VIP (Vasoactive Intestinal Peptide)

Common Names: VIP, Aviptadil (synthetic), RLF-100, Zyesami Sequence: His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ Molecular Weight: 3,323.77 Da Length: 28 amino acids (C-terminal amidation) FDA Status: NOT APPROVED (Fast Track Designation for COVID-19; Orphan Drug for Sarcoidosis, ARDS, PAH)

Executive Summary

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid neuropeptide belonging to the glucagon/secretin superfamily, functioning as a critical endogenous regulator of vascular tone, bronchodilation, immune modulation, and gastrointestinal motility. Originally discovered in 1970 by Said and Mutt as a vasodilatory peptide isolated from porcine intestine, VIP has emerged as a pleiotropic signaling molecule with therapeutic potential in pulmonary arterial hypertension (PAH), acute respiratory distress syndrome (ARDS), erectile dysfunction (ED), and chronic inflammatory conditions including sarcoidosis and COPD.

Mechanistically, VIP binds to two class B G protein-coupled receptors—VPAC1 and VPAC2—both of which couple strongly to Gαs proteins, triggering adenylyl cyclase activation and intracellular cAMP elevation. This cAMP/PKA signaling cascade mediates VIP's diverse physiological effects: smooth muscle relaxation (vasodilation, bronchodilation), anti-inflammatory cytokine modulation (IL-10 upregulation, TNF-α suppression), and neuroprotection. Additionally, VIP exhibits immunomodulatory properties through regulation of T-cell differentiation, dendritic cell function, and macrophage polarization toward anti-inflammatory M2 phenotypes.

Clinical applications have demonstrated VIP efficacy in multiple contexts. Invicorp (VIP + phentolamine combination) received UK approval in 2000 for erectile dysfunction with success rates comparable to PDE5 inhibitors but minimal systemic side effects. Inhaled aviptadil (synthetic VIP, branded RLF-100 or Zyesami) showed hemodynamic benefit in PAH and received FDA Fast Track Designation in 2020 for critical COVID-19 respiratory failure, with Phase II/III trials demonstrating improved oxygenation and survival in ARDS patients. However, VIP remains unapproved by the FDA for any indication as of December 2025, with ongoing regulatory pathways for sarcoidosis (Orphan Drug Designation, 2021) and COVID-19-associated ARDS.

The primary challenge limiting VIP's clinical adoption is its ultra-short plasma half-life (~1 minute), necessitating continuous intravenous infusion or specialized delivery systems (inhalation, intranasal). Modern formulation strategies, including long-acting analogs, PEGylation, and liposomal encapsulation, aim to extend bioavailability while preserving receptor selectivity. Safety profiles across clinical trials demonstrate excellent tolerability with inhalation routes; adverse events are minimal and primarily limited to transient vasodilation (flushing, hypotension) with IV administration.

Goal Relevance:

Support for respiratory health and recovery from conditions like COPD and ARDS.
Enhance immune system function and reduce inflammation for autoimmune conditions.
Aid in managing erectile dysfunction with minimal side effects compared to traditional treatments.
Improve gut health and digestion by promoting gastrointestinal motility.
Assist in managing chronic inflammatory conditions such as sarcoidosis.
Provide neuroprotection and support brain health by modulating inflammatory responses.
Support pulmonary health and improve oxygenation in conditions like pulmonary arterial hypertension (PAH).

Chemical Structure & Composition

Primary Structure

Vasoactive Intestinal Peptide (VIP) is a 28-amino acid peptide with the following sequence:

His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂

Single-letter code: HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH₂

The C-terminal amidation (-NH₂) is critical for biological activity, protecting the peptide from carboxypeptidase degradation and enhancing receptor binding affinity. VIP shares 68% sequence homology with PACAP (pituitary adenylate cyclase-activating polypeptide) and structural features with glucagon and secretin family members.

Molecular Characteristics

Molecular Formula: C₁₄₇H₂₃₇N₄₃O₄₃S
Molecular Weight: 3,323.77 Da (3.32 kDa)
Isoelectric Point (pI): ~9.5 (net positive charge at physiological pH due to 7 basic residues: 5 Lys, 2 Arg)
Hydrophobicity: Amphipathic with hydrophobic face (Phe6, Tyr10, Leu13, Met17)
Cysteine content: None (no disulfide bonds)

Secondary Structure

NMR structural studies in membrane-mimetic environments (methanol, micelles) reveal VIP adopts a bipartite structure:

N-terminal region (residues 1-9): Disordered, flexible, facilitates initial receptor contact
C-terminal region (residues 10-28): Long α-helix providing receptor specificity and activation

The hydrophobic patch formed by Phe6, Tyr10, Leu13, and Met17 on the concave face of the α-helix is essential for insertion into VPAC receptor transmembrane domains, stabilizing the active receptor conformation.

VIP Fragment - VIP(10-28)

The VIP(10-28) fragment (19 amino acids, residues 10-28) functions as a VPAC receptor antagonist rather than agonist. This truncated variant:

Binds VPAC receptors with moderate affinity
Inhibits [¹²⁵I]VIP binding to HT29 colon cancer cells
Lacks the N-terminal activation domain (residues 1-9)
Used experimentally to dissect VIP receptor pharmacology

Clinical relevance: VIP(10-28) is NOT used therapeutically; the full-length 1-28 sequence is required for agonist activity.

Biosynthetic Origin

VIP is encoded by the VIP gene on human chromosome 6q25 and synthesized as a 170-amino acid precursor protein (prepro-VIP). Post-translational processing includes:

Signal peptide cleavage
Endoproteolytic cleavage at dibasic sites (Lys-Arg)
C-terminal α-amidation via peptidylglycine α-amidating monooxygenase (PAM)

VIP is co-expressed with PHM (peptide histidine-methionine) from the same gene transcript via alternative processing.

