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A R Green - One of the best experts on this subject based on the ideXlab platform.

  • neuroprotective efficacy of ar a008055 a Clomethiazole analogue in a global model of acute ischaemic stroke and its effect on ischaemia induced glutamate and gaba efflux in vitro
    Neuropharmacology, 2001
    Co-Authors: R M Nelson, A R Green, T K Murray, A J Cross, Jennifer Jones, Atticus H Hainsworth, David G Lambert, D A Richards, J Gabrielsson
    Abstract:

    Abstract We have investigated the neuroprotective properties of AR-A008055 [(±)-1-(4-methyl-5-thiazolyl-1-phenyl-methylamine], a novel compound structurally related to Clomethiazole. Administration (i.p.) of (±)-AR-A008055 60 min after 5 min of global cerebral ischaemia in gerbils produced a dose-dependent protection of the hippocampus from damage. Both enantiomers [(R)-(+)-AR-A008055 and (S)-(−)- AR-A008055] at 600 μmol/kg produced similar protection to that following Clomethiazole (600 μmol/kg) and both produced similar and sustained neuroprotection, at 4, 7 and 21 days post-insult. When infused intravenously over a 2-h period, both enantiomers produced concentration-dependent neuroprotection, with the enantiomers providing similar protection at every plasma concentration (50–200 nmol/ml). The efficacy of (S)-(−)-AR-A008055 was similar to Clomethiazole, but it was slightly less potent. Ischaemia-induced glutamate efflux from rat brain cortical prisms in vitro was inhibited by both isomers (100 μM). The inhibitory effect of (R)-(+)-AR-A008055 was blocked by bicuculline (10 μM) and picrotoxin (100 μM), while the effect of (S)-(−)-AR-A008055 was only antagonised by picrotoxin. This indicated that (S)-(−)-AR-A008055, like Clomethiazole, is able to open the GABAA-chloride channel in the absence of endogenous GABA. (R)-(+)-AR-A008055 was more potent than (S)-(−)-AR-A008055 in enhancing the concentration of GABA in the medium following 30 min exposure of tissue to the ischaemic conditions, suggesting that it is an effective GABA uptake inhibitor. This action may explain both its effect on glutamate efflux in vitro and its neuroprotective effect in vivo.

  • on the regulation of ischaemia induced glutamate efflux from rat cortex by gaba in vitro studies with gaba Clomethiazole and pentobarbitone
    British Journal of Pharmacology, 2000
    Co-Authors: R M Nelson, A R Green, David G Lambert, Atticus H Hainsworth
    Abstract:

    Prisms of adult rat cortex were maintained in vitro in either aerobic conditions (control) or conditions simulating an acute ischaemic challenge (hypoxia with no added glucose). Endogenous glutamate efflux increased with time in ischaemic conditions, being 2.7 fold higher than control efflux at 45 min. Returning prisms to control solution after 20 min of simulated ischaemia resulted in glutamate efflux returning to near-control values. Endogenous GABA efflux in ischaemic conditions also increased, being 4.5 fold higher than control efflux at 45 min. Ischaemia-induced glutamate efflux was not accompanied by increased lactate dehydrogenase efflux and was unaltered by omitting calcium from the extra-cellular solution and adding EGTA (0.1 mM). Both GABA and the GABA-mimetic Clomethiazole inhibited ischaemia-induced glutamate efflux, with IC(50) values of 26 and 24 microM respectively. The maximum inhibition by either drug was 60 - 70%. Bicuculline (10 microM) abolished the inhibitory effect of GABA (100 microM) but not Clomethiazole (100 microM). Picrotoxin (100 microM) abolished the action of both GABA and Clomethiazole. Pentobarbitone inhibited glutamate efflux at 100 - 300 microM (maximal inhibition: 39%). Bicuculline (10 microM) abolished this effect. These data suggest that ischaemia-induced glutamate efflux from rat cerebral cortex is calcium-independent and not due to cell damage up to 45 min. The inhibitory effect of GABA, Clomethiazole and pentobarbitone on ischaemia-induced glutamate efflux appears to be mediated by GABA(A) receptors. The results suggest that Clomethiazole, unlike pentobarbitone, is able to activate the GABAA receptor-linked chloride channel directly and not merely potentiate the effect of endogenous GABA.

