . Participants were hospitalized for 3 to 6 months and consumed a  vitamin C-deficient  diet containing less than 0.005 g of vitamin C per day . At plasma vitamin C concentrations less than 8 mol/L , persons were depleted without signs of scurvy . Vitamin C , 0.015 g twice daily , was then administered orally until participants achieved a steady state for this dose ( 0.03 g daily ) . Participants received successive oral daily vitamin C doses of 0.03 g , 0.06 g , 0.1 g , 0.2 g , 0.4 g , 1.0 g , and 2.5 g until a steady state was achieved for each dose . Bioavailability sampling was conducted at a steady state for vitamin C doses of 0.015 g , 0.03 g , 0.05 g , 0.1 g , 0.2 g , 0.5 g , and 1.25 g. For each bioavailability sampling , vitamin C was administered in the fasting state . After oral administration , blood sample s were collected at 0 , 15 , and 30 minutes and at 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 19 , 22 , and 24 hours ( 3 , 4 ) . After intravenous administration at 250 mg/min , blood sample s were collected at 0 , 2.5 , 5 , 10 , 15 , and 30 minutes and at 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , 5 , 6 , 7 , 8 , 9 , and 10 hours . Data obtained from bioavailability samplings were used to determine peak plasma and urine vitamin C concentrations . Pharmacokinetic Modeling We used data from 7 men to construct a unique 3-compartment vitamin C pharmacokinetic model with parameters describing saturable absorption , tissue distribution , and renal excretion and reabsorption ( 14 ) . This model was used to predict peak plasma and urine vitamin C concentrations attained when pharmacologic doses of the vitamin are administered . For intravenous administration , it was assumed that vitamin C was infused at a rate of 1 g/min , and urine output was 100 mL/h . Vitamin C Assay Vitamin C was measured by using high-performance liquid chromatography with coulometric electrochemical detection ( 3 , 4 , 15 ) . Statistical Analysis We compared plasma vitamin C concentration curves ( against either dose or time ) by repeated- measures analyses of variance ( ANOVA ) . In addition to the repeating factor ( dose or time ) , other factors considered were sex and route of administration . In the comparison of routes of administration at multiple doses , in which sex not only was an important factor itself but also had an important interaction with route , separate ANOVA were determined for men and women to assess the importance of route of administration . Analyses were performed by using Data Desk , version 5 ( 1995 ) ( Data Description , Inc. , Ithaca , New York ) . Role of the Funding Source The funding source had no role in the design , conduct , and reporting of the study or in the decision to su bmi t the manuscript for publication . Results When 1.25 g of vitamin C was given intravenously , plasma concentrations were significantly higher than when the vitamin was given orally ( P < 0.001 by repeated- measures ANOVA ) ( Figure 1 ) . In addition , plasma concentrations were significantly higher over all doses ( P < 0.001 by repeated- measures ANOVA ) with intravenous compared with oral administration ( Figure 1 , inset ) . At the highest dose of 1.25 g , mean peak values from intravenous administration were 6.6-fold higher than mean peak values from oral administration . When all doses were considered , peak plasma vitamin C concentrations increased with increasing intravenous doses , whereas peak plasma vitamin C concentrations seemed to plateau with increasing oral doses . Urine vitamin C concentrations were higher for the same dose given intravenously compared with that administered by the oral route . At the highest dose of 1.25 g , peak urine concentrations from intravenous administration were approximately 3.5 times higher than from oral administration ( data not shown ) . Figure 1 . Plasma vitamin C concentrations in healthy volunteers after intravenous or oral administration of vitamin C. Inset : The 3-compartment vitamin C pharmacokinetic model that we developed predicted that a single oral dose of 3 g , the maximum tolerated single dose , produced a peak plasma concentration of 206 mol/L ( Figure 2 , top ) . Peak predicted concentration after a single 1.25-g oral dose was slightly lower at 187 mol/L. For 200 mg , an amount obtained from vitamin C-rich foods , peak predicted concentration was approximately 90 mol/L. Plasma concentrations for all of these amounts returned to steady-state values , approximately 70 to 85 mol/L , after 24 hours . With 3 g given orally every 4 hours , the maximum tolerable ( 6 ) , peak predicted plasma concentration was approximately 220 mol/L ( Figure 2 , top ) . By contrast , after intravenous administration , predicted peak plasma vitamin C concentrations were approximately 1760 mol/L for 3 g , 2870 mol/L for 5 g , 5580 mol/L for 10 g , 13 350 mol/L for 50 g , and 15 380 mol/L for 100 g ( Figure 2 , bottom ) . Doses of 60 g given intravenously are used for cancer treatment by complementary and alternative medicine practitioners ( 2 ) . Predicted peak urine vitamin C concentrations were as much as 140-fold higher after intravenous administration compared with oral administration ( data not shown ) . Figure 2 . Predicted plasma vitamin C concentrations in healthy persons after oral ( top ) or intravenous ( IV ) ( bottom ) administration of vitamin C. Discussion Our data show that vitamin C plasma concentrations are tightly controlled when the vitamin is taken orally , even at the highest tolerated amounts . By contrast , intravenous administration bypasses tight control and results in concentrations as much as 70-fold higher than those achieved by maximum oral consumption . Both findings have clinical relevance . Vitamin C oral supplements are among the most popular sold , and gram doses are promoted for preventing and treating the common cold , managing stress , and enhancing well-being ( 1 ) . Our data show that single supplement gram doses produce transient peak plasma concentrations that at most are 2- to 3-fold higher than those from vitamin C-rich foods ( 200 to 300 mg daily ) . In either case , plasma values return to similar steady-state concentrations in 24 hours . Because differences in plasma concentrations from supplements and from food intake are not large , supplements would be expected to confer little additional benefit , a finding supported by available evidence ( 16 , 17 ) . However , consumption of fruits and vegetables , which contain vitamin C , is beneficial for unknown reasons ( 16 , 17 ) . On the basis of current knowledge and the pharmacokinetics presented here , physicians should advise their patients to consume fruits and vegetables , not vitamin C supplements , to obtain potential benefits . Just as important , our data show that intravenous administration of vitamin C produces substantially higher plasma concentrations than can be achieved with oral administration of vitamin C. This difference was previously unrecognized and may have treatment implication s. Case series published by Cameron , Campbell , and Pauling ( l , 6 , 7 ) have been controversial . In these series , several hundred patients with terminal cancer treated with 10 g of vitamin C intravenously for 10 days and then 10 g orally indefinitely were compared with more than 1000 retrospective and prospect i ve controls . Patients treated with vitamin C  survived 150 to 300 days longer than controls ( 1 , 6 , 7 ) . Other research ers reported benefit consisting of increased survival , improved well-being , and reduced pain ( 1 ) . All of these
target: But evidence suggests that it could be justified in people exposed to brief periods of severe physical exercise or cold environments
background: BACKGROUND The role of vitamin C ( ascorbic acid ) in the prevention and treatment of the common cold  has been a subject of controversy for 60 years , but is widely sold and used as both a preventive and therapeutic agent .
  OBJECTIVES To discover whether oral doses of 0.2 g or more daily of vitamin C reduces the incidence , duration or severity of the common cold when used either as continuous prophylaxis or after the onset of symptoms .