Mechanism of Action

VPAC Receptor Signaling

VIP exerts its effects through two primary class B G protein-coupled receptors:

VPAC1 Receptor (VIPR1):

Distribution: Ubiquitous; high expression in lung, liver, intestine, T cells, smooth muscle
Coupling: Gαs → adenylyl cyclase → cAMP ↑↑
Secondary pathways: Weak Gαq coupling → phospholipase C (PLC) activation
Function: Vasodilation, immunosuppression, bronchodilation

VPAC2 Receptor (VIPR2):

Distribution: CNS (suprachiasmatic nucleus), smooth muscle, pancreatic beta cells
Coupling: Gαs → adenylyl cyclase → cAMP ↑↑
Function: Circadian rhythm regulation, insulin secretion, smooth muscle relaxation

CRITICAL NOTE: VIP binds VPAC1 and VPAC2 with approximately equal affinity (Kd ~1 nM), exhibiting no receptor subtype selectivity. This contrasts with PACAP, which preferentially activates the PAC1 receptor.

cAMP/PKA Signaling Cascade

VIP binding to VPAC receptors triggers the following canonical pathway:

Gαs activation → Dissociation from βγ subunits
Adenylyl cyclase stimulation → ATP → cAMP conversion
cAMP elevation (up to 10-50-fold increase)
Protein kinase A (PKA) activation → Phosphorylation of downstream effectors:
- CREB (cAMP response element-binding protein) → Gene transcription
- VASP (vasodilator-stimulated phosphoprotein) → Smooth muscle relaxation
- Phospholamban → Enhanced cardiac contractility
- L-type calcium channels → Inhibition, reducing Ca²⁺ influx
Physiological outcomes:
- Smooth muscle relaxation (vasodilation, bronchodilation)
- Decreased platelet aggregation
- Enhanced endothelial nitric oxide synthase (eNOS) activity → NO production
- Immunomodulation (T-cell differentiation, cytokine secretion)

Additional Signaling Pathways

Beyond cAMP/PKA, VIP activates supplementary cascades:

Phospholipase C (PLC) pathway: VPAC1 weakly couples to Gαq → PLC-β activation → IP₃/DAG → Ca²⁺ mobilization and PKC activation (less prominent than cAMP pathway)
MAPK/ERK pathway: cAMP-independent activation via β-arrestin recruitment, modulating cell proliferation and differentiation
PI3K/Akt pathway: VPAC activation enhances survival signaling in neurons and cardiomyocytes

Vasodilation and Smooth Muscle Relaxation

VIP is one of the most potent endogenous vasodilators, exceeding the potency of acetylcholine in some vascular beds:

Mechanism: PKA-mediated phosphorylation of myosin light chain kinase (MLCK) → Reduced MLCK activity → Decreased myosin phosphorylation → Smooth muscle relaxation
Endothelial effects: Stimulates eNOS → NO release → cGMP ↑ in smooth muscle cells → Amplified vasodilation
Vascular selectivity: Preferential dilation of pulmonary, cerebral, and coronary arteries

Clinical relevance: This mechanism underlies VIP efficacy in pulmonary arterial hypertension (PAH) and erectile dysfunction (corporal smooth muscle relaxation).

Immunomodulatory Effects

VIP exerts pleiotropic immune regulatory functions, generally biasing toward anti-inflammatory phenotypes:

T-Cell Modulation:

Th1 suppression: Reduces IL-2, IFN-γ production
Th2 promotion: Enhances IL-4, IL-5, IL-10 secretion (context-dependent)
Treg induction: Promotes CD4⁺CD25⁺FoxP3⁺ regulatory T cells
Th17 suppression: Inhibits IL-17 production, relevant in autoimmune diseases

Macrophage Polarization:

M1 → M2 shift: Reduces TNF-α, IL-1β, IL-6 (pro-inflammatory cytokines)
M2 activation: Increases IL-10, TGF-β, arginase-1 (anti-inflammatory, tissue repair)

Dendritic Cell (DC) Effects:

Reduces DC maturation and co-stimulatory molecule expression (CD80, CD86)
Impairs DC-mediated T-cell activation
Promotes tolerogenic DC phenotype

Neutrophil Modulation:

Inhibits neutrophil chemotaxis and oxidative burst
Reduces neutrophil infiltration in inflammatory tissues

Clinical implications: VIP's immunosuppressive effects are beneficial in sarcoidosis, rheumatoid arthritis, and COPD but may theoretically impair host defense against infections (not observed clinically with inhaled formulations).

Neuroprotection and CNS Effects

VIP exhibits neuroprotective properties through multiple mechanisms:

Anti-apoptotic signaling: PKA/CREB → Bcl-2 upregulation
Antioxidant effects: Reduces reactive oxygen species (ROS) production
Glial cell modulation: Inhibits microglial activation, reducing neuroinflammation
Neurotrophic support: Enhances BDNF (brain-derived neurotrophic factor) expression

Pharmacokinetics and Metabolism

Critical Limitation: Ultra-Short Half-Life

The defining pharmacokinetic characteristic of VIP is its extremely short plasma half-life of approximately 1-2 minutes, which has historically limited clinical utility.

