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3-33-01 Lubeluzole in acute ischemic stroke: International trial
Neuroprotection 3-42-08
Effect of diethyldithiocarbamate on iminodipropionitrile induced movement rats
M. Tariq, S. Al Deeb, K. Al Moutaery. Neuroscience Forces Hospital, Riyadh, Saudi Arabia
Research
3-43-02 disorders Group,
in
Armed
Studies on movement disorders have acquired greater importance during the past decade because of its occurance in almost epidemic proportion and the evidence that its prevalence may be increasing. Tardive dyskinesia is one of the major movement disorders which affects up to 20% of patients treated chronically with neuroleptic agents, inspite of numerous studies undertaken to investigate the mechanism of manifestation of abnormal movements, the manner by which neuroanatomical lesions and/or specific biochemical abnormalities lead to the manifestation of dyskinetic signs remains to be elucidated. Several studies suggest that reactive oxygen species are implicated in the pathogenesis of drug induced dyskinesia and antioxidants have been shown to protect neuronal cell against neurotoxic agents. The present investigation was undertaken to study the effect of diethyldithiocarbamate, an effective inhibitor of superoxide dismutase in brain on experimental dyskinesia in rats. The movement disorders in rats were produced by intraperitoneal administration of iminodipropionitrile (IDPN) in the dose of 100 mgncs per day for 12 days. Diethyldithiocarbamate was administered daily 30 minutes before IDPN in the doses of 25, 50 and 100 mg/kg bodyweight in different groups of rats. Animals were observed daily for any neurobehavioral changes including circling, backwalking, head weaving and twitching, motor activity, gait and grip strength. Immediately after behavioral studies animals were sacrificed, blood and brain specimens were collected for the analysis of cr-tocopherol, conjugated dienes and lipid hydroperoxide levels to measure the extent of oxidative stress. Our results showed that concurrent use of diethyldithiocarbamate significantly exacerbated IDPN induced dyskinetic changes in a dose dependent manner. Our biochemical studies suggest the involvement of free radicals in IDPN induced dyskinesia. It is suggested that antioxidants may play an important role in neuroleptic drug induced dyskinesia and antioxidants may attenuate this condition.
43
Neuroprotection
3-43-01 IZI
Lubeluzole trial
in acute ischemic stroke: international
H.C. Diener, M. Kaste, W. Hacke, P. Koudstaal, M. Hennetici for the LUB-INT-5 Lubeluzole Study Group. University of Essen, Essen, Germanx University of Helsinki, Helsinki, Finland, University of Heidelberg, Heidelberg, Germany, University of Rotterdam, Rotterdam, The Netherlands, Klinikum Mannheim, Mannheim, Germany Lubeluzole, a novel neuroprotective agent, was shown in preclinical models to alleviate neuronal damage and reduce lesion volume when administered up to 6 hours following stroke symptom onset. Lubeluzole interferes with key biochemical mechanisms that lead to irreversible tissue damage in the penumbra. In a phase II, double-blind, placebo-controlled trial in 232 patients, lubeluzole (7.5 mg over 1 hour followed by a continuous daily infusion IO mg for 5 days) was safe and significantly reduced mortality in ischemic stroke patients. In this 12-week, multicenter, double-blind, placebo-controlled, parallelgroup trial, conducted in Europa and Australia, 725 patients with acute ischemic stroke were randomized to receive lubeluzole (7.5 mg over 1 hour, followed by 10 mg/day for up to 5 days) or placebo within 6 hours of the onset of symptoms. The primary efficacy endpoint was mortality over 12 weeks. Secondary efficacy endpoints included functional recovery (the Barthel Index), neurologic recovery (the European Stroke Scale), and general outcome (the Fiankin Scale). Safety was evaluated by ECG parameters, clinical laboratory assessments, vital sign measurements, and adverse experience reports. Based on the defined endpoints, there were no significant differences in outcomes between the two treatments. Subgroup analyses revealed that patients over 75 years of age with a severe Clinical Global Impression of Stroke rating had a poor prognosis regardless of the treatment. When these patients were excluded from the analyses, lubeluzole was found to result in a significant reduction in mortality. No differences were found between the treatment groups in safety parameters.
