Ascorbic acid dose
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Optimal Ascorbic Acid Dose: Insights from Recent Research
High-Dose Intravenous Ascorbic Acid in Cancer Treatment
Safety and Tolerability
High-dose intravenous (i.v.) ascorbic acid has been explored as a monotherapy in patients with advanced solid tumors. A phase I clinical trial demonstrated that doses up to 70-110 g/m² were well tolerated, with no significant adverse effects reported 1. The pharmacokinetics showed that ascorbic acid was eliminated by simple first-order kinetics, with half-life and clearance values consistent across different doses 1.
Pharmacokinetics and Maximum Tolerated Dose
The study found that the maximum plasma concentration (Cmax) and area under the curve (AUC) values increased proportionately with the dose up to 70 g/m², beyond which they plateaued 1. This suggests that doses above 70 g/m² may not provide additional pharmacokinetic benefits. The recommended dose for future studies is 70-80 g/m² 1.
Oral Ascorbic Acid and Plasma Concentration Limits
Ceiling Effect in Plasma Concentrations
Oral administration of ascorbic acid shows a ceiling effect in plasma concentrations due to saturable gastrointestinal absorption and nonlinear renal clearance. When the daily dose is increased from 200 to 2500 mg, the plasma concentration only increases marginally from approximately 12 to 15 mg/L 2. This indicates that megadoses of oral ascorbic acid do not proportionally increase plasma levels, questioning the pharmacokinetic justification for such high doses 2.
Ascorbic Acid in Critically Ill Patients
Mortality Reduction in Critically Ill Patients
A meta-analysis revealed that intravenous ascorbic acid doses of 3-10 g/day significantly reduced mortality in critically ill patients, while lower (<3 g/day) and higher doses (≥10 g/day) did not show the same benefit 4. This suggests an optimal dose range for therapeutic efficacy in reducing mortality among critically ill patients 4.
Hemodynamic Benefits in Septic Shock
In patients with septic shock, high-dose ascorbic acid (25 mg/kg every 6 hours) significantly reduced the requirement and duration of vasopressor support, as well as 28-day mortality rates 5. This indicates that high-dose ascorbic acid can be an effective adjuvant therapy in managing septic shock 5.
Ascorbic Acid and Antioxidant Effects
Dose-Dependent Antioxidant Benefits
In a study on horses, intravenous ascorbic acid at 100 mg/kg decreased determinants of reactive oxygen metabolites (dROM) and increased plasma ascorbic acid concentrations in a dose-dependent manner 3. This suggests potential antioxidant benefits at higher doses, although the effects on other oxidative stress markers were not significant 3.
Ascorbic Acid and Microvascular Health
Preventing Microvascular Fragility
A systematic review and meta-analysis indicated that the current recommended daily intake of ascorbic acid, based on scurvy prevention, may be insufficient to prevent microvascular fragility. Supplementation reduced gingival bleeding tendency when baseline plasma levels were below 28 µmol/L, but not at higher levels 10. This suggests that higher daily intakes may be necessary to maintain optimal microvascular health 10.
Conclusion
The optimal dose of ascorbic acid varies depending on the condition being treated. For cancer patients, a dose of 70-80 g/m² i.v. is recommended, while critically ill patients benefit most from 3-10 g/day i.v. doses. Oral megadoses do not significantly increase plasma levels due to a ceiling effect. High-dose ascorbic acid shows promise in reducing oxidative stress and improving microvascular health, but further research is needed to refine these recommendations.
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Most relevant research papers on this topic
Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer
High-dose intravenous ascorbic acid administered at 1 g/min for 4 weeks in advanced cancer patients was well-tolerated but not shown to have an objective antitumor response.
Non-RCT
Highly CitedPharmacokinetic perspectives on megadoses of ascorbic acid.
Megadoses of ascorbic acid are not pharmacokinetically justified due to a ceiling effect in plasma concentrations, making them unsuitable for dietary supplementation.
Highly CitedEffects of intravenous administration of ascorbic acid (vitamin C) on oxidative status in healthy adult horses
High-dose ascorbic acid administration may provide antioxidant benefits in horses, potentially aiding in sepsis treatment.
RCT
Animal StudyEffects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis
Intravenous ascorbic acid doses of 3-10 g/d reduce overall mortality rates in critically ill patients, while low and high doses show no effect.
Meta-Analysis
Rigorous JournalEffect of high-dose Ascorbic acid on vasopressor's requirement in septic shock
High-dose ascorbic acid may be an effective and safe adjuvant therapy in surgical critically ill patients with septic shock, reducing vasopressor drug requirement and 28-day mortality.
RCTRigorous JournalHighly CitedSteady-state turnover and body pool of ascorbic acid in man.
A daily intake of 100 mg ascorbic acid would reach a steady-state body pool of 20 mg/kg bodyweight in 95% of the population, with half-life decreasing with higher dosages.
Non-RCTHighly CitedAscorbic acid and its pro-oxidant activity as a therapy for tumours of oral cavity -- a systematic review.
Ascorbic acid shows potential as an effective cytotoxic agent against oral neoplastic cells without harming normal oral cells, but more clinical trials and in vivo human studies are needed to confirm its effectiveness.
Systematic ReviewHighly CitedLong-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease.
Long-term ascorbic acid treatment improves endothelial function and may benefit patients with coronary artery disease.
RCTHighly CitedPhase I clinical trial of i.v. ascorbic acid in advanced malignancy.
High-dose i.v. ascorbic acid was well-tolerated but failed to demonstrate anticancer activity in patients with previously treated advanced malignancies.
Highly CitedBleeding tendency and ascorbic acid requirements: systematic review and meta-analysis of clinical trials.
Increasing daily ascorbic acid intake may help prevent gingival bleeding tendency and retinal hemorrhaging, which are linked to low AA levels and may be reversible with increased daily intake.
Meta-Analysis