PACAP-38vsVIP (Vasoactive Intestinal Peptide)

Molecular Formula

C₂₀₃H₃₃₁N₆₃O₅₃S

Molecular Weight

~4534 Da

Half-Life

Very short plasma half-life (minutes); rapid enzymatic degradation

Bioavailability

IV: systemic; Intranasal: direct CNS access bypassing BBB; poor oral bioavailability

CAS Number

137061-48-4

Molecular Formula

C₁₄₇H₂₃₇N₄₃O₄₃S

Molecular Weight

3325.83 Da

Half-Life

Approximately 1-2 minutes in plasma (rapid enzymatic degradation)

Bioavailability

IV: 100%; Inhaled: local pulmonary delivery; short systemic half-life

CAS Number

37221-79-7

Common

• Flushing
• Tachycardia
• Gastrointestinal Effects
• Transient Warmth Sensation

Uncommon

• Headache and Migraine Triggering
• Hypotension

Serious

• Systemic Hypotension and Cardiovascular Effects
• Systemic Inflammatory Activation

Common

• Facial Flushing
• Diarrhea
• Nausea

Uncommon

• Hypotension
• Tachycardia
• Cardiovascular Effects

Serious

• Hypotension
• Severe Flushing and Facial Erythema

Evidence Level

Strong human trials (Phase 3 or FDA approved)

FDA Status

Research compound

Safety Overview

PACAP-38 shows good tolerability in Phase II trials for migraine and pain conditions with minimal serious adverse events at IV doses of 2-6 mcg/kg. Primary side effects are transient flushing and headache (10-15% of subjects), likely related to vasodilation. Cardiovascular effects include mild heart rate increase and blood pressure changes, monitored in clinical settings. No carcinogenicity or teratogenicity in animal models; limited long-term safety data in humans.

Contraindications

• xActive migraine or headache disorder (PACAP-38 is a potent migraine trigger)
• xUncontrolled hypotension or cardiovascular instability
• xNot approved for clinical use outside research settings
• xInsufficient data for pregnancy and lactation safety

Evidence Level

Moderate human trials (Phase 1-2)

FDA Status

Research compound

Safety Overview

VIP (Vasoactive Intestinal Peptide) is a 28-amino acid endogenous neuropeptide with moderate evidence from Phase 1-2 human clinical trials. The synthetic pharmaceutical form (aviptadil/RLF-100) received FDA fast-track designation for COVID-19-associated ARDS, indicating recognition of its therapeutic potential. Critical safety considerations: VIP is a potent vasodilator that causes dose-dependent hypotension and compensatory tachycardia—hemodynamic monitoring is essential during IV administration. Common side effects include facial flushing and diarrhea from its GI effects. Phase 2b/3 COVID-19 ARDS trials (196 patients) reported NO serious drug-related adverse events, a favorable safety signal. However, individual responses to vasodilation vary significantly based on baseline cardiovascular status, medications, and underlying conditions. The peptide's short plasma half-life (1-2 minutes) limits systemic accumulation. Inhaled VIP shows excellent local tolerability for pulmonary applications with minimal systemic absorption.

Contraindications

• xUncontrolled hypotension or hemodynamic instability
• xSevere cardiac decompensation
• xNot approved for clinical use outside of trials
• xInsufficient data for pregnancy and lactation safety