Double-Blind Placebo-Controlled, Neuropsychological and Neurophysiological Investigations with Oxiracetam (CGP 21690E) in Memory-Impaired Patients with Epilepsy

Aldenkamp, Albert P.; Wieringen, Astrid Van; Alpherts, W.C.J.; Boas, W. van Emde; Haverkort, H.A.; Vries, Jacqueline de; Meinardi, H.

doi:10.1159/000119467

Cited by 13 publications

(5 citation statements)

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“…The AEDs with cognition‐enhancing activity or combination treatment of nootropics and AEDs might offer advantages for antiepileptic therapy. Piracetam has been reported to have positive influence on cognitive functions and to improve seizure protection in epilepsy patients receiving CBZ (57), whereas oxiracetam has been reported to show no meaningful effect on memory function in patients with epilepsy (58). The pharmacologic profile of NEF seems to bring about a benefit for epilepsy patients.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Kitano

Komiyama²,

Makino³

et al. 2005

Epilepsia

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Summary:Purpose: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognitionenhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy.Methods: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test.Results: NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models.Conclusions: These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy. Key Words: NefiracetamLevetiracetam-Nootropic-Seizure-Antiepileptic.Cognition-enhancing agents (or nootropics) are drugs used for the treatment of impaired brain function resulting from cerebral deficiencies such as senile dementia or cerebral vascular disorders (1-3). Nefiracetam [NEF; N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM-9384] is a novel pyrrolidone-type nootropic and has been reported to enhance learning acquisition and to improve experimentally induced amnesia in various animal models (4-7). Electrophysiologic and neurochemical studies have demonstrated that NEF activates N/L-type Ca 2+ channels (8,9), and cholinergic, monoaminergic and γ -aminobutyric acid (GABA)ergic systems (10-15).Some pyrrolidone derivatives such as piracetam and oxiracetam have been reported to possess anticonvulsant activities (16) or synergistic effects in combination with antiepileptic drugs (AEDs) (17,18). Piracetam has been Accepted February 6, 2005. Address correspondence and reprint requests to Dr. Y. Kitano at New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. E-mail: kitanpm...

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Section: Discussionmentioning

confidence: 99%

Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Kitano

Komiyama²,

Makino³

et al. 2005

Epilepsia

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“…The rationale is that the pathogenesis of the cognitive decline can be expected to differ for the various subgroups of elderly people with complaints. Examples of this approach are studies investigating the effects of cognition enhancers in patients suffering from the cognitive impairment due to neurotrauma,[33·204] alcoholic organic brain syndrome, [205] epilepsy, [206] organic solvent exposure [207] and hysterectomyP08]…”

Section: The Patient Population As a Target For Drug Studiesmentioning

confidence: 99%

Cognition Enhancers in Age-Related Cognitive Decline

Riedel

Jolles

1996

Drugs & Aging

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A review of recently published studies on the effect of cognition enhancers in non-demented human study participants is presented. The heterogeneity of the therapeutic target, age-associated cognitive decline, can be improved by separately treating groups in whom age-extrinsic factors may underlie cognitive pathology. Standardisation of cognitive assessments is necessary, since many different tests are applied to answer the same question. Modelling cognitive dysfunction, either by pharmacological or nonpharmacological means, in humans is highly recommended since it allows hypotheses to be tested in a clearly operationalised way. Predictive validity of the currently applied models for the clinical situation remains a problem, however. The scopolamine (hyoscine) model has, to a reasonable extent, predictive validity for the cholinergic agents. The results of 67 single-dose studies and 30 multiple-dose studies are summarised. All single-dose studies and 14 multiple-dose studies were carried out in young or elderly human volunteers. In 45 of 81 volunteer studies, models of cognitive dysfunction were employed. The scopolamine model was the most used (n = 21); the other studies induced cognitive dysfunction by means of benzodiazepines (8), hypoxia (7), alcohol (5) and sleep-deprivation (4). The remaining 16 multiple-dose studies were clinical trials of a duration varying between 2 weeks and 1 year (average duration was 14 weeks). In these trials, the effects of cognition enhancers were assessed in elderly people in whom impairment of memory, psychomotor performance or cognitive function was determined. These included age-associated memory impairment (AAMI) and age-associated cognitive decline (AACD). There were many studies in which the cognition enhancing properties of substances in humans were reliably demonstrated. The cognition enhancing properties of substances that are widely used, such as caffeine, nicotine and vitamins, may already be active against AACD. New developments such as serotonin (5-hydroxytryptamine3; 5-HT3) antagonists and N-methyl-D-aspartate (NMDA) antagonists have provided marginal and disappointing results in AAMI. There is no cognition enhancer that has reliably and repeatedly been demonstrated to be efficacious for the treatment of AACD. However, this situation may change as the selectivity, specificity and adverse effect profiles of substances that are being developed for the treatment of AD may be expected to be improved in the future.

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“…Both oxiracetam [13] and GVS-111 [14] have reported efficacy in the promotion of cognitive function, but this has not been confirmed in large-scale clinical trials. It is not clear whether these other nootropics simply recapitulate the effects of piracetam with greater potency, or whether they have improved or different selectivity in their effects which might suggest different clinical applications.…”

Section: Introductionmentioning

confidence: 99%

A Systematic Review and Meta-Analysis of the Efficacy of Piracetam and Piracetam-Like Compounds in Experimental Stroke

2007

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Background/Objective: Piracetam was a candidate neuroprotective drug for acute stroke ineffective in clinical trial. Here we use systematic review and meta-analysis to describe the evidence supporting a protective effect of piracetam and its derivatives in animal models of stroke. Methods: We present a systematic review of reports describing the use of piracetam and its derivatives in animal models of focal ischaemia, where the outcome was measured as an infarct size or neurological score (Der Simonian and Laird random effects meta-analysis). Results: Only 2 studies, published 10 years after the first clinical trial of piracetam had been initiated, described its efficacy in animal models of stroke. A further 4 studies described the efficacy of related compounds. Piracetam and its derivatives improved the outcome by 30.2% (95% CI = 16.1–44.4). The median study quality was 4/10 (inter-quartile range = 4–6). Conclusion: Piracetam and its derivatives demonstrate neuroprotective efficacy in experimental stroke, but our findings raise concerns about the amount of available data, the quality of the studies and publication bias.

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Double-Blind Placebo-Controlled, Neuropsychological and Neurophysiological Investigations with Oxiracetam (CGP 21690E) in Memory-Impaired Patients with Epilepsy

Cited by 13 publications

References 24 publications

Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Anticonvulsant Properties of the Novel Nootropic Agent Nefiracetam in Seizure Models of Mice and Rats

Cognition Enhancers in Age-Related Cognitive Decline

A Systematic Review and Meta-Analysis of the Efficacy of Piracetam and Piracetam-Like Compounds in Experimental Stroke

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