  • Clomethiazole protects against hemineglect in a primate model of stroke
    Brain Research Bulletin, 2000
    Co-Authors: J W B Marshall, A R Green, A J Cross, D M Jackson, H F Baker, R M Ridley
    Abstract:

    Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in the marmoset, a New World species of monkey, produces unilateral functional deficits, including motor neglect with the contralesional arm and contralesional spatial hemineglect. In this study we examined whether Clomethiazole, a drug which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of the hemineglect and other deficits in this primate model of stroke. Nine monkeys received pMCAO; 1 h later four of the nine were administered Clomethiazole by intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps, which released Clomethiazole for 48 h. The monkeys had been trained and tested on a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks later. Three weeks after pMCAO, monkeys treated with Clomethiazole had a significantly reduced degree of spatial neglect compared to untreated controls. Clomethiazole was not effective against the severe contralesional motor impairment in the current study, although it ameliorated a somewhat less severe motor deficit in a previous study in which the more distal, M2 segment of the middle cerebral artery had been occluded. Postmortem analysis of the brains showed that Clomethiazole treatment had significantly reduced the area of damage in part of the parietal cortex. These data suggest that Clomethiazole may reduce the neglect that can be a debilitating consequence of right-sided stroke in man.

  • Clomethiazole is neuroprotective in models of global and focal cerebral ischemia when infused at doses producing clinically relevant plasma concentrations
    Brain Research, 2000
    Co-Authors: Simon Sydserff, A J Cross, T K Murray, Jennifer Jones, A R Green
    Abstract:

    Abstract We investigated the neuroprotective effect of infusing various doses of Clomethiazole in models of global and focal cerebral ischemia. In a model of global ischemia, gerbils were infused with Clomethiazole (intravenous), attaining steady state plasma concentrations of between 1 and 13 μM for 24 h. In a transient middle cerebral artery occlusion model in rats, Clomethiazole was administered subcutaneously over 22.75 h using osmotic minipumps producing steady state plasma concentrations of between 1 and 13 μM. Clomethiazole was protective in these models at plasma concentrations of respectively 6.1 μM and above and 3.5 μM and above. Clomethiazole is thus neuroprotective in both global and focal ischemia at plasma concentrations known to be well tolerated in stroke patients.

  • The metabolism of Clomethiazole in gerbils and the neuroprotective and sedative activity of the metabolites.
    British journal of pharmacology, 2000
    Co-Authors: A R Green, T K Murray, A. Misra, M.f. Snape, J.a Jones, Alan J. Cross
    Abstract:

    A single dose of Clomethiazole (600 micromol kg(-1) i.p.) has previously been shown to be neuroprotective in the gerbil model of global ischaemia. In gerbils, Clomethiazole (600 micromol kg(-1)) injection produced a rapid appearance (peak within 5 min) of drug in plasma and brain and similar clearance (plasma t(1/2): 40 min) from both tissues. The peak brain concentration (226+/-56 nmol g(-1)) was 40% higher than plasma. One major metabolite, 5-(1-hydroxyethyl-2-chloro)-4-methylthiazole (NLA-715) and two minor metabolites 5-(1-hydroxyethyl)-4-methylthiazole (NLA-272) and 5-acetyl-4-methylthiazole (NLA-511) were detected in plasma and brain. Evidence suggested that Clomethiazole is metabolized directly to both NLA-715 and NLA-272. Injection of NLA-715, NLA-272 or NLA-511 (each at 600 micromol kg(-1)) produced brain concentrations respectively 2.2, 38 and 92 times greater than seen after Clomethiazole (600 micromol kg(-1)). Clomethiazole (600 micromol kg(-1)) injected 60 min after a 5 min bilateral carotid artery occlusion in gerbils attenuated the ischaemia-induced degeneration of the hippocampus by approximately 70%. The metabolites were not neuroprotective at this dose. In mice, Clomethiazole (600 micromol kg(-1)) produced peak plasma and brain concentrations approximately 100% higher than in gerbils, drug concentrations in several brain regions were similar but 35% higher than plasma. Clomethiazole (ED(50): 180 micromol kg(-1)) and NLA-715 (ED(50): 240 micromol kg(-1)) inhibited spontaneous locomotor activity. The other metabolites were not sedative (ED(50) >600 micromol kg(-1)). These data suggest that the neuroprotective action of Clomethiazole results from an action of the parent compound and that NLA-715 contributes to the sedative activity of the drug. British Journal of Pharmacology (2000) 129, 95 - 100

Patrick D Lyden - One of the best experts on this subject based on the ideXlab platform.

