Cilazapril
| 證據等級: L5 | 預測適應症: 4 個 |
目錄
- Cilazapril
- Cilazapril: From Hypertension to Pulmonary Hypertension with Unclear Multifactorial Mechanism
Cilazapril: From Hypertension to Pulmonary Hypertension with Unclear Multifactorial Mechanism
One-Sentence Summary
Cilazapril is an angiotensin-converting enzyme (ACE) inhibitor originally used for the treatment of hypertension and heart failure. The TxGNN model predicts it may be effective for Pulmonary Hypertension with Unclear Multifactorial Mechanism (WHO Group 5), with 0 clinical trials and 0 directly relevant publications currently supporting this specific direction. Three additional predicted indications are also evaluated in this report.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hypertension, heart failure (ACE inhibitor class) |
| Predicted New Indication | Pulmonary hypertension with unclear multifactorial mechanism |
| TxGNN Prediction Score | 99.20% |
| Evidence Level | L5 — Model prediction only, no clinical studies |
| UK Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the evidence pack. Based on known pharmacological information, Cilazapril is an ACE inhibitor that blocks the conversion of angiotensin I to angiotensin II. By inhibiting ACE, the drug reduces vasoconstriction, aldosterone secretion, and sodium retention, thereby lowering blood pressure. ACE inhibition also increases bradykinin levels, which promotes nitric oxide (NO) and prostacyclin release, contributing to vasodilation.
ACE is abundantly expressed in pulmonary vascular endothelium, and angiotensin II is involved in pulmonary vascular remodelling. In theory, ACE inhibition could attenuate pulmonary vascular remodelling and promote pulmonary vasodilation through the bradykinin–NO–prostacyclin pathway. This provides a plausible mechanistic basis for the TxGNN prediction.
However, it is important to note that clinical experience with ACE inhibitors in pulmonary arterial hypertension (PAH) has been disappointing. Current guidelines recommend PDE5 inhibitors, endothelin receptor antagonists, and prostacyclin analogues rather than ACE inhibitors. WHO Group 5 pulmonary hypertension (multifactorial/unclear mechanisms) is particularly data-poor, with virtually no ACE inhibitor-specific evidence. The mechanistic rationale is moderate at best, and translational barriers are significant.
Clinical Trial Evidence
Currently no related clinical trials registered for Cilazapril in pulmonary hypertension with unclear multifactorial mechanism.
Searches were conducted on ClinicalTrials.gov and the WHO ICTRP on 26 March 2026, returning zero results.
Literature Evidence
Currently no directly relevant literature available for Cilazapril in pulmonary hypertension with unclear multifactorial mechanism.
A PubMed search on 26 March 2026 returned zero results for this specific drug–disease combination.
UK Market Information
Cilazapril does not currently hold any active MHRA marketing authorisations in the United Kingdom. The drug is not marketed in the UK. Healthcare professionals considering this compound would need to access it through unlicensed medicine pathways or specials manufacturing, subject to appropriate governance and clinical oversight.
Safety Considerations
Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme.
Note: Key warnings, contraindications, and drug–drug interaction data were not available in the evidence pack. As an ACE inhibitor, prescribers should be aware of class-level safety concerns including hyperkalaemia, renal impairment, angioedema, first-dose hypotension, and teratogenicity. ACE inhibitors are contraindicated in pregnancy.
Additional Predicted Indications
Indication 2: Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia
| Item | Content |
|---|---|
| TxGNN Prediction Score | 99.20% |
| Evidence Level | L5 |
| Recommendation | Hold |
Mechanistic rationale: WHO Group 3 pulmonary hypertension is caused by lung disease and/or hypoxia. Hypoxic pulmonary vasoconstriction involves local renin–angiotensin system (RAS) activation. Animal models have shown that ACE inhibitors can partially attenuate hypoxic pulmonary vascular remodelling. However, systemic RAS inhibition may cause systemic hypotension rather than selective pulmonary vasodilation, creating substantial translational difficulties.
