Tolbutamide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Tolbutamide: From Type 2 Diabetes Mellitus to Opsismodysplasia
One-Sentence Summary
Tolbutamide is a sulfonylurea originally used to treat type 2 diabetes mellitus. The TxGNN model predicts it may be effective for opsismodysplasia (a rare skeletal dysplasia), but this is a graph-based prediction only, with 0 clinical trials and 0 publications directly supporting it.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Type 2 diabetes mellitus (the registered indication text for the Singapore licences is blank) |
| Predicted New Indication | Opsismodysplasia |
| TxGNN Prediction Score | 96.77% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for tolbutamide were not available in the data compiled for this report. Tolbutamide is known as a sulfonylurea that closes ATP-sensitive potassium (KATP) channels in pancreatic beta cells, which stimulates insulin secretion. Its efficacy in type 2 diabetes is established.
Opsismodysplasia is a skeletal dysplasia caused by INPPL1 mutations (SHIP2 deficiency), which affect PI3K/insulin signalling. A link to tolbutamide is only speculative. No mechanistic connection has been established, and the high score reflects a graph-based association rather than a therapeutic rationale.
Other top-ranked predictions show the same pattern. Stiff person syndrome and thiamine-responsive syndromes are linked mainly through diabetes comorbidity. The lipodystrophies appear to reflect an insulin/metabolic network association. Pancreatic agenesis is biologically implausible, because tolbutamide needs functional beta cells. Autoimmune oophoritis scored lower (77%) and has no identified mechanism.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
No literature was found for opsismodysplasia, the top prediction. The only literature retrieved was for the ninth-ranked prediction, pancreatic agenesis. It covers general sulfonylurea and beta-cell biology rather than treatment of that condition.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 15115830 | 2004 | Clinical/genetic study | N Engl J Med | Activating KCNJ11 (Kir6.2) mutations cause permanent neonatal diabetes, showing the role of KATP channels |
| 3057892 | 1988 | Review | Am J Med | Hyperinsulinemia and insulin responses, including to tolbutamide, in non-insulin-dependent diabetes |
| 791727 | 1975 | Review | Diabete & metabolisme | Diabetes mellitus secondary to liver disease |
| 180358 | 1976 | Case series | Mayo Clin Proc | Clinical and diagnostic features of 60 insulinoma cases |
| 23274908 | 2013 | Not classified | Diabetes | Congenital hyperinsulinism caused by hexokinase I expression or a glucokinase-activating mutation |
| 10482920 | 1999 | Preclinical (islets) | Br J Pharmacol | Sulphonylurea pretreatment disturbs Ca2+ regulation and insulin secretion in mouse islets |
| 9519717 | 1998 | Preclinical (animal) | Diabetes | Streptozotocin/nicotinamide rat model of NIDDM with responsiveness to sulfonylureas |
| 6114005 | 1981 | Preclinical (animal) | Diabetes | Islet secretion in a neonatal streptozotocin rat model of non-insulin-dependent diabetes |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN04045P | TOBUMIDE TABLET 500 mg | Tablet | Not stated in the registration record |
| SIN04257P | TOLMIDE TABLET 500 mg | Tablet | Not stated in the registration record |
Safety Considerations
- Contraindications (knowledge-graph associations, not label text): kidney disease, liver disease, gallbladder disease, hepatic porphyria, Addison disease and chronic primary adrenal insufficiency, thymus gland disease, substance abuse/dependence, and a wide range of pituitary deficiency and hypogonadotropic hypogonadism conditions (e.g., hypopituitarism, growth hormone deficiency, Kallmann syndrome, Sheehan syndrome).
- Drug Interactions: 100 interactions were identified, and 20 are shown in the data. Most are Moderate, and a few topical corticosteroids are Minor. Notable moderate ones include:
- Beta-agonists and sympathomimetics: epinephrine, salbutamol, formoterol, phenylephrine, pseudoephedrine
- Beta-blocker: acebutolol
- Acid suppressants: famotidine, ranitidine
- NSAIDs: ibuprofen, ketorolac
- Others: hydrochlorothiazide, acetazolamide, ethanol, ethinylestradiol, hydrocortisone, acitretin, albiglutide, nitazoxanide
Package insert warnings were not available. Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The 96.77% TxGNN score is not backed by any clinical trial or literature, and no plausible mechanism connects KATP channel blockade to INPPL1-related skeletal dysplasia. Evidence is L5 (model prediction only). None of the other nine predictions has stronger support.
To proceed, the following is needed:
- Package insert warnings and contraindications from the HSA (currently a blocking gap for safety screening)
- Detailed mechanism of action data (MOA) from DrugBank
- Preclinical or mechanistic evidence linking tolbutamide to SHIP2/INPPL1 or PI3K signalling in skeletal development
- Approved indication text for the two Singapore licences, which is currently blank
- Assessment of route compatibility and similarity to the original indication, both still pending
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.