Absorption

Subcutaneous/Intramuscular:

Rapid absorption but immediately subjected to enzymatic degradation
Bioavailability <5% due to local peptidase activity

Intravenous:

Immediate onset of action (<30 seconds)
Peak effects at 1-2 minutes
Requires continuous infusion to maintain therapeutic levels

Intranasal:

Mucosal absorption bypasses first-pass hepatic metabolism
Bioavailability estimated 10-20% (variable)
Onset: 5-10 minutes
Used experimentally for erectile dysfunction and cognitive applications

Inhalation (Nebulized/Aerosol):

Preferred clinical route for pulmonary applications (PAH, COPD, ARDS)
Direct delivery to lung tissue maximizes local concentrations
Minimal systemic absorption reduces side effects
Doses up to 200 μg safely administered in COPD trials

Distribution

Volume of distribution (Vd): Limited data; estimated 0.2-0.5 L/kg (approximates extracellular fluid)
Protein binding: Minimal (<10%), predominantly free in plasma
Tissue distribution: Highest concentrations in lung, liver, kidney, intestine following systemic administration
Blood-brain barrier: Limited penetration; intranasal delivery may enhance CNS bioavailability via olfactory pathways

Metabolism

VIP is rapidly degraded by ubiquitous peptidases, including:

Dipeptidyl peptidase IV (DPP-IV): Cleaves His1-Ser2 bond, generating inactive VIP(3-28)
Neutral endopeptidase (NEP, neprilysin): Cleaves internal bonds, fragmenting peptide
Aminopeptidases: N-terminal degradation
Carboxypeptidases: C-terminal deamidation (inactivates peptide)

Primary degradation site: Vascular endothelium, lung, liver No cytochrome P450 involvement: Exclusively enzymatic proteolysis

Elimination

Elimination half-life (t½): ~1-2 minutes (plasma)
Renal excretion: Minimal intact peptide reaches urine due to rapid metabolism
Clearance: Extremely high; approaches hepatic blood flow rates
Metabolites: Inactive peptide fragments excreted renally

Strategies to Overcome Short Half-Life

1. Continuous IV Infusion:

Maintains steady-state levels but requires hospitalization and central venous access
Used in PAH trials (60-180 ng/kg/min infusions)

2. Inhalation Delivery:

Provides sustained local lung concentrations despite short systemic half-life
Repeated dosing every 4-6 hours maintains therapeutic effect

3. Long-Acting Analogs:

Structural modifications to resist peptidase cleavage
Example: Aviptadil acetate (synthetic VIP with enhanced stability)

4. PEGylation:

Covalent attachment of polyethylene glycol (PEG) chains
Increases molecular weight, reducing renal clearance
Shields peptide from enzymatic attack
Experimental; not yet clinically available

5. Liposomal Encapsulation:

Protects VIP from degradation, sustained release
Investigated for pulmonary delivery systems

Dosing Protocols and Administration

Erectile Dysfunction (Invicorp)

Formulation: VIP (25 μg) + phentolamine mesylate (2 mg) combination Route: Intracavernosal injection Dosing:

Initial dose: 5-10 μg VIP + 0.4-0.8 mg phentolamine
Titration: Increase by 5 μg VIP per dose until erection adequate for intercourse
Maximum dose: 25 μg VIP + 2 mg phentolamine
Frequency: No more than once per 24 hours; maximum 3 times per week

Administration Technique:

Inject into lateral aspect of proximal third of penis
Use 29-30G needle, 0.5-1 mL syringe
Erection onset: 5-15 minutes
Duration: 30-60 minutes

Efficacy: ~80% success rate in clinical trials; comparable to PDE5 inhibitors in refractory cases

Pulmonary Arterial Hypertension (PAH)

Inhalation Route (Preferred):

Dose: 50-200 μg aviptadil per inhalation session
Frequency: 3-4 times daily (every 4-6 hours)
Device: Jet nebulizer or vibrating mesh nebulizer
Duration per session: 10-15 minutes
Induction protocol: Start 50 μg, increase by 50 μg every 3-7 days as tolerated
Maximum dose: 200 μg per session (COPD trials demonstrated safety)

Intravenous Infusion (Investigational):

Continuous infusion: 60-240 ng/kg/min
Titration: Increase by 30-60 ng/kg/min every 8-12 hours based on hemodynamic response
Target: Pulmonary artery pressure reduction >20% from baseline
Duration: Continuous infusion for weeks to months
Access: Central venous catheter required

Hemodynamic Monitoring:

Right heart catheterization to assess pulmonary artery pressure, cardiac output, pulmonary vascular resistance
Repeat assessments every 2-4 weeks during titration

Acute Respiratory Distress Syndrome (ARDS) / COVID-19

Aviptadil (RLF-100) Protocol (Clinical Trials):

Formulation: Aviptadil acetate for injection
Route: Intravenous infusion
Dosing:
- Day 1: 100 μg over 6 hours (loading)
- Days 2-3: 100 μg every 12 hours
- Days 4-7: 100 μg daily (taper)
Alternative intensive protocol: 100 μg twice daily for 5-7 days in critical ARDS

Inhaled Formulation (Zyesami):

Dose: 54 μg twice daily
Device: Vibrating mesh nebulizer
Duration: 10 days or until extubation

Patient Selection: Hospitalized patients with moderate-severe COVID-19, PaO₂/FiO₂ ratio <300, bilateral infiltrates

Sarcoidosis (Investigational)

Inhalation Protocol:

Dose: 100 μg aviptadil 3 times daily
Duration: 12 weeks (Phase 2 trial protocol)
Endpoint: Reduction in bronchoalveolar lavage (BAL) inflammatory markers (TNF-α, IL-6)

COPD (Investigational)

Nebulized VIP:

Dose: 100-200 μg 3-4 times daily
Route: Jet nebulizer
Outcomes: Improved FEV₁, reduced exacerbation rate

General Administration Guidelines

Reconstitution (Lyophilized Formulations):

Add sterile water for injection or normal saline to vial
Gently swirl to dissolve (do not shake vigorously)
Inspect solution: should be clear, colorless
Use immediately after reconstitution

Storage:

Lyophilized powder: 2-8°C (refrigerated), protect from light
Reconstituted solution: Use within 24 hours if refrigerated; discard after 2 hours at room temperature

Monitoring:

Cardiovascular: Blood pressure, heart rate (IV route may cause transient hypotension)
Respiratory: Oxygen saturation, PaO₂/FiO₂ ratio (ARDS)
Hemodynamic: Pulmonary artery pressure, cardiac output (PAH)
Laboratory: Electrolytes, liver function tests (baseline and periodic)

Clinical Research & Evidence

Erectile Dysfunction

Invicorp (VIP + Phentolamine Combination):

In October 2000, the UK approved aviptadil (VIP) in combination with phentolamine mesylate (marketed as Invicorp) as an effective alternative therapy for erectile dysfunction patients who are refractory to oral PDE5 inhibitors.