  • measurement properties of the national institutes of health stroke scale for people with right and left hemisphere lesions further analysis of the Clomethiazole for acute stroke study ischemic class i trial
    Archives of Physical Medicine and Rehabilitation, 2007
    Co-Authors: Scott R Millis, Don D Straube, Cherdsak Iramaneerat, Everett V Smith, Patrick D Lyden
    Abstract:

    Abstract Millis SR, Straube D, Iramaneerat C, Smith EV Jr, Lyden P. Measurement properties of the National Institutes of Health Stroke Scale for people with right- and left-hemisphere lesions: further analysis of the Clomethiazole for Acute Stroke Study–Ischemic (Class-I) trial. Objective To assess the psychometric properties of the National Institutes of Health Stroke Scale (NIHSS) in people with either left or right acute hemisphere stroke for the purpose of improving the scale's sensitivity in detecting neurologic impairment. Design Secondary analysis of data from the Clomethiazole for Acute Stroke Study–Ischemic using the Rasch partial credit model. We evaluated the data's measurement properties using item-total correlations, Rasch item fit statistics, principle component analysis of standardized person and item residuals, differential item functioning, separation reliability, and the separation ratio. Setting Original data were collected in academic and community hospitals as part of a clinical trial. Participants People with acute ischemic stroke who were seen within 12 hours of onset: 380 people with left-hemisphere stroke and 347 with right-hemisphere stroke. Interventions Not applicable. Main Outcome Measure The NIHSS. Results Items of the NIHSS function differently in the right- and left-hemisphere lesion groups. We constructed for each group separate linear scales consisting of a subset of items of the NIHSS to improve its measurement properties. Conclusions Our findings provide initial support for the use of individual, targeted scales for measurement of impairment after ischemic stroke. Low person separation reliability may be a consequence of the sample, which included only people with large ischemic cortical strokes.

  • population pharmacokinetics of Clomethiazole and its effect on the natural course of sedation in acute stroke patients
    British Journal of Clinical Pharmacology, 2003
    Co-Authors: Per-henrik Zingmark, Mats O. Karlsson, Patrick D Lyden, Tim Ashwood, Tomas Odergren, Marianne Ekblom, Niclas E Jonsson
    Abstract:

    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, V1, Q, and V2 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, V1, Q and V2 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 V1 and 4.7 l kg−1 for V2). 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.

  • Clomethiazole acute stroke study in ischemic stroke class i final results
    Stroke, 2002
    Co-Authors: Patrick D Lyden, Ashfaq Shuaib, Tim Ashwood, Tomas Odergren, L Claesson, K Levin, Richard P Atkinson, A Rajput, Lawrence R Wechsler, E Salazargrueso
    Abstract:

    Background and Purpose — A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that Clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. Methods — A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to Clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index ≥60 at last follow-up as the primary outcome measure. Results — The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9±5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of ≥60 was 42% in the Clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P =0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of Clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug. Conclusions — The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

  • the Clomethiazole acute stroke study in tissue type plasminogen activator treated stroke class t final results
    Neurology, 2001
    Co-Authors: Patrick D Lyden, M Jacoby, J Schim, G Albers, P Mazzeo, Tim Ashwood, Anders Nordlund, Tomas Odergren
    Abstract:

    Objective: To assess the safety of tissue-type plasminogen activator (t-PA) plus Clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy. Background: Clomethiazole is a neuroprotectant that appeared to improve outcome in patients with clinical deficits of a major stroke (total anterior circulation syndrome [TACS]) in a previous study, the Clomethiazole Acute Stroke Study (CLASS). Combining a neuroprotectant such as Clomethiazole with thrombolysis may augment the beneficial effects of the two agents. CLASS–t-PA (CLASS-T) was a pilot study to explore the safety of the combination and the feasibility of performing combination treatment in the setting of acute ischemic stroke. Methods: In a randomized, double-blind design (stratified for age, severity at admission, and time since onset of stroke), all patients received 0.9 mg/kg t-PA beginning within 3 hours of stroke onset and then either 68 mg/kg Clomethiazole (n = 97) IV over 24 hours or placebo (n = 93) beginning within 12 hours of stroke onset. Patients were followed for 90 days. The main measures of safety were mortality and serious adverse events, and the main measure of functional outcome was the Barthel Index. Results: The number of serious adverse event reports was 47 in the Clomethiazole group and 48 in the placebo group. Death during the 90 days after treatment occurred in 15 Clomethiazole and nine placebo patients (p = 0.26). Sedation was reported as an adverse event during therapy in 42% of Clomethiazole patients vs 13% of placebo patients. The proportion of patients with TACS was 53% in the Clomethiazole group and 41% in the placebo group. In the TACS subgroup, 52.9% of the Clomethiazole patients scored a Barthel Index greater than 60 vs 44.7% of placebo patients (odds ratio 1.39; 95% CI 0.60 to 3.23). Conclusion: In this pilot study, there were no safety concerns related to the combination of t-PA and Clomethiazole. The combination paradigm proved feasible, although many patients received Clomethiazole several hours after thrombolysis; future studies must require prompt administration of the neuroprotectant either before or during administration of the thrombolytic. Patients with major strokes (TACS) may have the potential to benefit from the combination of t-PA and Clomethiazole.

