Mechanism of action

VIP binds to the two G protein-coupled receptors VPAC1 and VPAC2 and stimulates adenylyl cyclase there. How tightly this activity depends on the peptide structure is shown by an alanine scan of all 28 positions on membranes from cells expressing human recombinant receptors (Nicole et al., 2000): substituting individual amino acids at 14 of the 28 positions increased the binding constant or the EC50 value at the VPAC1 receptor more than tenfold, while modeling describes a central alpha helix from Val5 to Asn24 with disordered termini. The comparison between the two receptors was largely congruent, with the exception of positions 11, 22 and 28; combining those three substitutions produced [Ala11,22,28]VIP, the first highly selective VPAC1 agonist. Pharmacokinetically, VIP is characterized by an exceptionally short systemic residence time: in an early human investigation, the peptide was infused intravenously into four healthy volunteers at graded doses over 30-minute periods; after the infusions ended, plasma levels fell by first-order kinetics with an average disappearance half-time of about one minute, with an apparent metabolic clearance of roughly 9 ml/kg/min and an apparent volume of distribution of about 14 ml/kg (Domschke et al., 1978). The authors concluded that their data do not support a role for VIP as a circulating hormone under physiological conditions. This small intravenous study is not a pharmacokinetic reference for intracavernous Invicorp. The combination medicine and the intravenous aviptadil COVID-19 trial (Brown et al., 2023) involve different formulations, routes and clinical questions.

State of evidence

The evidence tier here refers exclusively to the regulatory status of a fixed combination. Norway's current product register lists Invicorp, a fixed combination of aviptadil and phentolamine. A historical review reports UK authorization in October 2000 (Keijzers, 2001); the Scottish Medicines Consortium assessed this product in 2017 for restricted use within NHS Scotland, with the licensed indication of symptomatic treatment of erectile dysfunction in adult males of neurogenic, vasculogenic, psychogenic or mixed aetiology. That authorization covers neither VIP as a single substance nor systemic use: it applies to a fixed two-drug combination injected locally into the corpus cavernosum. That product-specific registration does not establish the authorization status of isolated VIP or other investigated routes and indications. The largest systemic trial to date was negative: in the randomized, placebo-controlled phase 3 trial TESICO (ACTIV-3b, NCT04843761) of intravenous aviptadil in COVID-19-associated hypoxaemic respiratory failure, the primary six-category endpoint at day 90 did not differ significantly from placebo in the modified intention-to-treat population of 461 participants (odds ratio 1.11; 95% confidence interval 0.80 to 1.55; p = 0.54). Mortality up to day 90 was 38 percent versus 36 percent (hazard ratio 1.04; 0.77 to 1.41; p = 0.78), and the independent monitoring board recommended stopping the aviptadil part of the trial for futility in May 2022 (Brown et al., 2023). Controlled data on further systemic applications, and robust pharmacokinetics beyond the small 1978 investigation, remain lacking. All of the results named here come from studies with pharmaceutically manufactured products under controlled conditions; they cannot be transferred to the efficacy or safety of research-grade material.

Questions about the research

Is VIP approved as a medicine?

The current Norwegian product register lists Invicorp, a fixed combination of aviptadil, the nonproprietary name for synthetic VIP, and phentolamine. A historical review also reports UK authorization in October 2000. The registration concerns the named intracavernous combination medicine, not isolated VIP research material or systemic indications. In COVID-19-associated respiratory failure, the intravenous TESICO trial found no significant benefit over placebo; that clinical result is separate from Invicorp's registration.

What does the very short half-life of VIP mean?

Domschke et al. (1978) studied intravenous VIP in four healthy volunteers and reported an average plasma disappearance half-time of about one minute after infusion ended. This is a small, route-specific study reference, not a universal constant or an intracavernous Invicorp value. Different formulations, routes and sampling methods require their own evidence; these measurements cannot establish the kinetics of a particular research product.

Sources

1. Domschke et al., Gut 1978DOI: 10.1136/gut.19.11.1049PMID: 730072
2. Nicole et al., J Biol Chem 2000DOI: 10.1074/jbc.M002325200PMID: 10801840
3. Keijzers, Curr Opin Investig Drugs 2001, review of aviptadil; historical UK combination approval in October 2000PMID: 11566015
4. Scottish Medicines Consortium 2017: aviptadil/phentolamine mesilate (Invicorp), SMC 1284/17
5. Brown et al., Lancet Respir Med 2023 (TESICO, ACTIV-3b, NCT04843761)DOI: 10.1016/S2213-2600(23)00147-9PMID: 37348524
6. Norwegian DMP: Invicorp aviptadil/phentolamine combination, marketing authorization 13-9854, current product register

