Transdermal Pharmacology of Small Molecule Cyclic C5a Antagonists

Proctor, Lavinia M., Woodruff, Trent M., Sharma, Prakirti, Shiels, Ian A., Taylor, Stephen M. and Lambris, John D. (2006). Transdermal Pharmacology of Small Molecule Cyclic C5a Antagonists. In John D. Lambris (Ed.), Current Topics in Complement (pp. 329-345) New York: Springer. doi:10.1007/0-387-34134-X_22

Author Proctor, Lavinia M.
Woodruff, Trent M.
Sharma, Prakirti
Shiels, Ian A.
Taylor, Stephen M.
Lambris, John D.
Title of chapter Transdermal Pharmacology of Small Molecule Cyclic C5a Antagonists
Title of book Current Topics in Complement
Place of Publication New York
Publisher Springer
Publication Year 2006
Sub-type Research book chapter (original research)
DOI 10.1007/0-387-34134-X_22
Series Advances in Experimental Medicine and Biology
ISBN 978-0-387-32231-5
ISSN 0065-2598
Editor John D. Lambris
Volume number 586
Start page 329
End page 345
Total pages 17
Total chapters 25
Language eng
Subjects 320599 Pharmacology not elsewhere classified
730102 Immune system and allergy
Abstract/Summary Overproduction or underregulation of the proinflammatory complement component C5a has been implicated in numerous immune and inflammatory conditions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous animal models of inflammation following intravenous, subcutaneous, intraperitoneal, and oral administration. In the present study the transdermal pharmacology of PMX53 and three analogs designed with increased lipophilicity, hydrocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administration (10 mg/50 cm(2) site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (I mg/kg i.v.). Interestingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (< 5 ng/ml) circulating levels following topical administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic effects. However, increasing lipophilicity in these compounds did not result in increased blood levels. Nonetheless, topical application of C5aR antagonists produced circulating levels of the drugs that antagonized the LPS-induced systemic responses of neutropenia and hypotension. This suggests that these small-molecule C5aR antagonists may be developed for topical administration for the treatment of local and systemic inflammatory conditions in the human and veterinary pharmaceutical markets.
Keyword Medicine, Research & Experimental
Anti-c5a Monoclonal-antibodies
Ischemia-reperfusion Injury
Receptor Antagonist
Rat Model
Polymorphonuclear Leukocytes
Skin Penetration
Q-Index Code B1
Additional Notes ISSN: 0065-2598

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Created: Tue, 14 Aug 2007, 12:58:01 EST