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Longevity & Immune system
VIP (Vasoaktives Intestinales Peptid)
VIP · Vasoaktives Intestinales Peptid · Vasoaktives intestinales Polypeptid · Aviptadil (synthetische Form) · RLF-100 / ZYESAMI (Arzneimittelname von Aviptadil)
VIP (Vasoactive Intestinal Peptide) is an endogenous neuropeptide of 28 amino acids that occurs in the nervous system, the lungs, the gastrointestinal tract and other tissues. It acts via the receptors VPAC1, VPAC2 and PAC1 and is involved in regulating vascular tone, the immune response and inflammatory processes. The synthetic form carries the drug name aviptadil (development designations RLF-100/ZYESAMI) and has been studied in clinical trials, among others in ARDS/COVID-19 and pulmonary hypertension — with mixed, in part negative data. VIP itself is not broadly approved as a substance; the human evidence for a proven therapeutic benefit is limited and the subject of ongoing research. This page places the state of knowledge in sober context and is expressly not a set of usage instructions.
Regulatory status
In clinical trials only · not approved
VIP/aviptadil is an investigational substance: studied in clinical trials, with orphan-drug designations, but without broad regular market approval for an established standard indication.
Drug class
Endogenous regulatory neuropeptide (28 amino acids) of the VIP/PACAP family; agonist at the G-protein-coupled receptors VPAC1/VPAC2/PAC1. As a drug: aviptadil (synthetic VIP), investigational substance.
Half-life (informative)
Very short: native VIP is rapidly broken down in the blood by peptidases (plasma half-life in the range of minutes), which represents a major hurdle for therapeutic use.
Studied in the literature
In the literature aviptadil/VIP has been studied predominantly parenterally — intravenously (e.g. in COVID-19 trials) as well as by inhalation/aerosol (e.g. in studies on pulmonary hypertension and in COVID-19). These statements describe solely how the substance was administered in studies and are not a usage recommendation.
Mechanism of action
VIP binds to the G-protein-coupled receptors VPAC1 and VPAC2 (and, secondarily, PAC1, which is preferentially activated by the related peptide PACAP). Via the Gs subunit, adenylate cyclase is stimulated and intracellular cAMP levels rise. From this arise effects described in the literature such as vasodilation (in particular a vasodilatory effect in the pulmonary circulation), relaxation of smooth muscle and an immunomodulatory, anti-inflammatory component. In lung tissue a VPAC1-mediated, anti-inflammatory mechanism is discussed (among other things a dampening effect on pro-inflammatory mediators such as IL-6 and TNF-alpha). Important: these mechanisms derive from laboratory and early clinical studies and on their own do not prove an established treatment benefit in humans.
Because of the rapid enzymatic inactivation, stability and route of administration are a central pharmacological problem; part of the research deals with more stable analogues or local (inhaled) administration. Quantitative dose, concentration or preparation data are deliberately not given here.
Research history
VIP was first isolated from intestinal tissue in the early 1970s by Sami I. Said and Viktor Mutt — hence "intestinal" — and was soon recognized as a widely distributed neuropeptide with functions reaching far beyond the gut. Over the following decades the receptor pharmacology (VPAC1, VPAC2, PAC1) was characterized together with the related peptide PACAP and summarized in 2012 in an IUPHAR review article in the British Journal of Pharmacology. The synthetic form aviptadil was developed as an investigational medicinal product; inhaled aviptadil was tested, among other things, in a small study in pulmonary hypertension in 2008. The substance received broader attention during the COVID-19 pandemic, when intravenous and inhaled aviptadil (RLF-100/ZYESAMI) was evaluated in clinical trials in critical COVID-19 and ARDS.
Regulatory status by region
Aviptadil (RLF-100/ZYESAMI) was studied under an FDA IND in clinical trials in critical COVID-19/ARDS (e.g. the Phase 2/3 study NCT04311697, completed) and received an orphan-drug designation for ARDS and pulmonary hypertension. No broad regular approval as standard therapy.
Inhaled aviptadil was studied in a European (Swiss) trial (multicenter COVID-19 study protocol, NCT04536350; sites including Cantonal Hospital Baselland and Cantonal Hospital St. Gallen). According to ClinicalTrials.gov this trial was terminated (stopped early). In the EU aviptadil holds an orphan-drug designation (EU/3/06/395, acute lung injury); as a medicinal product, however, VIP/aviptadil is not broadly approved.