  • the Clomethiazole acute stroke study in hemorrhagic stroke class h final results
    Journal of Stroke & Cerebrovascular Diseases, 2000
    Co-Authors: Patrick D Lyden, Ashfaq Shuaib, Timothy Ashwood, Anders Nordlund, Richard P Atkinson, Tomas Odergren
    Abstract:

    Abstract Background and Purpose: Clomethiazole (CMZ) is a neuroprotectant that may improve outcome in patients with acute major strokes. In a previous study that included 94 hemorrhagic stroke patients (CLASS), a mortality reduction and functional outcome favorable to CMZ was seen. We sought to establish the safety of CMZ in acute hemorrhagic stroke patients and to determine whether a trial of medical therapy for cerebral hemorrhage was feasible. Methods: The safety of CMZ (n = 96) versus a placebo (n = 102) in hemorrhagic stroke patients was evaluated in a randomized, double-blind trial. Treatment began after a computed tomography (CT) scan confirmed the presence of hemorrhage and within 12 hours from symptom onset. Patients received 68 mg/kg of CMZ intravenously over 24 hours. Safety was assessed by collecting serious adverse events (SAE), including deaths up to 90 days after treatment. Functional and neurologic outcome were also monitored. Results: Hemorrhage volumes were found to be similar between groups (26 ± 56 mL CMZ v 26 ± 35 mL placebo). Sedation was reported as an adverse event during therapy in 55% of the CMZ patients versus 13% of the placebo patients. The number of SAE reports was 53 in the CMZ group and 46 in the placebo group. Differences on functional outcome measures were minor. Death within 90 days occurred in 19 CMZ patients versus 11 placebo patients (Odds Ratio [OR] 2.04; 95% confidence interval [CI] 0.92, 4.55; P = .08). After adjusting for baseline covariate imbalances, the mortality difference was less apparent (OR 1.82; 95% CI 0.69, 4.81; P = .23). Conclusions: The feasibility of performing neuroprotectant trials for acute cerebral hemorrhage patients has been established, but requires careful balancing of important predictive indicators, including baseline severity, hematoma location, presence of intraventricular blood, and possibly, coumadin use. The clinical experience to date has identified no specific major safety concerns with the use of CMZ in acute hemorrhagic stroke patients. Additional clinical trials will be required to confirm safety and establish the efficacy of CMZ in acute hemorrhagic stroke patients.

Tomas Odergren - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetics of Clomethiazole and its effect on the natural course of sedation in acute stroke patients
    British Journal of Clinical Pharmacology, 2003
    Co-Authors: Per-henrik Zingmark, Mats O. Karlsson, Patrick D Lyden, Tim Ashwood, Tomas Odergren, Marianne Ekblom, Niclas E Jonsson
    Abstract:

    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, V1, Q, and V2 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, V1, Q and V2 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 V1 and 4.7 l kg−1 for V2). 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.

  • pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of Clomethiazole
    European Journal of Clinical Pharmacology, 2003
    Co-Authors: Carina Centerholt, Tomas Odergren, Marianne Ekblom, Olof Borga, Gabriela Popescu, Karlheinz Molz, Andrea Couturier, Angelika Weil
    Abstract:

    Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects. Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg Clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of Clomethiazole and its active α-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6. The fraction excreted unchanged in urine was less than 0.2% for Clomethiazole and less than 0.4% for NLA-715. Urine concentrations of Clomethiazole were strongly correlated (r2=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of Clomethiazole in all groups. Plasma clearance of Clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation. The reduced Clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of Clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.

  • Clomethiazole acute stroke study in ischemic stroke class i final results
    Stroke, 2002
    Co-Authors: Patrick D Lyden, Ashfaq Shuaib, Tim Ashwood, Tomas Odergren, L Claesson, K Levin, Richard P Atkinson, A Rajput, Lawrence R Wechsler, E Salazargrueso
    Abstract:

    Background and Purpose — A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that Clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. Methods — A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to Clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index ≥60 at last follow-up as the primary outcome measure. Results — The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9±5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of ≥60 was 42% in the Clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P =0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of Clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug. Conclusions — The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

  • the Clomethiazole acute stroke study in tissue type plasminogen activator treated stroke class t final results
    Neurology, 2001
    Co-Authors: Patrick D Lyden, M Jacoby, J Schim, G Albers, P Mazzeo, Tim Ashwood, Anders Nordlund, Tomas Odergren
    Abstract:

    Objective: To assess the safety of tissue-type plasminogen activator (t-PA) plus Clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy. Background: Clomethiazole is a neuroprotectant that appeared to improve outcome in patients with clinical deficits of a major stroke (total anterior circulation syndrome [TACS]) in a previous study, the Clomethiazole Acute Stroke Study (CLASS). Combining a neuroprotectant such as Clomethiazole with thrombolysis may augment the beneficial effects of the two agents. CLASS–t-PA (CLASS-T) was a pilot study to explore the safety of the combination and the feasibility of performing combination treatment in the setting of acute ischemic stroke. Methods: In a randomized, double-blind design (stratified for age, severity at admission, and time since onset of stroke), all patients received 0.9 mg/kg t-PA beginning within 3 hours of stroke onset and then either 68 mg/kg Clomethiazole (n = 97) IV over 24 hours or placebo (n = 93) beginning within 12 hours of stroke onset. Patients were followed for 90 days. The main measures of safety were mortality and serious adverse events, and the main measure of functional outcome was the Barthel Index. Results: The number of serious adverse event reports was 47 in the Clomethiazole group and 48 in the placebo group. Death during the 90 days after treatment occurred in 15 Clomethiazole and nine placebo patients (p = 0.26). Sedation was reported as an adverse event during therapy in 42% of Clomethiazole patients vs 13% of placebo patients. The proportion of patients with TACS was 53% in the Clomethiazole group and 41% in the placebo group. In the TACS subgroup, 52.9% of the Clomethiazole patients scored a Barthel Index greater than 60 vs 44.7% of placebo patients (odds ratio 1.39; 95% CI 0.60 to 3.23). Conclusion: In this pilot study, there were no safety concerns related to the combination of t-PA and Clomethiazole. The combination paradigm proved feasible, although many patients received Clomethiazole several hours after thrombolysis; future studies must require prompt administration of the neuroprotectant either before or during administration of the thrombolytic. Patients with major strokes (TACS) may have the potential to benefit from the combination of t-PA and Clomethiazole.

  • the Clomethiazole acute stroke study in hemorrhagic stroke class h final results
    Journal of Stroke & Cerebrovascular Diseases, 2000
    Co-Authors: Patrick D Lyden, Ashfaq Shuaib, Timothy Ashwood, Anders Nordlund, Richard P Atkinson, Tomas Odergren
    Abstract:

    Abstract Background and Purpose: Clomethiazole (CMZ) is a neuroprotectant that may improve outcome in patients with acute major strokes. In a previous study that included 94 hemorrhagic stroke patients (CLASS), a mortality reduction and functional outcome favorable to CMZ was seen. We sought to establish the safety of CMZ in acute hemorrhagic stroke patients and to determine whether a trial of medical therapy for cerebral hemorrhage was feasible. Methods: The safety of CMZ (n = 96) versus a placebo (n = 102) in hemorrhagic stroke patients was evaluated in a randomized, double-blind trial. Treatment began after a computed tomography (CT) scan confirmed the presence of hemorrhage and within 12 hours from symptom onset. Patients received 68 mg/kg of CMZ intravenously over 24 hours. Safety was assessed by collecting serious adverse events (SAE), including deaths up to 90 days after treatment. Functional and neurologic outcome were also monitored. Results: Hemorrhage volumes were found to be similar between groups (26 ± 56 mL CMZ v 26 ± 35 mL placebo). Sedation was reported as an adverse event during therapy in 55% of the CMZ patients versus 13% of the placebo patients. The number of SAE reports was 53 in the CMZ group and 46 in the placebo group. Differences on functional outcome measures were minor. Death within 90 days occurred in 19 CMZ patients versus 11 placebo patients (Odds Ratio [OR] 2.04; 95% confidence interval [CI] 0.92, 4.55; P = .08). After adjusting for baseline covariate imbalances, the mortality difference was less apparent (OR 1.82; 95% CI 0.69, 4.81; P = .23). Conclusions: The feasibility of performing neuroprotectant trials for acute cerebral hemorrhage patients has been established, but requires careful balancing of important predictive indicators, including baseline severity, hematoma location, presence of intraventricular blood, and possibly, coumadin use. The clinical experience to date has identified no specific major safety concerns with the use of CMZ in acute hemorrhagic stroke patients. Additional clinical trials will be required to confirm safety and establish the efficacy of CMZ in acute hemorrhagic stroke patients.

B Esteban - One of the best experts on this subject based on the ideXlab platform.

