The protective action of chlormethiazole against ischaemia‐induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity

Abstract

Sweden1 The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied.2 Chlormethiazole (600 pmol kg-', i.p.) given 60 min after ischaemia produced substantial (>60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3 Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 pmol kg-') was then infused intravenously for 30 min, 76.5 min or 10 min in ways resulting in sustained plasma concentrations of 200, 100 and 50 nmol ml-' respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml' were sustained for 10 min with no protection observed at 10 nmol ml'. 4 In contrast, when a plasma concentration of 10 nmol mlh was sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5 These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.

An Open Study of Clomethiazole in Patients with Acute Cerebral Infarction

“…Recent animal studies have demonstrated neuroprotective properties of clomethiazole following transient global ischemia in the gerbil [1, 2] as well as temporary [3] and permanent [4, 5] focal ischemia, ischemic brain edema [6] and certain drug-induced neurotoxicities in the rat [7]. Clomethiazole is a drug with sedative properties.…”

An Investigation of the Possible Interaction of Clomethiazole with Glutamate and Ion Channel Sites as an Explanation of its Neuroprotective Activity*

“…We found that the metabotropic glutamate receptor agonist ACPD stimulated phosphoinositol hydrolysis in an L-AP3-dependent manner, although L-AP3 did not completely inhibit hydrolysis and, when added alone, L-AP3 had a weak stimulatory action, supporting the suggestion that it might be a partial agonist (Irving et al 1990). While clomethiazole was found to also inhibit the stimulatory effect of ACPD it did so only at a concentration (10-3M) which is unlikely to have functional relevance, given the fact that neuroprotection can be achieved in vivo at a plasma concentration of approximately lO-'M (Cross et al 1995). However not all metabotropic glutamate receptor subtypes stimulate phosphoinositol hydrolysis (Schoepp & Conn 1993), so we cannot, at present, totally exclude an interaction of clomethiazole with other metabotropic glutamate receptor subtypes.…”

Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients

“…Clomethiazole has been shown to have neuroprotective effects in rat, gerbil, and marmoset models of cerebral ischaemia [6][7][8][9][10][11][12]. These findings suggested that clomethiazole might prevent neuronal degeneration following ischaemic stroke and the drug has undergone clinical development as a potential treatment.…”