Amlodipine

證據等級: L5

預測適應症: 10 個

Amlodipine: From Hypertension to Brain Stem Infarction

One-Sentence Summary

Amlodipine is a dihydropyridine calcium channel blocker (CCB) established in clinical practice for hypertension and chronic stable angina pectoris. The TxGNN model ranks Brain Stem Infarction as its top predicted new indication with a score of 99.94%; however, no clinical trials and no publications currently support this specific direction. Importantly, Amlodipine’s cerebrovascular evidence is considerably stronger for related indications — particularly intracerebral hemorrhage (rank 10), which is supported by a completed Phase 3 RCT with 1,671 participants.

Quick Overview

Item	Content
Original Indication	Hypertension / Chronic stable angina (globally recognised; no Canadian DIN records found in current dataset)
Predicted New Indication	Brain Stem Infarction
TxGNN Prediction Score	99.94%
Evidence Level	L5
Canada Market Status	Not Marketed (per current dataset — verification recommended)
Number of DINs	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this Evidence Pack. Based on known pharmacology, Amlodipine is a dihydropyridine-class CCB that inhibits voltage-gated L-type calcium channels in vascular smooth muscle cells, causing vasodilation, lowering peripheral resistance, and reducing blood pressure. Its efficacy in hypertension and angina pectoris has been extensively proven across decades of clinical use worldwide.

Brain stem infarction is an ischaemic stroke involving the posterior circulation (vertebrobasilar territory), for which hypertension is the single most important modifiable risk factor. By providing sustained blood pressure reduction, Amlodipine could theoretically reduce haemodynamic stress on the small perforating arteries supplying the brain stem, thereby lowering infarction risk. This mechanistic pathway is broadly applicable to all cerebrovascular stroke subtypes, not uniquely to brain stem infarction.

Beyond blood pressure control, animal models of cerebral ischaemia (primarily middle cerebral artery occlusion studies, see Cerebral Artery Occlusion — rank 6 below) suggest that Amlodipine may provide direct neuroprotection through blockade of calcium overload following ischaemic depolarisation and through antioxidative properties. However, no targeted preclinical or clinical studies in brain stem infarction specifically have been identified. The TxGNN high score most likely reflects knowledge-graph proximity between CCB pharmacological nodes and brain stem infarction disease nodes rather than direct experimental validation.

Clinical Trial Evidence

Currently no related clinical trials registered for brain stem infarction specifically.

Literature Evidence

Currently no related literature available for brain stem infarction specifically.

Other Predicted Indications with Stronger Evidence

The TxGNN model generated predictions across 10 ranked indications. The following carry substantially stronger evidence than top-ranked brain stem infarction and offer more actionable repurposing opportunities:

Rank	Predicted Indication	TxGNN Score	Evidence Level	Recommendation	Key Evidence
10	Intracerebral Hemorrhage	99.79%	L2	Proceed with Guardrails	TRIDENT Phase 3 completed (n=1,671); NCT07458880 recruiting (n=140)
6	Cerebral Artery Occlusion	99.89%	L3	Research Question	5 animal studies; 5 indirect clinical trials
8	MRI Defined Brain Infarct	99.86%	L4	Research Question	STEP trial (n=8,000; intensive BP control)
4	Malignant Renovascular Hypertension	99.90%	L4	Research Question	2 paediatric case reports; strong mechanistic rationale
2	Pulmonary Hypertension (Lung Disease/Hypoxia)	99.91%	L5	Hold	Non-specific literature; known safety concern (see Safety section)

Intracerebral Hemorrhage — Most Actionable Prediction (Rank 10)

Clinical Trials:

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02699645	Phase 3	Completed	1,671	TRIDENT: fixed-dose triple antihypertensive pill (CCB/Amlodipine component) vs standard care for prevention of recurrent stroke after intracerebral haemorrhage — primary efficacy trial
NCT07458880	—	Recruiting	140	Triple antihypertensive therapy (including Amlodipine) for blood pressure control after ICH, guided by TRICH scoring — directly targets post-ICH BP management
NCT00134160	Phase 4	Completed	1,000	CASE-J: ARB monotherapy vs ARB + CCB combination in high-cardiovascular-risk Japanese hypertensive patients — indirect evidence comparing CCB-inclusive strategies
NCT03264352	Phase 4	Recruiting	11,414	IPAD: antihypertensives in T2DM patients with high-normal BP — large BP-intervention trial with ICH as secondary endpoint
NCT03785067	Phase 3	Terminated	1	TRIDENT Cognitive Sub-Study — terminated early, no usable data

