Labradimil
Also known as: bradykinin analog BBB opener, Cereport, RMP-7
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Summary
Labradimil is an investigational nine‑amino‑acid peptide that acts as a selective agonist of the bradykinin B2 receptor. It is being studied as a blood‑brain barrier (BBB) modulator that transiently opens tight junctions to improve delivery of co‑administered drugs, particularly chemotherapeutics, into malignant brain tumours.
Mechanism of Action
Labradimil binds selectively to the bradykinin B2 receptor, triggering classic bradykinin‑like signalling including rises in intracellular calcium and phosphatidylinositol turnover. This signalling disengages endothelial tight‑junction proteins, creating a short‑lived increase in BBB permeability that reverses within minutes after infusion stops. The peptide’s metabolic stability prolongs its plasma half‑life, allowing it to act systemically while still targeting tumour microvasculature.
What the Research Shows
Pre‑clinical studies in rodents demonstrated that intravenous labradimil rapidly increases BBB permeability, enhancing uptake of radiolabelled tracers, gadolinium contrast agents, and small chemotherapy drugs such as carboplatin into glioma tissue while sparing normal brain. Dynamic contrast‑enhanced MRI showed increased tumour drug half‑life and area‑under‑the‑curve, and survival was improved in animal tumour models. Early clinical trials in glioma patients reported transient tumour‑specific BBB opening and increased carboplatin delivery without extra systemic toxicity. In vitro tight‑junction assays showed labradimil produced modest TEER reduction compared with other modulators, indicating a milder effect on junction integrity. A dermal extravasation study revealed that cyclo‑oxygenase inhibition attenuates labradimil‑induced vascular leakage, suggesting COX‑dependent pathways may contribute to its action.
Reported Benefits
Evidence suggests labradimil can selectively increase delivery of small chemotherapeutic agents into malignant brain tumours, potentially allowing lower systemic doses and improving tumour drug exposure. Its transient, reversible BBB opening limits prolonged exposure of normal brain tissue, and animal data indicate a survival advantage when combined with water‑soluble chemotherapy. The peptide’s metabolic stability provides a longer circulating window than native bradykinin, facilitating coordinated infusion with therapeutic agents.
Limitations of the Evidence
Data are limited to early‑phase human trials and pre‑clinical models; long‑term safety and efficacy remain unproven. The BBB‑opening effect is brief (minutes) and requires precise timing with drug infusion. In vitro testing showed weaker tight‑junction modulation than some alternatives, which may limit potency. The role of cyclo‑oxygenase pathways is suggested but not fully elucidated, and no large randomized clinical outcomes have been reported.
Safety Considerations
Transient reductions in systemic blood pressure have been observed and correlate with the peptide’s metabolic stability. Dermal extravasation studies indicate that COX inhibitors can diminish labradimil‑induced vascular leakage, implying potential interactions with anti‑inflammatory drugs. No serious adverse events were reported in the available abstracts, but the reversible opening of the BBB raises theoretical concerns about neurotoxicity or infection, underscoring the need for careful monitoring during infusion.
How It Is Administered
Labradimil is administered intravenously, typically as a short infusion co‑delivered with the chemotherapeutic agent. The peptide’s effect on BBB permeability appears within minutes of infusion start and begins to reverse 2–5 minutes after cessation, with residual drug half‑life extension lasting up to 90 minutes. Formulations used in studies are peptide solutions suitable for sterile IV infusion.
Routes of Administration
Goals & Uses
- Improved survival in glioblastomaOncologyLow
- Enhanced CNS drug deliveryPharmacokinetic AugmentationModerate
- Brain tumor chemotherapy augmentationOncologyModerate
Contraindications
- Hypersensitivity to bradykinin analogsAllergy/ImmunologyHigh
- Severe hypotension or hemodynamic instabilityCardiovascularHigh
- Active intracranial hemorrhageNeurologicalHigh
Adverse Effects
- HeadacheNeurologicCommonPain in the head or upper neck
- HypotensionCardiovascularCommonLow blood pressure
- Nausea/vomitingGastrointestinalUncommon
- FlushingVascularCommonWarmth and redness of the skin
- SeizuresNeurologicalUncommon
Drug Interactions
- CarboplatinModerate
- ACE inhibitorsModerate
- AntihypertensivesModerateMay potentiate hypotensive effects in some contexts
Population Constraints
- PregnancyReproductive SafetyRelative
- Pediatric patientsAgeRelative
- Patients with cardiovascular diseaseComorbidityRelative
Regulatory Status
- European UnionInvestigationalStudied in European clinical trials for glioblastoma; no marketing authorization granted.
- United StatesInvestigationalEvaluated in FDA-regulated clinical trials; never approved. IND held during development phase.
Never received FDA or EMA approval. Evaluated in Phase II/III clinical trials during the 1990s–2000s for brain tumor chemotherapy augmentation. Development largely discontinued after pivotal trials failed to demonstrate sufficient clinical benefit.
Evidence & Sources
- Journal ArticleModerateSaaber D, et al.2014-01-01T00:00:00.000000Z
- Journal ArticleLowGholamreza-Fahimi E, et al.2020-01-01T00:00:00.000000Z
- Journal ArticleLowBayés M, Rabasseda X, Prous JR2007-01-01T00:00:00.000000Z
- Journal ArticleLowSaaber D, Reichl S2019-01-01T00:00:00.000000Z
- Journal ArticleLowSarin H, et al.2009-01-01T00:00:00.000000Z
- Journal ArticleModerateEmerich DF, et al.2001-01-01T00:00:00.000000Z
Frequently Asked Questions
What is the primary purpose of labradimil?
Labradimil is being investigated as a blood‑brain barrier opener that transiently increases tumour‑specific vascular permeability, allowing co‑administered drugs—especially chemotherapy—to reach malignant brain tissue more effectively.
How does labradimil open the blood‑brain barrier?
The peptide selectively activates bradykinin B2 receptors on endothelial cells, initiating calcium‑mediated signalling that loosens tight‑junction proteins. This creates a brief, reversible opening of the barrier that closes within minutes after the infusion stops.
What evidence supports its use in brain tumour treatment?
Animal studies showed increased tumour uptake of contrast agents and chemotherapeutics, improved survival, and selective BBB opening. Early human trials in glioma patients reported enhanced carboplatin delivery without added systemic toxicity.
Are there safety concerns with labradimil?
Transient blood‑pressure drops have been recorded, and COX‑inhibiting drugs can reduce its vascular effects. While no serious adverse events were noted in the abstracts, the temporary BBB disruption could theoretically increase neuro‑toxicity risk, requiring close monitoring.
How is labradimil administered?
It is given by intravenous infusion, usually together with the chemotherapy drug. The permeability effect begins quickly, peaks during infusion, and starts to resolve within a few minutes after the infusion ends.
What is Labradimil used for?
Labradimil is educationally associated with: Improved survival in glioblastoma, Enhanced CNS drug delivery, Brain tumor chemotherapy augmentation. Educational only — not medical advice.
How is Labradimil administered?
Recorded routes of administration: Intravenous.
What are the potential side effects of Labradimil?
Reported adverse effects include: Headache, Hypotension, Nausea/vomiting, Flushing, Seizures. This list is not exhaustive — consult a qualified clinician.
Who should avoid Labradimil?
Recorded contraindications: Hypersensitivity to bradykinin analogs, Severe hypotension or hemodynamic instability, Active intracranial hemorrhage. Consult a qualified clinician before use.