Status inconsistent and country-dependent. Overall a substance at the research and investigational stage without an established, broadly approved standard indication.
Research areas
- Acute respiratory distress syndrome (ARDS) and severe COVID-19 — intravenous and inhaled aviptadil in clinical trials
- Pulmonary (arterial) hypertension — inhaled VIP/aviptadil as a selective pulmonary-vascular vasodilator (early, in part negative studies)
- Immunomodulation and anti-inflammation — VPAC-mediated dampening of pro-inflammatory signaling pathways (preclinical/translational)
- Neurobiology — VIP/PACAP receptors in relation to circadian rhythm, the stress response and neurological disorders (basic research)
- Pharmacological optimization — more stable VIP analogues and local routes of administration against the rapid enzymatic breakdown
Documented effects (from the literature)
- Vasodilation with a selective, in studies small and transient vasodilatory effect in the pulmonary circulation (pulmonary hypertension)
- Relaxation of smooth muscle (blood vessels, airways, gastrointestinal tract)
- Immunomodulatory, anti-inflammatory effects via VPAC receptors in preclinical and translational models
- Possible systemic circulatory effects (e.g. drop in blood pressure/flushing) as an expression of the vasodilatory action, described in clinical studies
Safety concerns & caution
- Limited and mixed human evidence: in pulmonary hypertension controlled studies showed no convincing sustained benefit; in COVID-19 the data are inconsistent and the value is disputed.
- Very short half-life and rapid breakdown complicate a controlled effect and make administration and dosing a clinically delicate matter.
- Circulatory activity (vasodilation) can have undesirable hemodynamic effects — relevant above all in critically ill or circulatory-unstable individuals.
- Long-term safety in humans has not been sufficiently studied; many statements are based on animal/cell models or small studies.
Risks of gray-market purchase
- VIP/aviptadil sold as a 'research peptide' is not subject to pharmaceutical quality control: identity, purity, sterility and actual content are unknown and may deviate strongly from the declaration.
- Contaminants (e.g. endotoxins, solvent, synthesis or degradation products) are a real risk with non-pharmaceutical goods, especially for a substance that was injected/inhaled in studies.
- Use outside medical supervision is not supported by robust efficacy and safety data; a circulation-active substance without medical monitoring carries incalculable risks.
- Success reports circulating online are anecdotal claims without controlled evidence and are not equivalent to the in part negative or inconsistent study results.
Frequently asked questions
Is VIP or aviptadil an approved medicine?
No, not in the sense of a broad standard approval. Aviptadil (the synthetic form of VIP, also RLF-100/ZYESAMI) has been studied in clinical trials — for example in critical COVID-19/ARDS and in pulmonary hypertension — and carries orphan-drug designations in part in the USA and the EU. It nonetheless remains an investigational substance without an established, broadly approved standard indication.
Is efficacy in lung diseases proven?
The data are mixed and in part disappointing. In pulmonary hypertension inhaled VIP showed only a small, transient vascular effect in a small study, and controlled studies found no convincing sustained benefit. In COVID-19/ARDS there are studies with differing results; an assured clinical benefit is not clearly established. Research is ongoing.
What does 'immunomodulatory' specifically mean for VIP?
VIP can, via its receptors (above all VPAC1/VPAC2), dampen pro-inflammatory signaling pathways and thus act anti-inflammatorily in models. This is a mechanism described in basic and translational research — on its own it does not prove an established therapeutic benefit and is not to be understood as a promise of cure.
Sources
Primary and reference sources for your own reading.
- British Journal of Pharmacology (Harmar et al., 2012) — PMID 22289055Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR Review 1
- European Respiratory Journal (Leuchte et al., 2008) — PMID 18978135Inhalation of vasoactive intestinal peptide in pulmonary hypertension
- Trials (Boesing et al., 2022) — PMID 36127739 / PMC9486780Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial
- ClinicalTrials.gov — NCT04311697ZYESAMI (Aviptadil) for the Treatment of Critical COVID-19 With Respiratory Failure (Phase 2/3, abgeschlossen)
- European Medicines Agency (EMA), Orphan-Designation vom 28.08.2006EU/3/06/395 — Orphan designation for aviptadil for the treatment of acute lung injury
Related substances
Unfamiliar terms? Look them up in the glossary or read the fundamentals.
This profile is for information and education only. It is not medical advice and deliberately contains no dosing or usage details. Decisions about use belong in a doctor’s hands.