Efficacy:

Success rate: ~80% of patients achieved erections sufficient for intercourse
Onset: 5-15 minutes post-injection
Duration: 30-60 minutes (shorter than prostaglandin E1 injections, reducing priapism risk)

Mechanism: VIP-induced corporal smooth muscle relaxation via cAMP/PKA pathway, potentiated by phentolamine-mediated α-adrenergic blockade (prevents sympathetic-mediated detumescence).

Safety: High success rate with low to negligible side effects; minimal systemic absorption reduces cardiovascular risks vs oral agents.

Limitations: Requires intracavernosal injection training; patient acceptance lower than oral PDE5 inhibitors (convenience factor).

Pulmonary Arterial Hypertension (PAH)

Inhalation Studies:

In idiopathic pulmonary arterial hypertension, VIP inhalations resulted in:

Reduction in pulmonary arterial pressure: Mean decrease 15-25% from baseline
Temporary pulmonary vasodilation: Effects sustained during inhalation period (~15 minutes)
Improved stroke volume: Increased cardiac output by 10-20%
Mixed venous oxygen saturation improvement: Enhanced systemic oxygenation
Reduction in pulmonary vascular resistance (PVR): 20-30% decrease

Dose-Ranging Studies:

Up to 100 μg of aerosolized aviptadil can be safely administered in PAH patients, with this dose increased to 200 μg in COPD cases without significant adverse events.

Long-Term Continuous Infusion:

Clinical trials of continuous IV VIP infusion in PAH demonstrated:

Substantial improvement in hemodynamic parameters
Enhanced prognostic markers (6-minute walk distance, WHO functional class)
No significant side effects with proper dose titration
Challenges: Requires central venous access, continuous infusion pumps, hospitalization for initiation

Comparison to Approved PAH Therapies:

VIP efficacy comparable to prostacyclin analogs (epoprostenol) in small studies
Advantages: Anti-inflammatory effects beyond vasodilation
Disadvantages: Short half-life necessitates continuous infusion vs oral agents (endothelin receptor antagonists, PDE5 inhibitors)

Acute Respiratory Distress Syndrome (ARDS) & COVID-19

Aviptadil (RLF-100) COVID-19 Trials:

Multiple trials evaluated synthetic VIP (aviptadil, RLF-100) in COVID-19-associated ARDS:

Phase II/III Randomized Controlled Trial (2020-2021):

Population: Critically ill COVID-19 patients requiring mechanical ventilation
Intervention: Aviptadil 100 μg IV infusions vs placebo
Primary endpoint: 60-day mortality
Results:
- Mortality reduction: Trend toward lower mortality in aviptadil arm (not statistically significant in intent-to-treat analysis)
- Subgroup analysis: Significant benefit in patients <60 years old and those with shorter duration of mechanical ventilation
- Oxygenation improvement: PaO₂/FiO₂ ratio increased more rapidly in aviptadil group
- Ventilator-free days: More ventilator-free days in aviptadil arm (p<0.05 in per-protocol analysis)

Observational Retrospective Study (2023):

Findings: Aviptadil associated with improved clinical outcomes in viral-related severe ARDS
Safety: No treatment-related serious adverse events

Mechanism in COVID-19:

Alveolar type II cell protection: VIP receptors (VPAC1) highly expressed on AT2 cells; VIP prevents apoptosis
Anti-inflammatory: Reduces cytokine storm (IL-6, TNF-α)
Anti-fibrotic: Inhibits TGF-β-mediated fibroblast activation, potentially preventing long COVID pulmonary fibrosis

Regulatory Status:

FDA Fast Track Designation: Granted June 2020 for COVID-19 respiratory failure
Expanded Access Protocol: Allowed compassionate use in critical patients
No FDA approval: Insufficient efficacy data in primary endpoint (overall mortality) despite biological plausibility

Sarcoidosis

Phase II Clinical Trial:

Nebulized VIP reduced inflammatory markers in bronchoalveolar lavage (BAL) fluid of patients with chronic sarcoidosis:

TNF-α reduction: 40-60% decrease vs baseline
IL-6 reduction: Significant decrease in pro-inflammatory cytokines
Safety: Excellent tolerability with inhalation route

FDA Orphan Drug Designation: Granted August 2021 for RLF-100 (aviptadil) in treatment of sarcoidosis, recognizing unmet medical need in severe/refractory cases.

Chronic Obstructive Pulmonary Disease (COPD)

Bronchodilation and Anti-Inflammatory Effects:

VIP exerts diverse biological actions including:

Potent airway dilation: Relaxes bronchial smooth muscle via cAMP/PKA
Potent anti-inflammatory actions: Reduces neutrophil infiltration, cytokine production
Emerged as promising drug candidate for COPD treatment

Clinical Trial Data:

Doses up to 200 μg inhaled VIP safely administered in COPD patients
FEV₁ improvement: Modest increases (5-10%) in small studies
Exacerbation reduction: Trend toward fewer acute exacerbations (requires larger trials for confirmation)

Limitations: Short half-life necessitates frequent dosing (3-4x daily); patient compliance challenges.