s199 The efficacy and safety of lubeluzole with acute ischemic stroke
J. Grotta for the LUB-INT-9 Medical School at Houston,
Lubeluzole Study Group. Houston, T%, USA
in patients
University
of Texas
Lubeluzole is a novel neuroprotective agent in clinical development for the treatment of acute ischemic stroke. Preclinical models have shown that lubeluzole can alleviate neuronal damage and reduce lesion volume, when administered intravenously up to 6 hours following stroke onset. From these animal studies it wasconcluded that lubeluzole interferes with key biochemical mechanisms that lead to irreversible tissue damage in the penumbra, including the downstream neurotoxic effects of nitric oxide and the increase in extracellular glutamate following ischemia. Results of a phase II double-blind, placebo-controlled trial in 232 patients showed that lubeluzole treatment, at a dosage regimen of 7.5 mg over 1 hour followed by a continuous daily infusion of lubeluzole 10 mg for 5 days, was safe and significantly reduced mortality. This study is a la-week, multicenter, randomized, double-blind, placebocontrolled, parallel-group trial conducted in the United States and Canada in 700 patients with a clinical diagnosis of ischemic stroke. Patients were randomized to receive either lubeluzole (7.5 mg over 1 hour followed by 10 mgfday for 5 days) or placebo treatment within 6 hours of stroke onset. 12-week mortality was chosen as the primary efficacy endpoint, whereas secondary efficacy endpoints included neurologic recovery (measured by the NIH Stroke Scale), functional recovery (measured by the Barthel Index), and overall disability (measured by the Rankin Scale). The safety of lubeluzole was evaluated by continuous and standard ECG monitoring, clinical laboratory assessments, vital sign measurements, and adverse events reports. Lubeluzole resulted in a reduction in mortality and significant improvement on the Barthel Index for functionality, the NIH Stroke Scale for neurologic recovery, and the Rankin Scale for disability, without increased safety concerns.
3-43-03
Cerebral
pellagra revisited
A.H. Koeppen, A.C. Dickson, K.D. Barron, C.Y. Lee, H. Hartmann. Center, Albany. N. Y 12208, USA, University of Wisconsin Medical Madison, WI 53706, USA
VA Medics/ School,
Epidemic pellagra with the characteristic cutaneous lesions has largely disappeared from developed countries but encephalopathy due to deficiency of nicotinamide still occurs in patients with malnutrition in the course of alcoholism. Since nicotinamide is a metabolite of tryptophan, pellagra should be considered a result of inadequate intake of this essential amino acid. Uncommon other causes are antituberculous treatment with isoniazid or inherited enzyme defects in tryptophan metabolism. Physicians may fail to diagnose brain pellagra because they are not familiar with the disorder, and the diagnostic skin lesion may be absent. The characteristic lesion in the brain is central chromatolysis of selected nerve cells. Bizarre expansion and rounding of Betz cells is invariably present but chromatolysis also affects other nerve cell groups of brain stem and spinal cord. In four cases of brain pellagra, the central nervous system was studied by routine cell stains, immunocytochemistry, and lectin affinity cytochemistry. Electron microscopy of Betz cells and the neurons of the lateral cuneate nucleus was possible in one case. Chromatolytic neurons showed no accumulation of phosphorylated neurofilament protein or ubiquitin, or loss of non-phosphorylated neurofilament protein. The lesion did no? cause a microglial response as assessed by affinity cytochemistry with biotinylated Ricinus communis agglutinin. An astroglial response was also absent. The Golgi apparatus identified by AaBs immunocytochemistry was retispersed in chromatolyzed cells. Ultrastructural examination confirmed central chromatolysis and retention of the endoplasmic reticulum near the neuronal nuclei. These observations are compatible with an axonal locus for the metabolic injury, leading to the described pellagroid cell change.
