Perindopril
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Perindopril: From Hypertension to Malignant Renovascular Hypertension
One-Sentence Summary
Perindopril is an ACE inhibitor originally used to treat hypertension. The TxGNN model predicts it may be effective for malignant renovascular hypertension, but there are currently 0 clinical trials and 0 publications supporting this specific prediction. The evidence rests on model prediction alone (Level L5).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hypertension (hypertensive disorder) |
| Predicted New Indication | Malignant renovascular hypertension |
| TxGNN Prediction Score | 99.77% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 20 |
| Recommended Decision | Hold |
Note: The registered approved-indication text for the Singapore licences is blank in the data compiled for this report. The original indication is taken from the drug's known indication records.
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. Based on known pharmacology, perindopril is an angiotensin-converting enzyme (ACE) inhibitor. Its efficacy in hypertension is established, and it may mechanistically apply to renovascular hypertension, which is strongly dependent on the renin-angiotensin system (RAS).
There is an important safety caveat. ACE inhibitors can cause acute renal failure in patients with bilateral renal artery stenosis. The knowledge graph also lists renal artery obstruction as a contraindication-related condition for this drug. The high TxGNN score (0.998) is a model prediction, probably driven by similarity to the original hypertension indication, and is not clinical proof.
Other Predicted Indications (for context)
| Rank | Predicted Indication | Score | Evidence Level | Note |
|---|---|---|---|---|
| 2 | Malignant hypertensive renal disease | 99.77% | L5 | The only retrieved paper (post-nephrectomy kidney function) is not relevant |
| 3 | Pulmonary hypertension, unclear multifactorial mechanism | 99.75% | L5 | No evidence; systemic vasodilators may be harmful |
| 4 | Pulmonary hypertension owing to lung disease/hypoxia | 99.75% | L4 | Rat studies only (e.g., PMID 11282121, 10602319) |
| 5 | Braddock syndrome | 99.66% | L5 | No evidence |
| 6 | Chronic pulmonary heart disease | 97.60% | L3 | Small human studies, many non-English; the most evidence-supported prediction |
| 7 | Familial hematuria-retinal arteriolar tortuosity-contractures syndrome | 67.49% | L5 | No evidence |
| 8 | Brain small vessel disease 1 | 65.65% | L4 | One indirect study in lacunar infarction |
| 9 | Polydipsia | 62.48% | L5 | Retrieved paper not relevant |
| 10 | Congenital temporomandibular joint ankylosis | 60.31% | L5 | Likely a spurious association |
Clinical Trial Evidence
Currently no related clinical trials registered for malignant renovascular hypertension. No registered trials were found for any of the top 10 predicted indications.
Literature Evidence
For the top prediction (malignant renovascular hypertension), currently no related literature is available.
The most relevant literature across the predicted indications relates to chronic pulmonary heart disease and pulmonary hypertension:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 11076421 | 2000 | Clinical study | Terapevticheskii arkhiv | Efficacy and safety of perindopril in chronic cor pulmonale |
| 16279041 | 2005 | Clinical study | Klinicheskaia meditsina | 42 patients with chronic obstructive bronchitis and secondary pulmonary hypertension; 4-week perindopril, haemodynamics and safety assessed |
| 16881230 | 2006 | Clinical study | Problemy tuberkuleza i boleznei legkikh | Course and long-term perindopril therapy in COPD with chronic cor pulmonale |
| 11399702 | 2001 | Clinical study | Chest | Long-term perindopril improved respiratory muscle strength in chronic heart failure |
| 8328368 | 1993 | Clinical study | Am J Cardiol | Perindopril 4 mg in 15 patients with severe congestive heart failure; haemodynamic efficacy, not specific to cor pulmonale |
| 15166388 | 2004 | Clinical study | Stroke | Effect of perindopril on cerebral vasomotor reactivity in lacunar infarction |
| 11282121 | 2001 | Preclinical (rat) | Eur J Pharmacol | Amlodipine plus perindopril fully prevented pulmonary vascular remodelling in hypoxic rats |
| 10602319 | 1999 | Preclinical (rat) | Br J Pharmacol | Perindopril reduced pulmonary artery pressure by 18% in hypoxic pulmonary hypertensive rats |
| 7974317 | 1994 | Clinical study | Thorax | ACE inhibition and sodium excretion in hypoxaemic COPD |
| 37678466 | 2023 | Case report | Rev Esp Anestesiol Reanim | Late-onset angioedema triggered by perindopril (safety signal) |
Many of the other retrieved papers (herbal formulas, hepatocellular carcinoma, islet biology) are not relevant to these predictions.
Singapore Market Information
Perindopril is marketed in Singapore, with 20 valid registrations. All are combination products and none is cancelled. The approved-indication text is not available in the data compiled for this report. Main authorisations:
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN13633P | COVERSYL PLUS Tablet 5 mg/1.25 mg | Film-coated tablet | Not available |
| SIN13826P | COVERAM Tablet 5 mg/5 mg | Tablet | Not available |
| SIN15400P | COSYREL Film-coated Tablet 10 mg/5 mg | Film-coated tablet | Not available |
| SIN15013P | TRIPLIXAM Film-coated Tablet 10 mg/2.5 mg/5 mg | Film-coated tablet | Not available |
| SIN15726P | AMLESSA Tablets 8 mg/10 mg | Tablet | Not available |
All products are oral formulations.
Safety Considerations
- Contraindication-related conditions (from the knowledge graph, not label text): kidney disease, renal artery obstruction, liver disease, gallbladder disease, angioedema (including hereditary, acquired and RAAS-blocker-induced), neutropenia, agranulocytosis, hypotensive disorder, connective tissue disease, bone disease, cartilage disease, pyoureter.
- Drug Interactions: 100 interactions were identified. Major-level interactions include potassium citrate and potassium bicarbonate (risk of hyperkalaemia). Moderate-level interactions include corticosteroids (hydrocortisone, dexamethasone, betamethasone, budesonide, triamcinolone), antidiabetic drugs (metformin, alogliptin, saxagliptin, canagliflozin, dapagliflozin, empagliflozin, chlorpropamide), acetylsalicylic acid, morphine, bupropion, dronabinol, picosulfuric acid and polyethylene glycol with electrolytes.
- Predicted-indication-specific cautions: Risk of acute renal failure in bilateral renal artery stenosis (relevant to renovascular hypertension). Systemic vasodilators may be harmful in pulmonary hypertension. ACE-inhibitor angioedema can be life-threatening (case reports PMID 37678466 and 40365500).
Package insert warnings and contraindications were not available. Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The top prediction, malignant renovascular hypertension, has plausible RAS-related biology but no trials or literature, and carries a real renal safety concern. Among the other predictions, chronic pulmonary heart disease has the most human data (L3), but those studies are small, of unclear design and often non-English, so it is best treated as a research question rather than a development candidate.
To proceed, the following is needed:
- Package insert warnings and contraindications from HSA (currently a blocking gap for safety screening)
- Mechanism-of-action data from DrugBank
- A targeted literature review of ACE inhibitors in renovascular hypertension, including renal safety in renal artery stenosis
- For chronic pulmonary heart disease, a systematic review and critical appraisal of the existing small studies, followed by a prospective controlled study if warranted
- Confirmation of the approved indications for the Singapore-registered products
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.