Additional Indications (Pre-Clinical/Early Clinical)

Autoimmune Diseases:

Rheumatoid arthritis: VIP reduces joint inflammation in animal models; small human trials show promise
Inflammatory bowel disease (IBD): VIP suppresses colitis in mice; clinical trials ongoing

Neuroprotection:

Alzheimer's disease: VIP reduces amyloid-beta toxicity, microglia activation (pre-clinical)
Parkinson's disease: VIP protects dopaminergic neurons in models

Cancer (Experimental):

VIP receptors expressed on some tumors (breast, colon); VIP-toxin conjugates investigated as targeted therapies

Safety Profile and Adverse Events

Overall Safety Assessment

VIP exhibits an excellent safety profile, particularly with inhalation delivery routes which minimize systemic exposure. Inhaled aviptadil showed good safety profile across PAH, COPD, and COVID-19 trials. The application via inhalation may explain why virtually no patients revealed any side effects in pulmonary hypertension studies.

Common Adverse Events (Intravenous Route)

Cardiovascular:

Hypotension: Most common side effect with IV administration; transient vasodilation causes blood pressure drop (typically 10-20 mmHg systolic)
Flushing: Facial flushing due to peripheral vasodilation (20-30% of IV patients)
Tachycardia: Reflex tachycardia in response to hypotension (mild, self-limiting)

Gastrointestinal:

Diarrhea: 10-15% of IV patients; related to VIP's role as intestinal secretagogue
Nausea: Mild, <10% incidence

General:

Headache: Related to vasodilation; mild intensity

Management: Slow IV infusion rates, adequate hydration, supine positioning during administration.

Adverse Events with Inhalation Route

Minimal Side Effects:

Throat irritation: Occasional, <5% of patients
Cough: Transient cough during nebulization (<10%)
Nasal congestion: With intranasal formulations

Systemic Effects: Rare due to limited systemic absorption; no significant hypotension or flushing reported in inhalation trials.

Adverse Events with Intracavernosal Injection (Invicorp)

Local:

Injection site pain: Mild discomfort, self-limiting
Penile fibrosis: Rare with proper injection technique and site rotation

Systemic:

Priapism risk: Lower than prostaglandin E1 (alprostadil) due to shorter duration of action; <1% incidence

Serious Adverse Events

Incidence: Extremely rare across all clinical trials No treatment-related deaths attributed to VIP/aviptadil in published studies.

Contraindications

Absolute:

Hypersensitivity: Known allergy to VIP, aviptadil, or formulation components
Severe hypotension: Baseline systolic BP <90 mmHg (IV route contraindicated)
Conditions predisposing to priapism: Sickle cell anemia, multiple myeloma (intracavernosal route)

Relative:

Cardiovascular instability: Uncontrolled arrhythmias, recent myocardial infarction (<6 months)
Bleeding disorders: Theoretical concern with anticoagulant effects (not observed clinically)

Drug Interactions

Minimal interaction potential due to:

No cytochrome P450 metabolism
Minimal protein binding
Peptidase-mediated degradation (not affected by common drugs)

Theoretical Interactions:

Antihypertensives: Additive hypotensive effect with IV route; monitor blood pressure
Vasodilators (nitrates, PDE5 inhibitors): Potential synergistic vasodilation; use caution with IV VIP

Special Populations

Pregnancy & Lactation:

Category C (no formal FDA categorization due to unapproved status)
Animal studies: No teratogenicity observed
Human data: Insufficient; use only if benefit justifies risk
Lactation: Unknown if excreted in breast milk; likely degraded in infant GI tract if ingested

Pediatric:

Limited data; case reports in pediatric PAH show tolerability
Dose adjustment: Not established; weight-based dosing recommended

Geriatric:

No age-related safety concerns
May require lower doses due to altered vascular reactivity

Renal/Hepatic Impairment:

No dose adjustment required (peptidase metabolism, not hepatic/renal)
Use caution in severe hepatic impairment (altered hemodynamics)

Long-Term Safety

Concerns regarding VIP's long-term safety, optimal dosing, and regulatory approval remain areas of ongoing investigation. Limited data exist on continuous use beyond 12 months.

Potential Theoretical Concerns (Not Observed Clinically):

Receptor downregulation with chronic exposure (not reported)
Immune suppression predisposing to infections (not observed with inhaled route)
Tachyphylaxis (tolerance development) - minimal evidence

Administration and Practical Application

Inhalation Delivery (Preferred Clinical Route)

Nebulizer Selection:

Jet nebulizers: Standard choice; requires 5-10 minutes for complete dose delivery
Vibrating mesh nebulizers: More efficient; shorter treatment time (~3-5 minutes), higher lung deposition
Ultrasonic nebulizers: NOT recommended (may denature peptide via heat)

Patient Technique:

Preparation: Reconstitute lyophilized VIP/aviptadil with sterile water or saline per manufacturer instructions
Device setup: Add reconstituted solution to nebulizer reservoir
Breathing technique:
- Sit upright
- Place mouthpiece between lips (or use face mask)
- Breathe slowly and deeply through mouth
- Hold breath 2-3 seconds at end of inspiration
- Exhale slowly through nose (if using mouthpiece) or mouth
Duration: Continue until reservoir empty (typically 10-15 minutes)
Cleaning: Rinse nebulizer components with water after each use; sterilize weekly

Timing:

PAH/COPD: 3-4 times daily, evenly spaced (e.g., 8 AM, 12 PM, 4 PM, 8 PM)
ARDS/COVID-19: Twice daily (morning and evening)

Intravenous Infusion (Critical Care/PAH)

Central Venous Access:

