Background and Purpose: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers. We tested the safety and tolerability of ZK 200775 in patients with acute ischaemic stroke. Methods: In a multicentre double-blind, randomised, placebo-controlled phase II trial, 61 ischaemic stroke patients were treated with either placebo or active drug in a dose finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 h (group 1) and 13 patients received a total dose of 525 mg in 48 h (group 2), and 11 patients received a total dose of 105 mg over a period of 6 h (group 3). We studied the pharmacokinetics of the compound and the effect of the infusion on the neurologic and haemodynamic parameters of the patients. The study was not powered to detect neuroprotective efficacy. Results: In group 2 there was a significant transient worsening in the mean NIH stroke scale score 14– 18 h after the start of treatment. This was due to reduction of consciousness (stupor and coma) in 8 out of 13 patients. Level of consciousness improved approximately 6 h after cessation of infusion. No significant haemodynamic responses were observed. Even after reduction of the administered dose and duration of infusion to 6 h (group 3), 2 patients experienced a reduction in level of consciousness. The effect of ZK 200775 on level of consciousness gave cause for concern and the trial was stopped prematurely for safety reasons. Conclusions: The AMPA antagonist ZK 200775 reversibly worsened the neurological condition in patients with acute ischaemic stroke. Our results suggest that ZK 200775 exerts significant sedative effects in patients with acute stroke which preclude its further development as a neuroprotective agent in this indication.

Keywords:
Stroke, AMPA antagonist, Glasgow Coma Scale, NIHSS, Blood pressure
1.
Boast C, Gergardt S, Pastor G: The NMDA antagonists CGS 19755 and CPP reduce ischaemic brain damage in gerbils. Brain Res 1988;442:345–348.
2.
Kawasaki-Yatsugi S, Ichiki C, Yatsugi S, Shimizu-Sasamata M, Yamaguchi T: YM90K, an AMPA receptor antagonist, protects against ischaemic damage caused by permanent and transient middle cerebral artery occlusion in rats. Naunyn-Schmiedebergs Arch Pharmacol1998;358:586–591.
3.
Lees GJ: Pharmacology of AMPA/Kainate receptor ligands and their therapeutic potential in neurological and psychiatric disorders. Drugs 2000;59:33–78.
4.
Turski L, Huth A, Sheardown M, McDonald F, Neuhaus R, Schneider HH, Dirnagl U, Wiegand F, Jacobsen P, Ottow E: ZK 200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc Natl Acad Sci USA 1998;95:10960–10965.
5.
Xue D, Huang ZG, Barnes K, Lesiuk HJ, Smith KE, Buchan AM: Delayed treatment with AMPA, but not NMDA, antagonists reduces neocortical infarction. J Cereb Blood Flow Metab 1994;14:251–261.
6.
Unpublished Schering Research Report AG99. Explorative investigation of safety, tolerability, pharmacodynamics and pharmacokinetics after infusions of ZK 200775 with increasing doses in older subjects. 1999.
7.
Unpublished Schering Research Report AO13. Ophthalmologic examination after a 4-hour infusion with ZK 200775 in elderly healthy male subjects. 1999.
8.
Unpublished Schering Research Report AO12. Exploratory investigation of safety, tolerability, and steady-state kinetics after a 24-hour infusion with ZK 200775 in 55- to 65-year-old male volunteers when administered as a loading and subsequent maintenance dose. 1999.
9.
Unpublished Schering Research Report AR35. The influence of impaired kidney function on the pharmacokinetics of ZK 200775 after a 4-hour infusion of 10 mg/hour ZK 200775 in male volunteers in the age groups 40 to 59 and 60 to 80 in an open-labeled trial design. 1999.
10.
Dyker AG, Edwards KR, Fayad PB, Hormes JT, Lees KR: Safety and tolerability study of aptiganel hydrochloride in patients with an acute ischaemic stroke. Stroke 1999;30:2038–2042.
11.
Grotta J, Clark W, Coull B, Pettigrew LC, Mackay B: Safety and tolerability of GCS 19755 (Selfotel) in patients with acute ischaemic stroke: results of a phase IIa randomised trial. Stroke 1995;26:602–605.
12.
Unpublished Schering Expert Opinion ad Schering Research Report AO12. Dose-effect relationship simulation of brain concentrations after 24-h infusion of the AMPA antagonist ZK 200775 using EEG parameters within a pharmacokinetic 3-compartment model. 2000.
13.
Elting JW, Sulter A, Kaste M, Lees KR, Diener HC, Hommel M, De Keyser J, Teelken AW: The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels. Stroke2002;33:2813–2818.
14.
Walters MR, Bradford APJ, Dyker AG, Lees KR: A phase 1 study of the glutamate antagonist CNS 5161. Stroke 1999;30:P67.
© 2005 S. Karger AG, Basel
2005
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.
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.
You do not currently have access to this content.