Pharmacological effects and lung-binding characteristics of a novel VIP analogue, [R15, 20, 21, L17]-VIP-GRR (IK312532).
ABSTRACT A novel VIP derivative, [R15, 20, 21, L17]-VIP-GRR (IK312532), relaxed potently the carbachol-induced contraction of guinea-pig isolated trachea with longer duration than that induced by VIP. IK312532 competed with [125I]VIP for the binding sites in the rat lung in a concentration-dependent manner. There was considerable decrease in specific [125I]VIP binding in each lobe of right and left lung 0.5 h after the intratracheal administration of IK312532 (50 microg/rat) as dry powder inhaler (DPI). Rosenthal analysis revealed that the administration of IK312532 (50 and 100 microg/rat)-DPI brought about a significant decrease of maximal number of binding sites (Bmax) for specific [125I]VIP binding in anterior and posterior lobes of rat right lung, suggesting a significant occupancy of lung VIP receptors. This effect by IK312532 in the posterior lobe of the right lung was dose-dependent and lasted until at least 2 h after the intratracheal administration. Furthermore, the antigen-evoked infiltration of granulocytes in the rat bronchiolar mucosa was markedly suppressed by the intratracheal administration of IK312532 (50 microg/rat)-DPI. In conclusion, the present study has shown that IK312532 exhibits long-lasting relaxation of tracheal smooth muscles and that the intratracheal administration of this peptide exerts a significant occupancy of lung VIP receptors as well as a suppression of the antigen-evoked infiltration of granulocytes in the bronchiolar mucosa. Thus, the formulation of IK312532 as DPI may be a pharmacologically useful drug delivery system for the therapy of pulmonary diseases such as asthma.
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ABSTRACT: In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood--brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase- 1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.Archivum Immunologiae et Therapiae Experimentalis 07/2005; 53(4):308-20. · 2.82 Impact Factor
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ABSTRACT: Vasoactive intestinal peptide (VIP) exerts a relaxing action on tracheal smooth muscle which is mediated through interaction with VIP receptors. The deficiency of VIP in the airways has been implicated in the pathogenesis of asthma. Thus, the administration of VIP may be useful for the therapy of pulmonary diseases. However, the therapeutic application of VIP is largely limited by its rapid degradation in addition to the systemic adverse effects due to the wide distribution of VIP receptors. To overcome these problems, we succeeded to synthesize a novel VIP derivative of VIP, [R15, 20, 21, L17]-VIP-GRR (IK312532), and to prepare its dry powder for the topical administration to the lung. The physicochemical properties of dry powder were evaluated by laser diffraction and cascade impactor. The laser diffraction analysis indicated that the carrier and fine particles had median diameter of 65.6 and 4.5 microm, respectively, and the air flow at the pressure of 0.15 MPa or higher resulted in the high dispersion and significant separation of fine particle containing peptide from the carrier molecule. The cascade impactor analysis clearly showed the high emission of dry powder from capsule and the deposition of peptide on stages 3 of the cascade impactor. The intratracheal administration of dry powder inhaler (DPI) of VIP or IK312532 brought about a significant decrease of maximal number of binding sites (Bmax) for [125I]VIP in anterior and posterior lobes of rat right lung, suggesting a significant occupancy of lung VIP receptors. This effect by IK312532-DPI compared with VIP-DPI lasted for a longer period. Thus, IK312532-DPI may be a pharmacologically useful drug delivery system for the VIP therapy of pulmonary diseases such as asthma.Life Sciences 07/2006; 79(2):138-43. DOI:10.1016/j.lfs.2005.12.049 · 2.30 Impact Factor
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ABSTRACT: In an effort to develop a peptide-based radiopharmaceutical for the detection of tumors overexpressed vasoactive intestinal peptide receptors with positron emission tomography, we have prepared a novel [R(8,15,21), L17]-VIP peptide for 18F-labeling. This peptide inhibited 125I-VIP binding to rats lung membranes with high affinity [half-maximal inhibitory concentrations (IC50) of 0.12 nm]. Additionally, [R(8,15,21), L17]-VIP showed higher stability than native vasoactive intestinal peptide in vivo of mice. With N-succinimidyl 4-[18F] fluorobenzoate as labeling prosthetic group, [18F]FB-[R(8,15,21), L17]-VIP was obtained in >99% radiochemical purity within 100 min in decay-for-corrected radiochemical yield of 33.6 +/- 3% (n = 5) and a specific radioactivity 255 GBq/micromol at the end of synthesis. Stability of [18F]FB-[R(8,15,21), L17]-VIP in vitro and in vivo were investigated. Biodistribution of this trace was carried out in mice with induced C26 colorectal tumor. Fast clearance of [18F]FB-[R(8,15,21), L17]-VIP from non-target tissues and specific uptakes by tumors realized higher tumor-to-muscle ratio (3.55) and tumor-to-blood ratio (2.37) 60 min postinjection. Clear difference was observed between the blocking and unblocking experiments in biodistribution and whole body radioautography. [18F]FB-[R(8,15,21), L17]-VIP has demonstrated its potential for diagnosing tumors overexpressed vasoactive intestinal peptide receptors both in vitro and in vivo.Chemical Biology & Drug Design 12/2006; 68(6):319-25. DOI:10.1111/j.1747-0285.2006.00453.x · 2.51 Impact Factor