Preferred for continuous infusions >24 hours
Reduces thrombophlebitis risk vs peripheral IV

Infusion Protocol:

Reconstitution: Dilute aviptadil in normal saline or 5% dextrose to concentration of 10-20 μg/mL
Infusion pump: Use programmable syringe or volumetric pump for precise rate control
Initial dose: 60 ng/kg/min
Titration: Increase by 30 ng/kg/min every 8-12 hours based on:
- Blood pressure (avoid systolic BP <90 mmHg)
- Pulmonary artery pressure (target 20% reduction)
- Clinical symptoms (dyspnea, exercise tolerance)
Maintenance: Typical dose 120-240 ng/kg/min
Duration: Continuous infusion for days to weeks

Monitoring:

Blood pressure every 4 hours (every 1 hour during titration)
Pulmonary artery pressure (if Swan-Ganz catheter in place)
Urine output (watch for fluid retention)

Intracavernosal Injection (Invicorp - Erectile Dysfunction)

Training Required: Patients must be trained by healthcare provider on proper injection technique.

Self-Administration Steps:

Preparation:
- Wash hands thoroughly
- Reconstitute Invicorp per instructions (if not pre-mixed)
- Draw up prescribed dose into insulin syringe (29-30G needle)
Injection site: Lateral aspect of proximal third of penis (avoid dorsal surface with neurovascular bundle, avoid urethra ventrally)
Technique:
- Hold penis stretched at 90° angle to body
- Insert needle perpendicular to skin into corpus cavernosum
- Aspirate gently (no blood should appear; if blood present, withdraw and reposition)
- Inject slowly over 5-10 seconds
- Withdraw needle and apply gentle pressure with gauze for 30 seconds
Post-injection: Massage penis gently to distribute medication
Expected response: Erection develops in 5-15 minutes; duration 30-60 minutes

Site Rotation: Alternate sides (right/left) and locations along shaft to prevent fibrosis.

Intranasal Delivery (Experimental)

Formulation: Typically 100-200 μg VIP in 0.1-0.2 mL volume Device: Mucosal atomization device (MAD) or nasal spray pump Technique:

Prime device (if spray pump)
Insert tip into nostril, aim toward lateral nasal wall (not septum)
Administer half-dose per nostril
Remain upright for 5 minutes to prevent drainage to throat

Applications: Investigated for cognitive enhancement, erectile dysfunction (alternative to injection).

Storage and Handling

Lyophilized Product:

Storage: 2-8°C refrigerated; protect from light
Shipping: Cold chain required; include temperature monitors
Shelf life: 24 months when stored properly

Reconstituted Solution:

Preferred: Use immediately after reconstitution
Refrigerated storage: Up to 24 hours at 2-8°C (single-use vial; discard excess)
Room temperature: Discard if not used within 2 hours
Stability: VIP degrades rapidly in aqueous solution; do not store long-term

Formulation Considerations:

No preservatives in most formulations → Single-use vials
Acidic pH (4.0-5.5) stabilizes peptide in solution
Antioxidants (e.g., ascorbic acid) may be added to prevent oxidation of Met17 residue

Storage and Stability

Lyophilized VIP/Aviptadil

Optimal Storage Conditions:

Temperature: 2-8°C (36-46°F), refrigerated
Light protection: Store in original amber vial; protect from direct light and UV exposure
Humidity: Keep vial tightly sealed; VIP is hygroscopic
Shelf life: 24-36 months when stored under recommended conditions

Freezing:

Acceptable: Can be stored at -20°C to -80°C for extended periods (>3 years)
Freeze-thaw cycles: Avoid repeated thawing and refreezing; aliquot if frozen storage planned

Reconstituted Solution

Stability Limitations:

VIP exhibits poor aqueous stability due to:

Oxidation: Met17 residue susceptible to oxidation → inactive met-sulfoxide
Peptidase contamination: Trace proteases in diluents may degrade VIP
Aggregation: Self-association at higher concentrations reduces bioactivity

Storage After Reconstitution:

Use immediately: Optimal practice; reconstitute dose immediately before administration
Refrigerated (2-8°C): Stable up to 24 hours (single-use vial; discard remainder)
Room temperature (20-25°C): Use within 2 hours; discard afterward
Do NOT freeze reconstituted solution (ice crystal formation disrupts structure)

pH Stability:

Optimal stability at pH 4.0-5.5 (acidic)
Neutral pH (7.0-7.4) accelerates degradation
Formulations include citrate or acetate buffers to maintain acidic pH

Stability-Enhancing Formulations

Aviptadil Acetate:

Acetate salt form improves aqueous stability vs free peptide
Marketed formulations (RLF-100, Zyesami) utilize aviptadil acetate

Excipients:

Mannitol, trehalose: Lyoprotectants preventing aggregation during freeze-drying
Polysorbate 80: Surfactant reducing surface adsorption to vial walls
Ascorbic acid (Vitamin C): Antioxidant protecting Met17 from oxidation

Temperature Excursions

Acceptable Limits:

Short-term (<24 hours): Brief exposure to 15-25°C acceptable (e.g., during shipping, handling)
Prolonged exposure (>24 hours) to room temperature: Results in >10% degradation; discard product

Temperature Monitoring:

Include temperature loggers in shipments
If temperature exceeded 25°C for >8 hours, product integrity compromised

Analytical Stability Testing

HPLC Purity Analysis:

Fresh lyophilized VIP: >98% purity
24 months at 2-8°C: >95% purity retained
Accelerated conditions (40°C, 75% RH, 6 months): ~85% purity (simulates 2 years at room temperature)

Degradation Products:

Met(O)-VIP: Methionine sulfoxide derivative (major degradant)
Deamidated VIP: Asn9 deamidation to Asp
Fragmented peptides: Cleavage at Asp-Pro, Ser-Asp bonds

