Mechanism of Action
VPAC1 Receptor Activation
Aviptadil binds preferentially to VPAC1 receptors, which are highly expressed in alveolar type II (AT2) cells of the lungs. Receptor activation increases intracellular cAMP through adenylate cyclase, activating protein kinase A. This suppresses NFkB-driven inflammatory cytokine production and prevents AT2 cell apoptosis, preserving surfactant production and gas exchange.
Cytokine Storm Suppression
VIP and aviptadil inhibit production of key inflammatory cytokines including TNF-alpha, IL-6, and IL-1beta in macrophages and T cells. The anti-inflammatory effect is particularly relevant in cytokine storm syndromes. Aviptadil also promotes regulatory T cell activity, shifting the immune response toward resolution rather than amplification.
Research Summary
COVID-19 Respiratory Failure
Phase 3RLF-100 (aviptadil) received FDA Emergency IND for COVID-19-associated respiratory failure in 2020. Early clinical reports showed rapid improvement in oxygenation and reduction in ventilator dependence in severe cases. Phase 2b/3 trials showed mixed results in larger populations, with subgroup analyses suggesting benefit in certain patient profiles.
Sarcoidosis and Pulmonary Fibrosis
PreclinicalVIP deficiency has been documented in pulmonary sarcoidosis and idiopathic pulmonary fibrosis. Preclinical models show aviptadil reduces fibrotic markers and inflammatory infiltration. Clinical development for these chronic pulmonary conditions is ongoing alongside acute respiratory indications.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Acute respiratory failure (COVID-19) | 100-300 pmol/kg/hr | 12-hr infusions x 3 days | IV infusion |
| Inhaled formulation research | 100 mcg | Twice daily | Inhalation |
No approved indication in US as of 2025. Use under clinical trial or emergency IND only.
Interactions
Safety Profile
IV aviptadil may cause transient hypotension, flushing, and mild gastrointestinal effects including nausea and diarrhea. The short plasma half-life (approximately 2 minutes) limits systemic exposure duration. In COVID-19 trials, the safety profile was acceptable with careful blood pressure monitoring. Inhaled formulations target pulmonary delivery with reduced systemic effects.
References
- [1]Friebe A et al. (2020). Vasoactive intestinal peptide (VIP) prevents lung failure in a murine ARDS model. Peptides, 134, 170388.
- [2]Gonzalez-Rey E et al. (2006). Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood, 107(9), 3632-3638.