Human VIP-α: an emerging biologic response modifier to treat primary pulmonary hypertension

Abstract

Primary pulmonary hypertension (PPH) is a rare life-threatening disorder of unknown etiology manifested by chronic elevation of pulmonary arterial pressure. Given that pulmonary vasoconstriction, endothelial and vascular smooth muscle cell proliferation and in situ thrombosis contribute appreciably to the evolution of PPH, treatment with vasodilators, antiproliferative drugs and anticoagulants, alone or in combination, constitute the pharmacologic standard of care. To this end, long-term administration of oral calcium channel blockers, prostacyclin analogs by various routes and oral endothelin-1 receptor antagonists, alone or in combination, is efficacious in treating patients with PPH. Unfortunately, efficacy is hampered by poor stability, delivery and bioavailability, and by systemic toxicity. Hence, there is an ongoing need to develop and test new drugs to treat patients with PPH. To address this issue, a novel, targeted, long-acting, biocompatible and safe sterically stabilized liposomal and micellar formulation of human vasoactive intestinal peptide (VIP) was developed and tested for human use: the 28-amino acid pleiotropic biologic response modifier, human VIP-α. The long-lasting salutary effects of phospholipid-associated VIP on vasomotor tone and arterial pressure were expressed at low concentrations solely in diseased animals and were independent of its route of administration. Thus, the author proposes that human VIP-α could be developed as a safe long-acting drug to treat patients with PPH.

Keywords::

• cGMP
• drug delivery
• liposomes
• micelles
• microcirculation
• neuropeptide
• nitric oxide
• PPH
• proteolysis
• vascular smooth muscle
• vasoactive intestinal peptide

Acknowledgements

The author wishes to thank all past and present collaborators and graduate students for invaluable contribution to the work outlined in this monograph. Supported, in part, by NIH grants RO1 AG024026 and RO1 HL72343 and VA Merit Review grant.