  • studies on the neuroprotective effect of the enantiomers of ar a008055 a compound structurally related to Clomethiazole on mdma ecstasy induced neurodegeneration in rat brain
    Psychopharmacology, 2001
    Co-Authors: Isabel M Colado, Esther Oshea, B Esteban, Richard A Green
    Abstract:

    Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") administration produces neurotoxic degeneration of 5-HT nerve endings in several regions of rat brain. Administration of the GABAmimetic drug Clomethiazole protects against this damage. Objective: We wished to see whether the enantiomers of AR-A008055 (1-4-methyl-5-thiazolyl-1-phenyl-methylamine), a compound structurally related to Clomethiazole, were also neuroprotective against MDMA-induced degeneration. Methods: (R)-(+)-AR-A008055 or (S)-(–)-AR-A008055 (100 mg/kg IP) was injected 5 min prior to and 55 min after MDMA (15 mg/kg IP) administration to Dark Agouti rats. Rectal temperature was measured during this time and the concentration of 5-HT and 5-HIAA measured in hippocampus, cortex and striatum 7 days later. [3H]-Paroxetine binding was also measured in cortex. Results: Both enantiomers abolished the acute MDMA-induced hyperthermia and attenuated the subsequent neurotoxic loss of 5-HT, 5-HIAA and [3H]-paroxetine binding. When rats given the enantiomer plus MDMA were warmed to keep their rectal temperature elevated to near that of animals given only MDMA, the neuroprotective effect of (S)-(–)-AR-A008055 was still seen, while the effect of (R)-(+)-AR-A008055 was abolished. Protection was also seen when (S)-(–)-AR-A008055 (50 mg/kg) was given, a dose which produced only a modest attenuation of MDMA-induced hyperthermia. Conclusions: The current data suggest that a major proportion of the neuroprotective action of (S)-(–)-AR-A008055 did not involve an attenuating effect on MDMA-induced hyperthermia. The protection afforded by (R)-(+)-AR-A008055, which is not a GABA agonist, appears to be solely due to its action on body temperature, strengthening the contention that abolishing the acute MDMA-induced hypothermia can produce neuroprotection. Since (S)-(–)-AR-A008055 has a similar pharmacology to Clomethiazole, these data suggest that drugs which increase GABAA receptor channel opening are neuroprotective against MDMA-induced damage.

  • studies on the role of dopamine in the degeneration of 5 ht nerve endings in the brain of dark agouti rats following 3 4 methylenedioxymethamphetamine mdma or ecstasy administration
    British Journal of Pharmacology, 1999
    Co-Authors: M I Colado, Esther Oshea, R Granados, B Esteban, A B Martin, A R Green
    Abstract:

    1. We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration. 2. Haloperidol (2 mg kg(-1) i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg(-1) i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA + haloperidol treated rats was kept elevated, this protective effect was marginal. 3. MDMA (15 mg kg(-1)) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg(-1) i.p., plus benserazide, 6.25 mg kg(-1) i.p.) injected 2 h after MDMA (15 mg kg(-1)) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg(-1)) injected before a sub-toxic dose of MDMA (5 mg kg(-1)) failed to induce neurodegeneration. 4. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5. The neuroprotective drug Clomethiazole (50 mg kg(-1) i.p.) did not influence the MDMA-induced increase in extracellular dopamine. 6. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. 7. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an 'amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.

  • in vivo evidence against Clomethiazole being neuroprotective against mdma ecstasy induced degeneration of rat brain 5 ht nerve terminals by a free radical scavenging mechanism
    Neuropharmacology, 1999
    Co-Authors: M I Colado, Esther Oshea, R Granados, B Esteban, A R Green
    Abstract:

    Clomethiazole is an effective neuroprotective agent against the degeneration of 5-HT neurones that follows administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). Since there is good evidence that free radical formation resulting from auto-oxidation of MDMA metabolites is responsible for the degeneration we have examined whether Clomethiazole is a free radical scavenger. MDMA (15 mg/kg i.p.) increased the formation of 2,3- and 2,5-dihydroxybenzoic acids (2,3-DHBA and 2,5-DHBA) from salicylic acid perfused through a microdialysis tube implanted in the hippocampus, indicating increased free radical formation. Clomethiazole (50 mg/kg i.p.) administered 5 min prior and 55 min post MDMA prevented both the acute MDMA-induced hyperthermia and the rise in 2,3- and 2,5-DHBA. However, when the temperature of the MDMA + Clomethiazole treated rats was kept elevated to that of the MDMA treated rats with a homeothermic blanket there was no inhibition of the MDMA-induced increase in 2,3-DHBA or 2,5-DHBA. These data suggest firstly that free radical formation is inhibited when the acute MDMA-induced hyperthermia is prevented. Secondly the data further indicate that Clomethiazole has no free radical scavenging activity since the drug produces substantial neuroprotection when MDMA + Clomethiazole treated rats are kept hyperthermic. This conclusion was strengthened by our observation that Clomethiazole is a weak inhibitor (IC50 > 1 mM) of lipid peroxidation in synaptosomes when it had been induced by addition of FeCl2 + ascorbic acid.