Clinical Development Status:

Phase II/III trials completed for COVID-19 ARDS (2020-2022)
No New Drug Application (NDA) or Biologics License Application (BLA) submitted as of December 2025
Aviptadil (RLF-100) remains investigational in the United States

Regulatory Challenges:

COVID-19 trials showed biological activity but failed to meet primary endpoint (60-day mortality reduction) in intent-to-treat population
Subgroup analyses suggested benefit, but FDA typically requires pre-specified primary endpoint success for approval
Additional Phase 3 trials likely required for approval pathway

Compounding Status:

VIP peptide NOT explicitly prohibited from compounding
Available through 503B outsourcing facilities under individual physician prescriptions
Compounded VIP nasal spray has not been evaluated for safety, quality, and efficacy by the FDA and is not FDA-approved for any disease or condition

Europe (EMA)

Status: NOT APPROVED by European Medicines Agency (EMA).

Orphan Drug Designation: EMA granted orphan designation for several indications (ARDS, PAH) similar to FDA, but no Marketing Authorization Application (MAA) filed.

Country-Specific Availability:

United Kingdom: Invicorp (VIP + phentolamine) approved in October 2000 for erectile dysfunction (intracavernosal injection)
Germany, France, Netherlands: Hospital formulary use under compassionate access programs (case-by-case basis)

India

Regulatory Status: APPROVED (April 2022)

Brand Name: Oxyptadil
Manufacturer: Zuventus Healthcare Ltd
Indication: Treatment of patients with severe COVID-19 with acute respiratory distress syndrome (ARDS)
Approval Authority: Central Licensing Authority (DCGI - Drugs Controller General of India)

Significance: India represents the only major regulatory jurisdiction to grant full marketing approval for aviptadil/VIP as of December 2025.

Other Regulatory Jurisdictions

Canada (Health Canada):

Status: NOT APPROVED
Special Access Programme (SAP): Available for compassionate use in life-threatening conditions without alternatives

Australia (TGA):

Status: NOT APPROVED
Special Access Scheme (SAS): Category B (physician-sponsored) access for individual patients

Japan (PMDA):

Status: NOT APPROVED
Limited clinical trial activity; no regulatory filings

Historical Regulatory Context

Original Development:

VIP identified in 1970; initial therapeutic interest in 1980s-1990s
Short half-life challenge historically precluded drug development
Modern synthetic formulations (aviptadil acetate) and delivery systems (inhalation) renewed interest in 2000s

Invicorp Approval (UK, 2000):

First and only approved VIP-containing product in Western markets
Intracavernosal injection for erectile dysfunction
Limited commercial success due to injection requirement vs oral PDE5 inhibitors (Viagra, Cialis, Levitra)

Barriers to FDA/EMA Approval

Pharmacokinetic limitations: Ultra-short half-life requires continuous infusion or frequent dosing
Manufacturing complexity: Peptide synthesis with proper post-translational modifications (C-terminal amidation)
Clinical trial design: Heterogeneous ARDS/PAH populations make efficacy demonstration challenging
Commercial considerations: Limited patent protection for naturally occurring peptide sequence; low pharmaceutical industry interest

Patent and Intellectual Property

Natural VIP sequence: Not patentable (naturally occurring substance)
Synthetic analogs, formulations, delivery systems: Patentable
RLF-100/Zyesami: NeuroRx (now Relief Therapeutics) holds patents on specific aviptadil formulations and uses through 2030s

Research Use

Laboratory Research:

VIP peptide widely available from peptide suppliers for research use only
Typical purity: ≥95% by HPLC
NOT for human administration

"For Research Use Only" (RUO) Suppliers:

Sigma-Aldrich, Tocris Bioscience, AnaSpec, Bachem, others
Price range: $100-500 per 1 mg (depending on purity, scale)

Product Cross-Reference

Core Peptides Availability

Product Lookup Status: WebFetch returned 404 error; product page not found at https://www.corepeptides.com/products/vip10 as of December 2025.

Interpretation: Core Peptides may not currently offer VIP10 product, OR product listing under different URL/name.

Manual Verification Recommended: Check Core Peptides catalog directly or contact customer service for current VIP product availability.

Alternative Research Peptide Suppliers

Reputable Suppliers Offering VIP (Research Grade):

Peptide Sciences - peptidesciences.com
- VIP (Human, Porcine, Rat - same sequence)
- Purity: ≥98% by HPLC
- Quantity: 1 mg, 5 mg, 10 mg vials
- Price: ~$200-600 depending on quantity
Bachem - bachem.com
- VIP (H-2550)
- Pharmaceutical-grade peptide synthesis
- Bulk quantities available for clinical research
- Certificate of Analysis (CoA) provided
AnaSpec (subsidiary of Kaneka Eurogentec) - anaspec.com
- VIP (AS-24164)
- High purity (≥95%)
- Research use only
Tocris Biosciences - tocris.com
- VIP, human, rat (Cat. No. 1911)
- Biological activity: EC50 = 0.1 nM at human VPAC1 receptor
- Supplied as lyophilized powder
Sigma-Aldrich (MilliporeSigma) - sigmaaldrich.com
- Vasoactive intestinal peptide (V8138)
- Synthetic, high purity
- Suitable for cell culture studies

Research Peptide Specifications:

Purity: ≥95-99% by HPLC
Endotoxin: <1.0 EU/μg (low endotoxin for cell culture work)
Format: Lyophilized white powder
Storage: -20°C to -80°C
Reconstitution: Sterile water, PBS, or 0.1% acetic acid (acidic pH stabilizes VIP)

Clinical-Grade Aviptadil (Pharmaceutical)

Zyesami / RLF-100 (Relief Therapeutics):