Mechanism of action

VIP binds to the two G protein-coupled receptors VPAC1 and VPAC2 and stimulates adenylyl cyclase there. How tightly this activity depends on the peptide structure is shown by an alanine scan of all 28 positions on membranes from cells expressing human recombinant receptors (Nicole et al., 2000): substituting individual amino acids at 14 of the 28 positions increased the binding constant or the EC50 value at the VPAC1 receptor more than tenfold, while modeling describes a central alpha helix from Val5 to Asn24 with disordered termini. The comparison between the two receptors was largely congruent, with the exception of positions 11, 22 and 28; combining those three substitutions produced [Ala11,22,28]VIP, the first highly selective VPAC1 agonist. Pharmacokinetically, VIP is characterized by an exceptionally short systemic residence time: in an early human investigation, the peptide was infused intravenously into four healthy volunteers at graded doses over 30-minute periods; after the infusions ended, plasma levels fell by first-order kinetics with an average disappearance half-time of about one minute, with an apparent metabolic clearance of roughly 9 ml/kg/min and an apparent volume of distribution of about 14 ml/kg (Domschke et al., 1978). The authors concluded that their data do not support a role for VIP as a circulating hormone under physiological conditions. This small intravenous study is not a pharmacokinetic reference for intracavernous Invicorp. The combination medicine and the intravenous aviptadil COVID-19 trial (Brown et al., 2023) involve different formulations, routes and clinical questions.

State of evidence

The evidence tier here refers exclusively to the regulatory status of a fixed combination. Norway's current product register lists Invicorp, a fixed combination of aviptadil and phentolamine. A historical review reports UK authorization in October 2000 (Keijzers, 2001); the Scottish Medicines Consortium assessed this product in 2017 for restricted use within NHS Scotland, with the licensed indication of symptomatic treatment of erectile dysfunction in adult males of neurogenic, vasculogenic, psychogenic or mixed aetiology. That authorization covers neither VIP as a single substance nor systemic use: it applies to a fixed two-drug combination injected locally into the corpus cavernosum. That product-specific registration does not establish the authorization status of isolated VIP or other investigated routes and indications. The largest systemic trial to date was negative: in the randomized, placebo-controlled phase 3 trial TESICO (ACTIV-3b, NCT04843761) of intravenous aviptadil in COVID-19-associated hypoxaemic respiratory failure, the primary six-category endpoint at day 90 did not differ significantly from placebo in the modified intention-to-treat population of 461 participants (odds ratio 1.11; 95% confidence interval 0.80 to 1.55; p = 0.54). Mortality up to day 90 was 38 percent versus 36 percent (hazard ratio 1.04; 0.77 to 1.41; p = 0.78), and the independent monitoring board recommended stopping the aviptadil part of the trial for futility in May 2022 (Brown et al., 2023). Controlled data on further systemic applications, and robust pharmacokinetics beyond the small 1978 investigation, remain lacking. All of the results named here come from studies with pharmaceutically manufactured products under controlled conditions; they cannot be transferred to the efficacy or safety of research-grade material.

Questions about the research

Is VIP approved as a medicine?

The current Norwegian product register lists Invicorp, a fixed combination of aviptadil, the nonproprietary name for synthetic VIP, and phentolamine. A historical review also reports UK authorization in October 2000. The registration concerns the named intracavernous combination medicine, not isolated VIP research material or systemic indications. In COVID-19-associated respiratory failure, the intravenous TESICO trial found no significant benefit over placebo; that clinical result is separate from Invicorp's registration.

What does the very short half-life of VIP mean?

Domschke et al. (1978) studied intravenous VIP in four healthy volunteers and reported an average plasma disappearance half-time of about one minute after infusion ended. This is a small, route-specific study reference, not a universal constant or an intracavernous Invicorp value. Different formulations, routes and sampling methods require their own evidence; these measurements cannot establish the kinetics of a particular research product.

Sources

1. Domschke et al., Gut 1978DOI: 10.1136/gut.19.11.1049PMID: 730072
2. Nicole et al., J Biol Chem 2000DOI: 10.1074/jbc.M002325200PMID: 10801840
3. Keijzers, Curr Opin Investig Drugs 2001, review of aviptadil; historical UK combination approval in October 2000PMID: 11566015
4. Scottish Medicines Consortium 2017: aviptadil/phentolamine mesilate (Invicorp), SMC 1284/17
5. Brown et al., Lancet Respir Med 2023 (TESICO, ACTIV-3b, NCT04843761)DOI: 10.1016/S2213-2600(23)00147-9PMID: 37348524
6. Norwegian DMP: Invicorp aviptadil/phentolamine combination, marketing authorization 13-9854, current product register