  • role of hyperthermia in the protective action of Clomethiazole against mdma ecstasy induced neurodegeneration comparison with the novel nmda channel blocker ar r15896ar
    British Journal of Pharmacology, 1998
    Co-Authors: M I Colado, Esther Oshea, R Granados, B Esteban, A R Green
    Abstract:

    1. The immediate effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on rectal temperature and the effect of putative neuroprotective agents on this change has been examined in rats. The influence of the temperature changes on the long term MDMA-induced neurodegeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals was also examined. 2. The novel low affinity N-methyl-D-aspartate (NMDA) receptor channel blocker AR-R15896AR (20 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1), i.p.) did not prevent the MDMA-induced hyperthermia and did not alter either the MDMA-induced neurodegenerative loss of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, striatum and hippocampus or loss of [3H]-paroxetine binding in cortex 7 days later. 3. The neuroprotective agent Clomethiazole (50 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1)) abolished the MDMA-induced hyperthermic response and markedly attenuated the loss of 5-HT, 5-HIAA and [3H]-paroxetine binding in the brain regions examined 7 days later. 4. When rats treated with MDMA plus Clomethiazole were kept at high ambient temperature for 5 h post-MDMA, thereby keeping their body temperature elevated to near that seen in rats given MDMA alone, the MDMA-induced loss of 5-HT, 5-HIAA and [3H]-paroxetine was still attenuated. However, the protection (39%) afforded by the Clomethiazole administration was less than seen in rats kept at normal ambient temperature (75%). 5. These data support the proposals of others that NMDA receptor antagonists are neuroprotective against MDMA-induced degeneration only if they induce hypothermia and further suggest that increased glutamate activity may not be involved in the neurotoxic action of MDMA. 6. These data further demonstrate that a proportion of the neuroprotective action of Clomethiazole is due to an effect on body temperature but that, in addition, the compound protects against MDMA-induced damage by an unrelated mechanism.

Esther Oshea - One of the best experts on this subject based on the ideXlab platform.

  • studies on the neuroprotective effect of the enantiomers of ar a008055 a compound structurally related to Clomethiazole on mdma ecstasy induced neurodegeneration in rat brain
    Psychopharmacology, 2001
    Co-Authors: Isabel M Colado, Esther Oshea, B Esteban, Richard A Green
    Abstract:

    Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") administration produces neurotoxic degeneration of 5-HT nerve endings in several regions of rat brain. Administration of the GABAmimetic drug Clomethiazole protects against this damage. Objective: We wished to see whether the enantiomers of AR-A008055 (1-4-methyl-5-thiazolyl-1-phenyl-methylamine), a compound structurally related to Clomethiazole, were also neuroprotective against MDMA-induced degeneration. Methods: (R)-(+)-AR-A008055 or (S)-(–)-AR-A008055 (100 mg/kg IP) was injected 5 min prior to and 55 min after MDMA (15 mg/kg IP) administration to Dark Agouti rats. Rectal temperature was measured during this time and the concentration of 5-HT and 5-HIAA measured in hippocampus, cortex and striatum 7 days later. [3H]-Paroxetine binding was also measured in cortex. Results: Both enantiomers abolished the acute MDMA-induced hyperthermia and attenuated the subsequent neurotoxic loss of 5-HT, 5-HIAA and [3H]-paroxetine binding. When rats given the enantiomer plus MDMA were warmed to keep their rectal temperature elevated to near that of animals given only MDMA, the neuroprotective effect of (S)-(–)-AR-A008055 was still seen, while the effect of (R)-(+)-AR-A008055 was abolished. Protection was also seen when (S)-(–)-AR-A008055 (50 mg/kg) was given, a dose which produced only a modest attenuation of MDMA-induced hyperthermia. Conclusions: The current data suggest that a major proportion of the neuroprotective action of (S)-(–)-AR-A008055 did not involve an attenuating effect on MDMA-induced hyperthermia. The protection afforded by (R)-(+)-AR-A008055, which is not a GABA agonist, appears to be solely due to its action on body temperature, strengthening the contention that abolishing the acute MDMA-induced hypothermia can produce neuroprotection. Since (S)-(–)-AR-A008055 has a similar pharmacology to Clomethiazole, these data suggest that drugs which increase GABAA receptor channel opening are neuroprotective against MDMA-induced damage.

