Background: 619C89 is a use-dependent sodium channel blocker which reduces hemispheric infarction volume by up to 60% after permanent middle cerebral artery occlusion in rats. Intravenous doses of up to 1 mg/kg have been well tolerated by healthy young and elderly volunteers. This study sought to assess safety and tolerability of 619C89 in the treatment of acute stroke. Methods: Patients were randomised within 12 h of onset of stroke to receive 619C89 or placebo as an intravenous loading dose, followed by maintenance doses given 8 hourly for 64 h in a double-blind, ascending-dose tolerance study. Dosing commenced at 0.5 mg/kg loading plus 0.25 mg/kg/8 h maintenance for the first group and increased in increments of 0.5 mg/kg loading +0.25 mg/kg/8 h maintenance thereafter. Safety evaluation was continued for 3 months. Results: 48 patients were recruited. 12 received placebo and 36 received 619C89 in doses up to 2.5 mg/kg loading plus 1.25 mg/kg/8 h. Dose escalation was stopped after the occurrence of hallucinations in 5 of 18 patients who received 2 mg/kg +1 mg/kg/8 h or more. Gastro-intestinal upset and confusion were also possibly drug related. No drug-related effects on cardiovascular function were found. Conclusions: 619C89 was associated with significant central nervous system side-effects at doses of 2 mg/kg +1 mg/kg/8 h or greater as discrete intravenous infusions within 12 h of stroke onset. It may also cause gastro-intestinal side-effects. Doses below this are well tolerated in patients. No adverse cardiovascular effects were seen.

1.
Rothman SM: Synaptic activity mediates death of hypoxic neurons. Science 1983;220:536–537.
2.
Choi DW: Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 1985;58:293–297.
3.
Olney JR: Neurotoxicity of excitatory amino acids; in McGreer EG, Olney JW, McGreer PJ (eds): Kainic Acid as a Tool in Neurobiology. New York, Raven Press, 1978, pp 95–171.
4.
Park CK, Nehls DG, Graham DI, Teasdale GM, McCulloch J: The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 1988;24:543–551.
5.
Buchan AM, Lesiuk H, Barnes KA, Li H, Huang ZG, Smith KE, Xue D: AMPA antagonists: Do they hold more promise for clinical stroke trials than NMDA antagonists? Stroke 1993;24:I148–I152.
6.
Muir KW, Grosset DG, Gamzu E, Lees KR: Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers. Br J Clin Pharmacol 1994;38:33–38.
7.
Albers GW, Atkinson R, Kelley R, Rosenbaum DM: Safety, tolerability, and pharmacokinetics of the N-methyl D-aspartate antagonist dextrorphan in patients with an acute stroke. Neurology 1994;44(suppl 2):A270–A271.
8.
Muir KW, Lees KR: Clinical experience with excitatory amino acid antagonist drugs. Stroke 1995;26:503–513.
9.
Leach MJ, Swan JH, Eisenthal D, Dopson M, Nobbs M: BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke 1993;24:1063–1067.
10.
Smith SE, Lekieffre D, Sowinski P, Meldrum BS: Cerebroprotective effect of BW619C89 after focal or global cerebral ischaemia in the rat. Neuroreport 1993;4:1339–1342.
11.
Graham SH, Chen J, Lan J, Leach MJ, Simon RP: Neuroprotective effects of a use-dependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion. J Pharmacol Exp Ther 1994;269:854–859.
12.
Mercer AJ, Lamb RJ, Hussein Z, Hobbiger S, Posner J: The tolerability, pharmacokinetics and pharmacodynamics of increasing intravenous doses of 619C89, a novel compound for the acute treatment of stroke, in healthy volunteers. Ann NY Acad Sci 1995;765:324–326.
13.
Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Rorick M, Moomaw CJ, Walker M: Measurements of acute cerebral infarction: A clinical examination scale. Stroke 1989;20:864–870.
14.
Bamford J, Sandercock P, Dennis M, Burn J, Warlow C: Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991;337:1521–1526.
15.
Mahoney FI, Barthel DW: Functional evaluation: The Barthel index. Md State Med J 1965;14:61–65.
16.
Rankin J: Cerebral vascular accidents in patients over the age of 60. 2. Prognosis. Scott Med J 1957;2:200–215.
17.
Hussein Z, Fraser IJ, Lees KR, Muir KW, Lunnon MW, Hobbiger SF: Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions. Br J Clin Pharmacol 1996;41:505–511.
18.
Clark WM, Coull BM: Randomised trial of CGS19755, a glutamate antagonist, in acute ischemic stroke treatment. Neurology 1994;44(suppl 2):A270.
19.
White PF, Way WL, Trevor AJ: Ketamine – Its pharmacology and therapeutic uses. Anesthesiology 1982;56:119–136.
20.
Boyce S, Rupniak NMJ, Steventon MJ, Cook G, Iversen SD: Psychomotor activity and cognitive disruption attributable to NMDA, but not sigma, interactions in primates. Behav Brain Res 1991;42:115–121.
21.
Deutsch SI, Weizman A, Goldman ME, Morihisa JM: The sigma receptor: A novel site implicated in psychosis and antipsychotic drug efficacy. Clin Neuropharmacol 1988;11:105–119.
22.
Meldrum BS, Smith SE, Lekieffre D, Chapman AG, Graham JL, Pearce PC: Sodium channel blockade and glutamate release: The mechanism of cerebroprotection by lamotrigine, BW 1003C87 and BW 619C89; in Krieglstein J, Oberpichler-Schwenk H (eds): Pharmacology of Cerebral Ischemia. Stuttgart, Medpharm, 1994, pp 203–209.
23.
Takagi K, Ginsberg MD, Globus MYT, Dietrich WD, Martinez E, Kraydieh S, Busto R: Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat: Correlation with histopathology. J Cereb Blood Flow Metab 1993;13:575–585.
24.
Wahl F, Obrenovitch TP, Hardy AM, Plotkine M, Boulu RG, Symon L: Glutamate effluxes from the rat striatum during focal cerebral ischaemia: Time course and calcium dependency; in Krieglstein J, Oberpichler-Schwenk H (eds): Pharmacology of Cerebral Ischemia. Stuttgart, Medpharm, 1994, pp 157–164.
25.
Nicholls D, Attwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 1990;11:462–468.
26.
Fujisawa H, Dawson D, Browne SE, MacKay KB, Bullock R, McCulloch J: Pharmacological modification of glutamate neurotoxicity in vivo. Brain Res 1993;629:73–78.
27.
Obrenovitch TP, Urenjak J: Na+ channel blockade: An underrated approach to cerebroprotection; in Krieglstein J, Oberpichler-Schwenk H (eds): Pharmacology of Cerebral Ischemia. Stuttgart, Medpharm, 1994, pp 551–563.
28.
Baker AJ, Moulton RJ, MacMillan VH, Shedden PM: Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans. J Neurosurg 1993;79:369–372.
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.