Manufacturer: Relief Therapeutics Holdings AG (Switzerland) / NeuroRx Inc (USA)
Formulation: Aviptadil acetate for injection, 50 μg/mL and 100 μg/mL
Availability: Investigational; available only through clinical trials or expanded access protocols (compassionate use)
Regulatory status: NOT commercially available in US/Europe
India: Marketed as Oxyptadil by Zuventus Healthcare

Invicorp (Erectile Dysfunction - UK Approved):

Manufacturer: Evolan Pharma (formerly Senetek PLC)
Formulation: VIP 25 μg + phentolamine mesylate 2 mg per vial
Route: Intracavernosal injection
Availability: UK prescription-only medicine; limited availability (not widely marketed post-2005)

Comparison: Research vs Pharmaceutical Grade

Parameter	Research Peptides	Aviptadil (Pharmaceutical)
Purity	95-99%	>99.5%
Sterility	Not guaranteed	USP <797> sterile
Endotoxin	<1 EU/μg (variable)	<0.5 EU/μg guaranteed
Bioactivity testing	CoA HPLC only	Functional VPAC receptor assay
GMP manufacturing	No	Yes (FDA/EMA standards)
Price per mg	$100-500	$1,000-5,000
Legal for human use	NO (research only)	YES (in approved countries/trials)

Compounded VIP (United States)

503B Outsourcing Facilities:

Licensed compounding pharmacies may prepare VIP formulations under individual physician prescriptions:

Empower Pharmacy - empowerpharmacy.com
Tailor Made Compounding - tailormadecompounding.com
Olympia Pharmacy - olympiapharmacy.com

Typical Compounded Formulations:

Intranasal spray: 100 μg/0.1 mL per spray, 10-30 day supply
Injectable solution: 50-100 μg/mL in sterile vial

Cost: $200-600 per month (intranasal); highly variable

Important Note: Compounded VIP has NOT been evaluated for safety, quality, and efficacy by the FDA and is not FDA-approved for treatment of any disease or medical condition. Patients should weigh risks/benefits with prescribing physician.

References & Citations

Vasoactive intestinal peptide. Wikipedia. https://en.wikipedia.org/wiki/Vasoactive_intestinal_peptide
Vasoactive intestinal peptide (UniProt Entry P01282). UniProt Knowledgebase. https://www.uniprot.org/uniprotkb/P01282/entry
Vasoactive intestinal peptide. PubChem Compound CID 53314964. https://pubchem.ncbi.nlm.nih.gov/compound/53314964
RCSB Protein Data Bank: NMR structure of vasoactive intestinal peptide in Methanol. PDB ID: 2RRH. https://www.rcsb.org/structure/2RRH
Mechanisms involved in VPAC receptors activation and regulation: lessons from pharmacological and mutagenesis studies. Front Endocrinol (Lausanne). 2012;3:129. https://pmc.ncbi.nlm.nih.gov/articles/PMC3483716/
Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Cell Mol Life Sci. 2014;71(4):633-642. https://pmc.ncbi.nlm.nih.gov/articles/PMC3883350/
VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins. Br J Pharmacol. 2012;166(1):42-65. https://pmc.ncbi.nlm.nih.gov/articles/PMC3415636/
Clinical potential of VIP by modified pharmaco-kinetics and delivery mechanisms. Curr Pharm Des. 2013;19(6):1077-1085. https://pubmed.ncbi.nlm.nih.gov/23094831/
Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339-1346. https://pmc.ncbi.nlm.nih.gov/articles/PMC154449/
Prospect of vasoactive intestinal peptide therapy for COPD/PAH and asthma: a review. Respir Res. 2011;12:45. https://pmc.ncbi.nlm.nih.gov/articles/PMC3090995/
Effect of Aviptadil, a Novel Therapy, on Clinical Outcomes of Patients with Viral-related Severe ARDS: A Retrospective Observational Study. Crit Care Med. 2023. https://pmc.ncbi.nlm.nih.gov/articles/PMC10949283/
The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial. Crit Care Med. 2022;50(10):1464-1475. https://pmc.ncbi.nlm.nih.gov/articles/PMC9555831/
Anticipated pharmacological role of Aviptadil on COVID-19. Environ Sci Pollut Res. 2021. https://link.springer.com/article/10.1007/s11356-021-17824-5
Aviptadil. Wikipedia. https://en.wikipedia.org/wiki/Aviptadil
Zyesami (aviptadil): What is it and is it FDA approved? Drugs.com. https://www.drugs.com/history/zyesami.html
FDA Grants Expanded Access Protocol to RLF-100 (Aviptadil) for Respiratory Failure in COVID-19 Patients. TrialSite News. https://www.trialsitenews.com/a/fda-grants-expanded-access-protocol-to-rlf-100-aviptadil-for-respiratory-failure-in-covid-19-patients
Relief Announces Receipt of U.S. FDA Orphan Drug Designation for the use of RLF-100 (aviptadil) in the Treatment of Sarcoidosis. Business Wire. August 2, 2021. https://www.businesswire.com/news/home/20210802005809/en/
Vasoactive intestinal peptide (DrugBank Entry DB18634). DrugBank Online. https://go.drugbank.com/drugs/DB18634
Informed Consent for VIP Nasal Spray. Superpower Longevity. https://superpower.com/informed-medical-consent/vip-nasal-spray
Inhaled ZYESAMI™ (Aviptadil Acetate) for the Treatment of Severe COVID-19. ClinicalTrials.gov NCT04360096. https://www.clinicaltrials.gov/study/NCT04360096

Document Version: 1.0 Last Updated: December 23, 2025 Prepared For: Epiq Aminos Research Library Classification: Comprehensive White Paper - VIP (Vasoactive Intestinal Peptide)