  • studies on the role of dopamine in the degeneration of 5 ht nerve endings in the brain of dark agouti rats following 3 4 methylenedioxymethamphetamine mdma or ecstasy administration
    British Journal of Pharmacology, 1999
    Co-Authors: M I Colado, Esther Oshea, R Granados, B Esteban, A B Martin, A R Green
    Abstract:

    1. We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration. 2. Haloperidol (2 mg kg(-1) i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg(-1) i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA + haloperidol treated rats was kept elevated, this protective effect was marginal. 3. MDMA (15 mg kg(-1)) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg(-1) i.p., plus benserazide, 6.25 mg kg(-1) i.p.) injected 2 h after MDMA (15 mg kg(-1)) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg(-1)) injected before a sub-toxic dose of MDMA (5 mg kg(-1)) failed to induce neurodegeneration. 4. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5. The neuroprotective drug Clomethiazole (50 mg kg(-1) i.p.) did not influence the MDMA-induced increase in extracellular dopamine. 6. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. 7. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an 'amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.

  • in vivo evidence against Clomethiazole being neuroprotective against mdma ecstasy induced degeneration of rat brain 5 ht nerve terminals by a free radical scavenging mechanism
    Neuropharmacology, 1999
    Co-Authors: M I Colado, Esther Oshea, R Granados, B Esteban, A R Green
    Abstract:

    Clomethiazole is an effective neuroprotective agent against the degeneration of 5-HT neurones that follows administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). Since there is good evidence that free radical formation resulting from auto-oxidation of MDMA metabolites is responsible for the degeneration we have examined whether Clomethiazole is a free radical scavenger. MDMA (15 mg/kg i.p.) increased the formation of 2,3- and 2,5-dihydroxybenzoic acids (2,3-DHBA and 2,5-DHBA) from salicylic acid perfused through a microdialysis tube implanted in the hippocampus, indicating increased free radical formation. Clomethiazole (50 mg/kg i.p.) administered 5 min prior and 55 min post MDMA prevented both the acute MDMA-induced hyperthermia and the rise in 2,3- and 2,5-DHBA. However, when the temperature of the MDMA + Clomethiazole treated rats was kept elevated to that of the MDMA treated rats with a homeothermic blanket there was no inhibition of the MDMA-induced increase in 2,3-DHBA or 2,5-DHBA. These data suggest firstly that free radical formation is inhibited when the acute MDMA-induced hyperthermia is prevented. Secondly the data further indicate that Clomethiazole has no free radical scavenging activity since the drug produces substantial neuroprotection when MDMA + Clomethiazole treated rats are kept hyperthermic. This conclusion was strengthened by our observation that Clomethiazole is a weak inhibitor (IC50 > 1 mM) of lipid peroxidation in synaptosomes when it had been induced by addition of FeCl2 + ascorbic acid.

  • role of hyperthermia in the protective action of Clomethiazole against mdma ecstasy induced neurodegeneration comparison with the novel nmda channel blocker ar r15896ar
    British Journal of Pharmacology, 1998
    Co-Authors: M I Colado, Esther Oshea, R Granados, B Esteban, A R Green
    Abstract:

    1. The immediate effect of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on rectal temperature and the effect of putative neuroprotective agents on this change has been examined in rats. The influence of the temperature changes on the long term MDMA-induced neurodegeneration of cerebral 5-hydroxytryptamine (5-HT) nerve terminals was also examined. 2. The novel low affinity N-methyl-D-aspartate (NMDA) receptor channel blocker AR-R15896AR (20 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1), i.p.) did not prevent the MDMA-induced hyperthermia and did not alter either the MDMA-induced neurodegenerative loss of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, striatum and hippocampus or loss of [3H]-paroxetine binding in cortex 7 days later. 3. The neuroprotective agent Clomethiazole (50 mg kg(-1), i.p.) given 5 min before and 55 min after MDMA (15 mg kg(-1)) abolished the MDMA-induced hyperthermic response and markedly attenuated the loss of 5-HT, 5-HIAA and [3H]-paroxetine binding in the brain regions examined 7 days later. 4. When rats treated with MDMA plus Clomethiazole were kept at high ambient temperature for 5 h post-MDMA, thereby keeping their body temperature elevated to near that seen in rats given MDMA alone, the MDMA-induced loss of 5-HT, 5-HIAA and [3H]-paroxetine was still attenuated. However, the protection (39%) afforded by the Clomethiazole administration was less than seen in rats kept at normal ambient temperature (75%). 5. These data support the proposals of others that NMDA receptor antagonists are neuroprotective against MDMA-induced degeneration only if they induce hypothermia and further suggest that increased glutamate activity may not be involved in the neurotoxic action of MDMA. 6. These data further demonstrate that a proportion of the neuroprotective action of Clomethiazole is due to an effect on body temperature but that, in addition, the compound protects against MDMA-induced damage by an unrelated mechanism.