3-43-04
Glia conditioned medium protects dopamine neurons in culture from apoptosis and MPP+ neurotoxicity
M.A. Mena, M.J. Casarejos, J.G. de Yebenes. Departamento de Investigation, Hospital Ramon y Caja/, Madrid, Spain, Servicio de Neurologia, Fundacion Jimenez Dia.?, Madrid, Spain Apoptosis has been implicated in neuronal death in Parkinson’s disease (PD) and I-methyl-4-phenylpyridinium (MPP+) neurotoxicity Glia protects dopamine (DA) neurons from different insults. Fetal midbrain neuronal cultures were treated with MPP+, 10 PM, for 24 hours, in the presence or absence of mesencephalic glia conditioned medium (GCM). In the absence of GCM, MPP+ greatly reduced the number of tyrosine hydroxylase immunoreactive (THIR) neurons an increased the number of apoptotic cells. GCM prevented these effects of MPP+ and increased the length and arborization of neurites of the THIR. The effects of GCM on DA neurons were mediated, at least in part, by inhibition of apoptosis. The num-
Effect of diethyldithiocarbamate on iminodipropionitrile induced movement rats
M. Tariq, S. Al Deeb, K. Al Moutaery. Neuroscience Forces Hospital, Riyadh, Saudi Arabia
Research
3-43-02 disorders Group,
in
Armed
Studies on movement disorders have acquired greater importance during the past decade because of its occurance in almost epidemic proportion and the evidence that its prevalence may be increasing. Tardive dyskinesia is one of the major movement disorders which affects up to 20% of patients treated chronically with neuroleptic agents, inspite of numerous studies undertaken to investigate the mechanism of manifestation of abnormal movements, the manner by which neuroanatomical lesions and/or specific biochemical abnormalities lead to the manifestation of dyskinetic signs remains to be elucidated. Several studies suggest that reactive oxygen species are implicated in the pathogenesis of drug induced dyskinesia and antioxidants have been shown to protect neuronal cell against neurotoxic agents. The present investigation was undertaken to study the effect of diethyldithiocarbamate, an effective inhibitor of superoxide dismutase in brain on experimental dyskinesia in rats. The movement disorders in rats were produced by intraperitoneal administration of iminodipropionitrile (IDPN) in the dose of 100 mgncs per day for 12 days. Diethyldithiocarbamate was administered daily 30 minutes before IDPN in the doses of 25, 50 and 100 mg/kg bodyweight in different groups of rats. Animals were observed daily for any neurobehavioral changes including circling, backwalking, head weaving and twitching, motor activity, gait and grip strength. Immediately after behavioral studies animals were sacrificed, blood and brain specimens were collected for the analysis of cr-tocopherol, conjugated dienes and lipid hydroperoxide levels to measure the extent of oxidative stress. Our results showed that concurrent use of diethyldithiocarbamate significantly exacerbated IDPN induced dyskinetic changes in a dose dependent manner. Our biochemical studies suggest the involvement of free radicals in IDPN induced dyskinesia. It is suggested that antioxidants may play an important role in neuroleptic drug induced dyskinesia and antioxidants may attenuate this condition.
43
Neuroprotection
3-43-01 IZI
Lubeluzole trial
in acute ischemic stroke: international
H.C. Diener, M. Kaste, W. Hacke, P. Koudstaal, M. Hennetici for the LUB-INT-5 Lubeluzole Study Group. University of Essen, Essen, Germanx University of Helsinki, Helsinki, Finland, University of Heidelberg, Heidelberg, Germany, University of Rotterdam, Rotterdam, The Netherlands, Klinikum Mannheim, Mannheim, Germany Lubeluzole, a novel neuroprotective agent, was shown in preclinical models to alleviate neuronal damage and reduce lesion volume when administered up to 6 hours following stroke symptom onset. Lubeluzole interferes with key biochemical mechanisms that lead to irreversible tissue damage in the penumbra. In a phase II, double-blind, placebo-controlled trial in 232 patients, lubeluzole (7.5 mg over 1 hour followed by a continuous daily infusion IO mg for 5 days) was safe and significantly reduced mortality in ischemic stroke patients. In this 12-week, multicenter, double-blind, placebo-controlled, parallelgroup trial, conducted in Europa and Australia, 725 patients with acute ischemic stroke were randomized to receive lubeluzole (7.5 mg over 1 hour, followed by 10 mg/day for up to 5 days) or placebo within 6 hours of the onset of symptoms. The primary efficacy endpoint was mortality over 12 weeks. Secondary efficacy endpoints included functional recovery (the Barthel Index), neurologic recovery (the European Stroke Scale), and general outcome (the Fiankin Scale). Safety was evaluated by ECG parameters, clinical laboratory assessments, vital sign measurements, and adverse experience reports. Based on the defined endpoints, there were no significant differences in outcomes between the two treatments. Subgroup analyses revealed that patients over 75 years of age with a severe Clinical Global Impression of Stroke rating had a poor prognosis regardless of the treatment. When these patients were excluded from the analyses, lubeluzole was found to result in a significant reduction in mortality. No differences were found between the treatment groups in safety parameters.
