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Table of Contents
Vol. 90, No. 3-4, 2012
Issue release date: October 2012
Section title: Original Paper
Pharmacology 2012;90:223–232
(DOI:10.1159/000342380)

Therapeutic Potential of ASP3258, a Selective Phosphodiesterase 4 Inhibitor, on Chronic Eosinophilic Airway Inflammation

Kobayashi M.a · Kubo S.a · Shiraki K.b · Iwata M.d · Hirano Y.a · Ohtsu Y.c · Takahashi K.a · Shimizu Y.a
aDrug Discovery Research, Pharmacology Research Labs, Astellas Pharma Inc., Tsukuba, bDrug Discovery Research, Drug Safety Research Labs and cDrug Metabolism Research Labs, Astellas Pharma Inc., Osaka, and dIntellectual Property, Astellas Pharma Inc., Tokyo, Japan

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 27, 2012
Accepted: July 31, 2012
Published online: September 13, 2012
Issue release date: October 2012

Number of Print Pages: 10
Number of Figures: 5
Number of Tables: 3

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA

Abstract

We investigated and compared the pharmacological effects of a PDE4 inhibitor ASP3258 (3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl] propanoic acid), with those of roflumilast, the most clinically advanced PDE4 inhibitor known. ASP3258 inhibited human PDE4A, 4B, 4C, and 4D with respective IC50 values of 0.036, 0.050, 0.45, and 0.035 nmol/l, all approximately 3–6 times more potent than roflumilast. ASP3258 inhibited LPS-induced TNF-α production and PHA-induced IL-5 production in human whole blood cells with respective IC50 values of 110 and 100 nmol/l, both approximately 10 times less potent than roflumilast. Repeatedly administered ASP3258 and roflumilast both suppressed chronic airway eosinophilia induced by repeated exposure to ovalbumin in Brown Norway rats with respective ED50 values of 0.092 and 0.17 mg/kg. We also evaluated the toxicological profiles of ASP3258. Although PDE4 inhibitors induce emesis by mimicking the pharmacological action of an α2-adrenoceptor antagonist, repeated administration of ASP3258 (3 mg/kg) had no such inhibitory effect on rats anesthetized with α2-adrenoceptor agonist. PDE4 inhibitors are also known to induce vascular injury in rats. Although repeatedly administered ASP3258 (3 and 10 mg/kg) significantly increased plasma fibrinogen, a biomarker for toxicity, 1 mg/kg of ASP3258 did not. These results suggest that ASP3258 is an attractive PDE4 inhibitor for treating chronic eosinophilic airway inflammation due to asthma.

© 2012 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 27, 2012
Accepted: July 31, 2012
Published online: September 13, 2012
Issue release date: October 2012

Number of Print Pages: 10
Number of Figures: 5
Number of Tables: 3

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.