Literature: 20 publications were retrieved, but all relate to general hypoxia biology (reviews and basic science) rather than to Cilazapril or ACE inhibitors in pulmonary hypertension. No directly relevant evidence was identified. Representative examples:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 33862277 | 2021 | Review | Ageing Res Rev | General review of hypoxia and neurodegeneration; no ACE inhibitor data |
| 34618295 | 2022 | Review | Metab Brain Dis | Review of cognitive impairment from hypoxia; not relevant to pulmonary vascular disease |
| 21328446 | 2011 | Review | J Cell Biochem | General review of hypoxia-mediated biological control |
| 11172576 | 2000 | Review | Respir Care Clin N Am | Review of hypoxaemia mechanisms; basic physiology |
| 40347693 | 2025 | Review | Redox Biol | Hypoxia in multiple sclerosis; not relevant |
Assessment: None of the 20 retrieved publications provide evidence for Cilazapril use in WHO Group 3 pulmonary hypertension. The literature appears to have been retrieved on the keyword “hypoxia” alone and lacks drug-specific relevance.
Indication 3: Malignant Hypertensive Renal Disease
| Item | Content |
|---|---|
| TxGNN Prediction Score | 99.12% |
| Evidence Level | L4 |
| Recommendation | Research Question |
Mechanistic rationale: Strong mechanistic link. The core pathology of malignant hypertensive renal disease involves severe RAS over-activation leading to angiotensin II-driven glomerular hypertension, endothelial injury, and fibrinoid necrosis. ACE inhibitors directly block this pathway. Substantial evidence from landmark trials (REIN, AASK) confirms the renoprotective benefit of ACE inhibitors (enalapril, ramipril) in hypertensive nephropathy. Cilazapril, as a member of the same class, has a sound mechanistic rationale.
Caution: In the acute phase of malignant hypertension, ACE inhibitors must be used with caution as they may precipitate acute kidney injury, particularly when renal perfusion pressure is dependent on angiotensin II.
Clinical trials: Currently no related clinical trials registered. Literature: Currently no related literature available.
Indication 4: Malignant Renovascular Hypertension
| Item | Content |
|---|---|
| TxGNN Prediction Score | 99.12% |
| Evidence Level | L4 |
| Recommendation | Hold |
⚠️ Safety Alert: There is a mechanistic contradiction for this indication. Renovascular hypertension is caused by renal artery stenosis. The affected kidney depends on angiotensin II to maintain glomerular filtration rate (GFR). ACE inhibitors block this compensatory mechanism and may cause acute renal failure — this is an established contraindication, particularly in bilateral renal artery stenosis or a solitary kidney. Even in unilateral stenosis, combining malignant hypertension with renovascular disease makes ACE inhibitor use extremely high-risk.
Clinical trials: Currently no related clinical trials registered. Literature: Currently no related literature available.
Conclusion and Next Steps
Decision: Hold
Rationale: The TxGNN model prediction scores are high (99.12–99.20%) across all four indications, but clinical evidence is essentially absent. No clinical trials have been registered, and no directly relevant literature supports the use of Cilazapril specifically in any of the predicted indications. Cilazapril is not currently marketed in the UK, adding a significant access barrier. Additionally, the fourth predicted indication (malignant renovascular hypertension) carries a clear safety contraindication that warrants particular caution. Only the third indication (malignant hypertensive renal disease) demonstrates a strong mechanistic rationale consistent with established ACE inhibitor class evidence, and could merit further investigation.
To proceed, the following is needed:
- Obtain detailed mechanism of action data from DrugBank
- Obtain SmPC safety data (key warnings, contraindications) for ACE inhibitor class-level review
- Conduct a targeted literature search for ACE inhibitors (class-level, not Cilazapril-specific) in WHO Group 5 and Group 3 pulmonary hypertension
- Evaluate whether existing ACE inhibitor trial data in hypertensive nephropathy (REIN, AASK) can be extrapolated to Cilazapril for malignant hypertensive renal disease
- Assess UK access pathways for Cilazapril (unlicensed medicine, specials) or consider whether other marketed ACE inhibitors with equivalent profiles may serve as alternatives
- Confirm that malignant renovascular hypertension is flagged as a contraindication, not a repurposing target
This report was generated on 5 April 2026. Data cutoff: 5 April 2026. This analysis is for research purposes only and does not constitute medical advice. All drug repurposing candidates require clinical validation before application. Report suspected adverse reactions via the Yellow Card Scheme.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.