Nisoldipine
| Evidence Level: L4 | Predicted Indications: 5 |
Table of Contents
- Nisoldipine
- Nisoldipine: From Hypertension to Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia
Nisoldipine: From Hypertension to Pulmonary Hypertension Owing to Lung Disease and/or Hypoxia
One-Sentence Summary
Nisoldipine is a dihydropyridine calcium channel blocker, originally used to treat hypertension. The TxGNN model predicts it may be effective for pulmonary hypertension owing to lung disease and/or hypoxia, but no clinical trials are registered and the 19 retrieved publications are almost entirely preclinical, so support is indirect.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hypertension (hypertensive disorder) |
| Predicted New Indication | Pulmonary hypertension owing to lung disease and/or hypoxia |
| TxGNN Prediction Score | 99.77% |
| Evidence Level | L4 |
| US Market Status | Cancelled only (no active marketing) |
| Number of NDAs | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, nisoldipine is a dihydropyridine L-type calcium channel blocker. Its efficacy in hypertension rests on relaxing vascular smooth muscle, and mechanistically this may be applicable to the pulmonary circulation.
Hypoxic pulmonary vasoconstriction depends partly on calcium influx through L-type channels and on calcium release from intracellular stores in pulmonary arterial smooth muscle. This gives a plausible link between calcium channel blockade and the predicted indication. Older animal work, such as a 1985 canine study comparing nisoldipine, nifedipine and bepridil in experimental pulmonary hypertension, is consistent with this idea.
There is an important caution. Calcium channel blockers are generally not recommended for pulmonary hypertension associated with lung disease or hypoxia, because they may worsen ventilation/perfusion mismatch and cause systemic hypotension. The high TxGNN score therefore should not be read as clinical support.
Other predictions in the list are weaker:
- Pulmonary hypertension with unclear multifactorial mechanism: computational prediction only (L5).
- Malignant renovascular hypertension: only a general 1987 review, and the condition is an emergency usually managed with revascularization and intravenous agents (L4).
- Malignant hypertensive renal disease: computational prediction only (L5).
- Braddock syndrome: no clear mechanistic rationale (L5).
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
Of the 19 publications retrieved for the lead prediction, none is a clinical study. The most relevant are listed below.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 3872360 | 1985 | Animal study | J Pharmacol Exp Ther | Compared pulmonary vasodilator effects of nisoldipine, bepridil and nifedipine in anesthetized dogs with experimental pulmonary hypertension |
| 2476607 | 1989 | Animal study | J Cardiovasc Pharmacol | Tested four calcium antagonists, including nisoldipine, on hypoxia-induced right ventricular pressure rise in rats |
| 9298524 | 1997 | Ex vivo animal | Br J Pharmacol | Intracellular calcium release plays a prominent role in hypoxic vasoconstriction of canine pulmonary artery |
| 1566816 | 1992 | Preclinical | Am J Physiol | Potassium channel inhibition contributes directly to hypoxic pulmonary vasoconstriction |
| 15613369 | 2005 | Cell study | J Physiol | Hypoxia mobilizes sarcoplasmic reticulum stores and activates capacitative calcium entry in canine pulmonary artery smooth muscle cells |
| 10630745 | 2000 | Animal study | J Cardiovasc Pharmacol | Compared nifedipine and nisoldipine on coronary vasoconstriction in perfused rat hearts |
| 15528240 | 2005 | Cell study | J Physiol | L-type channels, sensitive to nisoldipine, carry part of the calcium current in rabbit carotid body cells |
| 10980033 | 2000 | Cell electrophysiology | J Neurophysiol | Hypoxia augments L-type calcium current in carotid body glomus cells through a PKC-sensitive pathway |
The remaining retrieved papers are mostly carotid body or cardiac electrophysiology studies and are only tangentially related.
For the lower-ranked prediction of malignant renovascular hypertension, the only reference is 3481633 (1987, a review in J Hypertens Suppl). It reports that calcium antagonism, including nisoldipine, prevented salt-induced hypertension and renovascular damage in Dahl salt-sensitive rats. It is not specific to the human condition.
US Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA020356 | Sular (Covis Pharma US, Inc) | Film-coated extended-release tablet (oral) | Not available; status: cancelled |
Safety Considerations
- Contraindication signals from the knowledge graph (not label text): liver failure, hypotensive disorder, coronary artery disease, coronary atherosclerosis, arteriosclerosis disorder, atherosclerosis. These should be verified against the package insert.
- Drug Interactions: 100 interactions were identified. Among those reviewed, most are Moderate.
- Major: dolasetron.
- Moderate examples: hydrocortisone, dexamethasone, betamethasone, budesonide, triamcinolone, bupropion, aprepitant, morphine, acetylsalicylic acid, cimetidine, magnesium sulfate, canagliflozin, dapagliflozin, empagliflozin.
- Minor: omeprazole.
- 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 mechanistic link is plausible, but the evidence is limited to old preclinical studies (L4) with no registered clinical trials. Calcium channel blockers are generally not recommended in hypoxia-related pulmonary hypertension, and the only US authorization is cancelled. The other four predictions rest on computational scores alone or on non-specific references.
To proceed, the following is needed:
- FDA package insert warnings and contraindications, which are currently missing and block safety screening
- Mechanism of action data (for example, from DrugBank)
- Clinical evidence in pulmonary hypertension, ideally human hemodynamic or controlled studies, addressing the risk of worsened V/Q mismatch and hypotension
- Review of the drug’s cancelled market status and the availability of the extended-release formulation
- A comparison against current standard therapy for pulmonary hypertension associated with lung disease
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.