The effect of chlormethiazole on neuronal damage in a model of transient focal ischaemia

Sydserff, S G; Cross, A.J.; West, Karl; Green, A.R.

doi:10.1111/j.1476-5381.1995.tb14950.x

Cited by 57 publications

(16 citation statements)

References 23 publications

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“…In global ischemia, its protective effect tended to disappear long-term and may have been mediated by hypothermia (Chaulk et al, 2003). Focal ischemia studies included a study of 1-h MCA suture occlusion in rats, followed by 24-h reperfusion, in which clomethiazole was given either 60 min prior to occlusion or at 10 min after the start of reperfusion (i.e., at 70 min after onset of ischemia) (Sydserff et al, 1995b). Histological protection was observed.…”

Section: Gaba Agonism: Clomethiazole Diazepammentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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Section: Gaba Agonism: Clomethiazole Diazepammentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Zingmark

Ekblom

Odergren

et al. 2003

Brit J Clinical Pharma

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Aims This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. Methods One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg -1 clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. Results Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V 1, Q, and V 2 was estimated to be 52.7 l h -1 , 82.5 l, 167 l h -1 and 335 l, respectively. The interindividual variability in CL, V 1, Q and V 2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h -1 kg -1 and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg -1 for V 1 and 4.7 l kg -1 for V 2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. Conclusions The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

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“…Ligation of the middle cerebral artery in rats for 60 min followed by a return to normal cerebral perfusion produces dramatic loss of cortical and striatal tissue on the side of the lesion (45). Following an i.p.…”

Section: Rodentsmentioning

confidence: 99%

The Pharmacology of Chlormethiazole: A Potential Neuroprotective Agent?

Wilby

Hutchinson

2004

CNS Drug Reviews

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Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.

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The effect of chlormethiazole on neuronal damage in a model of transient focal ischaemia

Cited by 57 publications

References 23 publications

Neuroprotection for ischemic stroke: Past, present and future

Neuroprotection for ischemic stroke: Past, present and future

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

The Pharmacology of Chlormethiazole: A Potential Neuroprotective Agent?

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