Cilazapril

證據等級: L5

預測適應症: 4 個

Cilazapril: From Hypertension to Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia

One-Sentence Summary

Cilazapril is an ACE (Angiotensin-Converting Enzyme) inhibitor belonging to the RAAS-blocking drug class, traditionally used for systemic hypertension and heart failure. The TxGNN model predicts it may be effective for Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia (Group 3 PH), scoring 99.20% on the prediction model. However, the evidence base is limited — 0 clinical trials and no cilazapril-specific publications were identified for this indication, with retrieved literature covering only general hypoxia biology.

Quick Overview

Item	Content
Original Indication	Hypertension (ACE inhibitor class; no Canada DIN on file)
Predicted New Indication	Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia (Group 3 PH)
TxGNN Prediction Score	99.20%
Evidence Level	L4 — Mechanistic inference only, no clinical studies
Canada Market Status	Not Marketed
Number of DINs	0
Recommended Decision	Hold

Why Is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available from the evidence pack. Based on known pharmacological class, cilazapril is an ACE inhibitor that blocks the conversion of Angiotensin I to Angiotensin II, thereby suppressing the renin-angiotensin-aldosterone system (RAAS). This leads to systemic and — theoretically — pulmonary vasodilation, reduced vascular resistance, and attenuation of vascular remodeling driven by Angiotensin II.

In Group 3 PH (pulmonary hypertension secondary to lung disease or chronic hypoxia), RAAS activation has been documented as a contributing pathophysiological mechanism. Hypoxia-induced pulmonary vasoconstriction involves local Angiotensin II signaling, and ACE inhibition could theoretically interrupt this cycle, reduce pulmonary artery pressure, and slow vascular remodeling. This mechanistic linkage explains why a graph-based model like TxGNN would flag ACE inhibitors as candidates.

However, the clinical translation risk is significant. ACE inhibitors cause systemic vasodilation, which can worsen ventilation-perfusion (V/Q) mismatch and aggravate hypoxemia in patients with underlying lung disease — potentially the opposite of the intended effect. Current ESC/ERS pulmonary hypertension guidelines do not recommend ACE inhibitors as specific therapy for Group 3 PH. The prediction is mechanistically plausible but faces substantial clinical barriers that have not been resolved in published trials.

Clinical Trial Evidence

Currently no related clinical trials registered for cilazapril in pulmonary hypertension owing to lung disease and/or hypoxia.

Literature Evidence

The 20 publications retrieved address general hypoxia biology and are not specific to cilazapril or ACE inhibitors in pulmonary hypertension. They provide contextual background only. The 10 most relevant are listed below:

PMID	Year	Type	Journal	Key Findings
11172576	2000	Review	Respiratory Care Clinics of North America	Describes mechanisms of hypoxemia including V/Q mismatch and shunt — relevant to understanding why systemic vasodilators may worsen oxygenation in lung disease
34535359	2021	Review	Clinical Oncology (RCR)	Reviews therapeutic strategies targeting tumor hypoxia; illustrates the complexity of hypoxia modification as a treatment approach
33862277	2021	Review	Ageing Research Reviews	Explores hypoxia’s dual role in neurodegeneration and neuroprotection; general HIF-pathway biology
31961750	2020	Review	Annual Review of Immunology	Covers HIF-mediated innate immune responses under physiologic and inflammatory hypoxia
21328446	2011	Review	Journal of Cellular Biochemistry	Overview of cellular oxygen sensing, angiogenesis, and vascular disease under hypoxia
27423661	2016	Review	Cell and Tissue Research	HIF-1 signaling in tissue repair and fibrosis — relevant to vascular remodeling in chronic hypoxia
34618295	2022	Review	Metabolic Brain Disease	Clinical and molecular review of hypoxia-induced cognitive impairment; general hypoxia pathophysiology
31706510	2019	Review	Trends in Cancer	DUB-HIF axis in hypoxic tumors; not directly relevant to pulmonary vascular disease
36100192	2022	Review	Journal of Controlled Release	Hypoxia-targeted nanomedicines in solid tumors; background on hypoxic tumor microenvironment
40347693	2025	Review	Redox Biology	Examines hypoxia’s role in multiple sclerosis pathology and vascular dysfunction

Note: None of the retrieved publications directly study cilazapril, ACE inhibitors, or RAAS blockade in Group 3 pulmonary hypertension. The evidence gap is confirmed.

Canada Market Information

Cilazapril is not currently marketed in Canada. No Drug Identification Numbers (DINs) are on file, and no approved product monographs are available through the Health Canada database.

Safety Considerations

Please refer to the package insert for safety information.

Important class-level caution: As an ACE inhibitor, cilazapril carries well-known class risks relevant to this predicted indication:

Contraindicated in bilateral renal artery stenosis or single functioning kidney (risk of acute renal failure)

Risk of worsening hypoxemia via systemic vasodilation causing V/Q mismatch in patients with underlying lung disease

Hyperkalemia risk, particularly in patients with renal impairment

Dry cough (ACE inhibitor class effect) may be poorly tolerated in patients with existing respiratory disease

These class-level concerns are especially pertinent for the proposed Group 3 PH indication.

Conclusion and Next Steps

Decision: Hold

Rationale: While the mechanistic basis for ACE inhibition in Group 3 pulmonary hypertension is theoretically plausible through RAAS suppression, there are zero clinical trials and no drug-specific publications to support cilazapril’s use in this setting. More critically, ACE inhibitors carry a recognized risk of worsening hypoxemia in patients with underlying lung disease — the very population this indication targets — and current ESC/ERS guidelines do not endorse this therapeutic approach. Cilazapril is also not marketed in Canada, creating an additional regulatory barrier.

To proceed, the following is needed:

Mechanism of action data: Retrieve full DrugBank entry for cilazapril (DB01340) to confirm RAAS mechanism and any known pulmonary pharmacodynamics
Cilazapril-specific literature search: Conduct a dedicated PubMed search combining cilazapril with “pulmonary hypertension,” “ACE inhibitor pulmonary,” or “RAAS lung disease” — the current 20 results appear to be generic hypoxia background literature, not drug-specific evidence
Class evidence review: Review existing evidence for other ACE inhibitors (enalapril, ramipril) in Group 3 PH to determine whether class-level data could support extrapolation
Safety dossier: Download and parse the product monograph from markets where cilazapril is approved (e.g., EU/UK — marketed as Vascace/Inhibace) to obtain formal contraindications, warnings, and drug interaction data
ESC/ERS guideline alignment check: Confirm current guideline stance on RAAS inhibition in Group 3 PH before any clinical development planning
Regulatory pathway assessment: If evidence is assembled, determine whether a Health Canada NOC submission or a compassionate use framework would apply, given zero current Canadian DINs
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.