Ascorbic Acid
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Ascorbic Acid
- Ascorbic Acid: From Ascorbic Acid Deficiency and Scurvy to Non-Syndromic Esophageal Malformation
Ascorbic Acid: From Ascorbic Acid Deficiency and Scurvy to Non-Syndromic Esophageal Malformation
One-Sentence Summary
Ascorbic acid (vitamin C) was originally used to treat ascorbic acid deficiency and scurvy. The TxGNN model's top-ranked prediction is non-syndromic esophageal malformation, but this prediction has 0 clinical trials and 0 publications behind it, and no plausible mechanism has been identified. Among the other predictions, "injury" (16 clinical trials, 20 publications) and "vitamin deficiency disorder" (6 clinical trials, 20 publications) have the most supporting evidence; the latter is largely an on-label use.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ascorbic acid deficiency; scurvy (no approved indication text is recorded in the Singapore licences) |
| Predicted New Indication | Non-syndromic esophageal malformation |
| TxGNN Prediction Score | 99.96% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 3 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not currently available. Ascorbic acid is a well-known water-soluble vitamin that acts as an antioxidant and as a cofactor for collagen synthesis. Its efficacy in correcting vitamin C deficiency and scurvy is established.
For the top-ranked prediction, non-syndromic esophageal malformation, no mechanistic rationale has been identified. This is a congenital structural malformation, and ascorbic acid is not expected to correct it. The high score reflects a graph-based prediction only, with no supporting trials or literature.
Other predictions have more plausible links:
- Injury (L2, Phase 2 RCTs exist): Ascorbic acid may attenuate oxidative stress, endothelial dysfunction and inflammation after tissue injury. However, "injury" is a very broad category, the trials are small, and several were terminated or have unknown status, so condition-specific evaluation is needed.
- Vitamin deficiency disorder (L3): This overlaps with the existing indications (deficiency and scurvy), so it is largely on-label rather than true repurposing. Extension to deficiencies of other vitamins is unsupported.
- Esophageal disease (L4): Evidence is preclinical, epidemiological or review-level and the direction is mixed. One rat study reported enhanced esophageal carcinogenesis in a reflux model treated with ascorbic acid.
- Perinatal disease (L4): One small trial in neonatal hypoxic-ischemic encephalopathy combined ascorbic acid with ibuprofen, which confounds attribution.
Clinical Trial Evidence
Currently no related clinical trials are registered for the top-ranked prediction (non-syndromic esophageal malformation).
For reference, the best-supported prediction is injury. The most relevant trials are listed below.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02106975 | Phase 2 | Completed | 170 | IV vitamin C for sepsis-induced acute lung injury; endpoints include SOFA score, oxygenation and inflammatory biomarkers |
| NCT03509662 | Phase 2 | Completed | 270 | Early high-dose vitamin C in post-cardiac arrest syndrome (ischemia-reperfusion injury) |
| NCT04344184 | Phase 2 | Completed | 47 | Safety of a 96-hour IV vitamin C protocol in COVID-19 acute lung injury |
| NCT04153487 | Phase 2 | Completed | 40 | Ascorbic acid infusion in transfusion-related acute lung injury |
| NCT01167569 | Phase 4 | Completed | 57 | Double-blind RCT of high-dose vitamin C in cardiac surgery |
| NCT03965637 | Phase 3 | Completed | 80 | Ascorbic acid on blood loss and wound healing in abdominal hysterectomy |
| NCT05327348 | Phase 3 | Unknown | 34 | Perioperative parenteral ascorbic acid to reduce oxidative stress in free flap surgery |
| NCT00624871 | Not specified | Completed | 60 | Ascorbic acid plus ibuprofen in neonatal hypoxic-ischemic encephalopathy (perinatal disease) |
| NCT03467022 | Not applicable | Completed | 47 | Observational study of latent scurvy risk in alcohol withdrawal patients (vitamin deficiency) |
| NCT02606773 | Phase 1 | Completed | 32 | Bioavailability of a liposomal vitamin C supplement versus licensed products |
Literature Evidence
No literature is available for the top-ranked prediction. The most relevant publications for the better-supported predictions are listed below.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38051821 | 2024 | Guideline | J Burn Care Res | American Burn Association guideline on burn shock resuscitation |
| 31440996 | 2020 | Review | Neurocrit Care | High-dose IV ascorbic acid in traumatic brain injury |
| 27600125 | 2016 | Review | Crit Care Clin | Vitamin C in burn resuscitation; antioxidant attenuation of capillary permeability |
| 23994411 | 2013 | Review/Meta-analysis | J Am Coll Cardiol | Ascorbic acid for prevention of contrast-induced acute kidney injury |
| 8598417 | 1995 | Review | J Am Coll Nutr | Ascorbic acid and GI cancer; evidence stronger for gastric, weaker for esophageal cancer |
| 17953708 | 2008 | Animal study | Cancer Sci | Ascorbic acid with sodium nitrite enhanced esophageal carcinogenesis in reflux model rats (possible harm) |
| 38291316 | 2024 | Cohort | ANZ J Surg | Ascorbic acid deficiency among spondylodiscitis patients |
| 38821739 | 2024 | Case report/Review | Reumatol Clin | Scurvy as a forgotten pseudovasculitis |
| 32937094 | 2021 | Case report/Review | Paediatr Int Child Health | Paediatric scurvy is frequently misdiagnosed |
| 11984597 | 2002 | Animal study | Nat Med | Slc23a1 vitamin C transporter is essential for brain vitamin C uptake and perinatal survival in mice |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN05858P | Ascorbic Acid Injection USP 500 mg/5 ml | Injection | Not recorded |
| SIN11609P | Panadol Cold & Flu Hot Remedy | Powder | Not recorded |
| SIN11975P | Cernevit for Injection | Injection, powder, for solution | Not recorded |
Safety Considerations
- Contraindications flagged in the knowledge graph (not label text): The TxGNN knowledge graph links ascorbic acid to a number of conditions as contraindications, including kidney disease, anuria, nephrocalcinosis, primary hyperoxaluria, hereditary hemochromatosis, sickle cell anemia, diabetes mellitus, peptic ulcer disease, liver disease, hypertension, epilepsy, and hypercalcemia. These need verification against the official package insert.
- Drug Interactions: 25 interactions were identified. Moderate-level interactions include amphetamine, dextroamphetamine, lisdexamfetamine, metamfetamine, benzphetamine, aluminum hydroxide, bortezomib and deferoxamine. Others, such as paclitaxel, cisplatin, doxorubicin, pseudoephedrine, ephedrine, ethinylestradiol, flecainide, fluphenazine, indinavir and mexiletine, are minor.
- Esophageal context: Preclinical data suggest possible harm in reflux settings, which is relevant to the esophageal predictions.
Please refer to the package insert for label warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction, non-syndromic esophageal malformation, has a high model score but no trials, no literature and no plausible mechanism, so it is supported by model prediction only (L5). Of the other candidates, "injury" (L2) is worth pursuing as a research question but is too broad and heterogeneous to act on directly. "Vitamin deficiency disorder" (L3) is essentially the existing indication and could proceed with guardrails, but it is not true repurposing.
To proceed, the following is needed:
- Package insert warnings and contraindications for the Singapore-registered products
- Mechanism of action data
- Narrowing "injury" to specific conditions (for example sepsis-induced lung injury, burns or cardiac surgery) and a condition-specific evidence review
- Reconciliation of the knowledge-graph contraindications (e.g. kidney disease, hyperoxaluria, hemochromatosis) with label information
- A decision on whether "vitamin deficiency disorder" should be treated as an on-label extension rather than repurposing
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.