Literature:

PMID	Year	Type	Journal	Key Findings
34994269	2022	Trial Protocol	Int J Stroke	TRIDENT rationale and design: single-pill combination BP therapy (including Amlodipine) to prevent recurrent ICH in high-risk patients
14717341	2003	RCT Design	Hypertension Res	CASE-J design: ARB vs ARB+CCB strategy in high-risk hypertensive patients — cardiovascular event endpoints including stroke
23053838	2013	Review	Neurol Sci	β-blocker vs CCB comparison in acute ICH blood pressure management; contextualises CCB role in acute cerebrovascular haemorrhage
3154329	1988	Review	Cardiovasc Drugs Ther	Calcium antagonist mechanisms in hypertension and cerebrovascular disease — foundational pharmacology review
19299323	2009	Case Report	Ann Pharmacother	Amlodipine-associated angioedema in a right thalamic haemorrhagic stroke patient — safety signal worth noting

Cerebral Artery Occlusion — Strongest Preclinical Evidence (Rank 6)

Literature:

PMID	Year	Type	Journal	Key Findings
21538457	2011	Animal Study	J Neurosci Res	Amlodipine + atorvastatin reduce infarct size and neuronal apoptosis after transient MCAO in metabolic syndrome rats — antiapoptotic and antiautophagic protection
20971084	2011	Animal Study	Brain Res	Synergistic neuroprotection with amlodipine + atorvastatin in Zucker rat MCAO model — additive effect on infarct volume reduction
21276424	2011	Animal Study	Brain Res	Combination therapy with amlodipine + atorvastatin protects against ischaemic stroke damage in metabolic syndrome model
17070425	2006	Animal Study	Am J Hypertens	Amlodipine reduces stroke size in ApoE-deficient mice after focal cerebral ischaemia — L-type CCB mechanism
17904110	2007	Animal Study	Brain Res	CCBs with antioxidative effects prevent neuronal damage after focal ischaemia in rats; Amlodipine’s antioxidative properties implicated in neuroprotection

Canada Market Information

No Canadian Drug Identification Number (DIN) records were identified for Amlodipine in the current dataset. This finding is inconsistent with Amlodipine’s well-established global availability as a first-line antihypertensive (Norvasc® and numerous generics are known to be approved and marketed in Canada). A verification query against Health Canada’s Drug Product Database is strongly recommended before drawing any regulatory conclusions from this data.

Safety Considerations

Key Safety Note — Pulmonary Hypertension Group 3 (Rank 2 Prediction): The mechanistic analysis in this Evidence Pack flags a clinically important contraindication. In WHO Group 3 pulmonary hypertension (arising from lung disease and/or hypoxia), CCBs such as Amlodipine may cause systemic vasodilation without selective pulmonary vasodilation, worsening ventilation-perfusion (V/Q) mismatch and aggravating hypoxaemia. Current guidelines restrict CCB use in pulmonary hypertension to WHO Group 1 patients with demonstrated acute vasoreactivity. This rank 2 prediction should therefore be considered a safety contraindication rather than a repurposing opportunity.

For all other indications, please refer to the package insert for full safety information.

Conclusion and Next Steps

Decision: Hold (for brain stem infarction — TxGNN rank 1 prediction)

Rationale: The L5 evidence level for brain stem infarction reflects a model prediction only — no clinical trials, observational studies, or targeted preclinical data have been identified for this specific anatomical stroke subtype. Advancing a repurposing programme without any supporting evidence is not warranted at this time.

To proceed, the following is needed:

Targeted literature review specifically for Amlodipine or dihydropyridine CCBs in posterior circulation stroke and vertebrobasilar ischaemia
Mechanism of action (MOA) data retrieval from DrugBank (DB00381) to formalise the pharmacological rationale
Verification of Canada DIN status via Health Canada’s Drug Product Database — the 0-DIN result likely reflects a data pipeline issue rather than actual non-availability
Safety data retrieval from the drug monograph (TFDA/Health Canada package insert) to complete the S1 safety screening
Priority recommendation: Redirect primary evaluation to intracerebral hemorrhage (rank 10), where the completed TRIDENT Phase 3 RCT (n=1,671) establishes an L2 evidence level and supports a “Proceed with Guardrails” recommendation — this is the most actionable finding in the current Evidence Pack

Disclaimer: This report is for research reference purposes only and does not constitute medical advice. Drug repurposing candidates require clinical validation before any clinical application. All findings should be interpreted in conjunction with full regulatory review and clinical expert assessment.

Disclaimer

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