VIP

What it is. VIP is a 28-residue neuropeptide of the secretin/glucagon family, released by nerves throughout the gut, lung and vasculature. It relaxes smooth muscle, dilates pulmonary and systemic vessels and has substantial anti-inflammatory and immunoregulatory activity. The lung carries among the highest densities of VIP receptors in the body, which is why almost all of its drug development has been respiratory [5][6]. As a pharmaceutical it is called aviptadil.

Sarcoidosis. In an open phase 2 study, 20 patients inhaled VIP. It was safe and well tolerated, and produced measurable immunoregulatory effects in cells isolated from bronchoalveolar lavage - the first demonstration of that effect in humans [1]. Open-label, 20 patients, no control group.

Pulmonary hypertension. Twenty patients - nine with pulmonary arterial hypertension, eight with pulmonary hypertension from lung disease - inhaled aviptadil. Six had a pulmonary vascular resistance reduction greater than 20%, systemic blood pressure was unaffected, and oxygenation tended to improve in those with significant lung disease [2]. Modest, and consistent with the biology. VIP-deficient mice develop pulmonary hypertension [7], which is the animal evidence that made the idea attractive.

COVID-19, which is where it became famous. Aviptadil was promoted heavily during the pandemic. A randomised trial in 196 patients with critical COVID-19 respiratory failure missed its primary endpoint - the odds ratio for being alive and free from respiratory failure was 1.6 (95% CI 0.86-3.11) - but reported improved survival at 60 days, OR 2.0 (95% CI 1.1-3.9, p = 0.035) [3].

Then TESICO, part of the ACTIV-3b platform, randomised 473 participants across 28 US sites; 94% were in intensive care at baseline and 40% were already on invasive mechanical ventilation. The odds ratio for the primary ordinal outcome at day 90 was 1.11 (95% CI 0.80-1.55). Mortality at 60 days was 38% on aviptadil against 36% on placebo, hazard ratio 1.04 [4]. That is a well-powered, well-conducted null result, and it is the one that should be believed.

Where it is actually approved. Not for lungs. Aviptadil combined with phentolamine is marketed in some countries as an intracavernosal injection for erectile dysfunction.

VIP acts on VPAC1 and VPAC2, G-protein-coupled receptors that raise intracellular cyclic AMP. In airway and vascular smooth muscle that produces relaxation and vasodilation; on immune cells it shifts cytokine production away from inflammatory patterns and modulates regulatory T cell populations [5].

The rationale for the lung indications is straightforward: high receptor density, local delivery by inhalation, and a combination of vasodilation and immunomodulation that suits both pulmonary hypertension and granulomatous inflammation [6]. Genetic support exists - male mice lacking the VIP gene develop moderate pulmonary arterial hypertension [7] - and receptor expression changes in experimental pulmonary hypertension [8].

The COVID-19 rationale was different and weaker: VIP is concentrated in alveolar type II cells, the cells SARS-CoV-2 infects, and was proposed to protect them. TESICO tested that and it did not hold [4].

The pharmacological obstacle throughout is the half-life. VIP is degraded within minutes, so any systemic effect requires continuous infusion, and any lung effect is easier to obtain by putting the peptide directly into the lung [6].

Three routes appear in the literature: nebulised inhalation for the lung indications [1][2], intravenous infusion in the COVID-19 trials [3][4], and intracavernosal injection in the licensed erectile dysfunction combination with phentolamine.

Inhalation is the pharmacologically sensible route for lung disease: it delivers peptide to the tissue with the highest receptor density while minimising the flushing, diarrhoea and hypotension that systemic VIP causes [6].

Inhaled VIP was safe and well tolerated in both lung studies [1][2]. That is the strongest tolerability signal, and it is for local delivery.

Systemic VIP is a potent vasodilator and gut secretagogue, and infusion causes flushing, diarrhoea and hypotension - the same effects seen pathologically in VIPoma, a tumour that secretes it. In TESICO, aviptadil was given by infusion in critically ill patients and the trial reported no survival benefit; 60-day mortality was 38% against 36% on placebo [4]. Nothing in that trial suggests harm, but nothing suggests benefit either.

Two things to keep straight. First, the favourable tolerability data are for inhaled delivery in stable outpatients; the systemic route in critical illness is a different exposure. Second, the compound sold online as "VIP" for self-administration has no established route, dose or indication outside these trials, and the peptide's rapid degradation means a subcutaneous injection has no published pharmacokinetic basis at all.

No formal interaction studies have been published. Mechanistically, VIP is a vasodilator acting through cyclic AMP, so combination with other vasodilators - including PDE5 inhibitors, with which it shares the cyclic nucleotide pathway in erectile tissue - would be expected to be additive on blood pressure. The licensed erectile dysfunction product deliberately pairs it with phentolamine, an alpha-blocker.

No interactions with other compounds on this site have been documented.