s199 The efficacy and safety of lubeluzole with acute ischemic stroke
J. Grotta for the LUB-INT-9 Medical School at Houston,
Lubeluzole Study Group. Houston, T%, USA
in patients
University
of Texas
Lubeluzole is a novel neuroprotective agent in clinical development for the treatment of acute ischemic stroke. Preclinical models have shown that lubeluzole can alleviate neuronal damage and reduce lesion volume, when administered intravenously up to 6 hours following stroke onset. From these animal studies it wasconcluded that lubeluzole interferes with key biochemical mechanisms that lead to irreversible tissue damage in the penumbra, including the downstream neurotoxic effects of nitric oxide and the increase in extracellular glutamate following ischemia. Results of a phase II double-blind, placebo-controlled trial in 232 patients showed that lubeluzole treatment, at a dosage regimen of 7.5 mg over 1 hour followed by a continuous daily infusion of lubeluzole 10 mg for 5 days, was safe and significantly reduced mortality. This study is a la-week, multicenter, randomized, double-blind, placebocontrolled, parallel-group trial conducted in the United States and Canada in 700 patients with a clinical diagnosis of ischemic stroke. Patients were randomized to receive either lubeluzole (7.5 mg over 1 hour followed by 10 mgfday for 5 days) or placebo treatment within 6 hours of stroke onset. 12-week mortality was chosen as the primary efficacy endpoint, whereas secondary efficacy endpoints included neurologic recovery (measured by the NIH Stroke Scale), functional recovery (measured by the Barthel Index), and overall disability (measured by the Rankin Scale). The safety of lubeluzole was evaluated by continuous and standard ECG monitoring, clinical laboratory assessments, vital sign measurements, and adverse events reports. Lubeluzole resulted in a reduction in mortality and significant improvement on the Barthel Index for functionality, the NIH Stroke Scale for neurologic recovery, and the Rankin Scale for disability, without increased safety concerns.
3-43-03
Cerebral
pellagra revisited
A.H. Koeppen, A.C. Dickson, K.D. Barron, C.Y. Lee, H. Hartmann. Center, Albany. N. Y 12208, USA, University of Wisconsin Medical Madison, WI 53706, USA
VA Medics/ School,
Epidemic pellagra with the characteristic cutaneous lesions has largely disappeared from developed countries but encephalopathy due to deficiency of nicotinamide still occurs in patients with malnutrition in the course of alcoholism. Since nicotinamide is a metabolite of tryptophan, pellagra should be considered a result of inadequate intake of this essential amino acid. Uncommon other causes are antituberculous treatment with isoniazid or inherited enzyme defects in tryptophan metabolism. Physicians may fail to diagnose brain pellagra because they are not familiar with the disorder, and the diagnostic skin lesion may be absent. The characteristic lesion in the brain is central chromatolysis of selected nerve cells. Bizarre expansion and rounding of Betz cells is invariably present but chromatolysis also affects other nerve cell groups of brain stem and spinal cord. In four cases of brain pellagra, the central nervous system was studied by routine cell stains, immunocytochemistry, and lectin affinity cytochemistry. Electron microscopy of Betz cells and the neurons of the lateral cuneate nucleus was possible in one case. Chromatolytic neurons showed no accumulation of phosphorylated neurofilament protein or ubiquitin, or loss of non-phosphorylated neurofilament protein. The lesion did no? cause a microglial response as assessed by affinity cytochemistry with biotinylated Ricinus communis agglutinin. An astroglial response was also absent. The Golgi apparatus identified by AaBs immunocytochemistry was retispersed in chromatolyzed cells. Ultrastructural examination confirmed central chromatolysis and retention of the endoplasmic reticulum near the neuronal nuclei. These observations are compatible with an axonal locus for the metabolic injury, leading to the described pellagroid cell change.
3-43-04
Glia conditioned medium protects dopamine neurons in culture from apoptosis and MPP+ neurotoxicity
M.A. Mena, M.J. Casarejos, J.G. de Yebenes. Departamento de Investigation, Hospital Ramon y Caja/, Madrid, Spain, Servicio de Neurologia, Fundacion Jimenez Dia.?, Madrid, Spain Apoptosis has been implicated in neuronal death in Parkinson’s disease (PD) and I-methyl-4-phenylpyridinium (MPP+) neurotoxicity Glia protects dopamine (DA) neurons from different insults. Fetal midbrain neuronal cultures were treated with MPP+, 10 PM, for 24 hours, in the presence or absence of mesencephalic glia conditioned medium (GCM). In the absence of GCM, MPP+ greatly reduced the number of tyrosine hydroxylase immunoreactive (THIR) neurons an increased the number of apoptotic cells. GCM prevented these effects of MPP+ and increased the length and arborization of neurites of the THIR. The effects of GCM on DA neurons were mediated, at least in part, by inhibition of apoptosis. The num-