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Drugs & Aging

, Volume 4, Issue 3, pp 257–273 | Cite as

Aniracetam

An Overview of its Pharmacodynamic and Pharmacokinetic Properties, and a Review of its Therapeutic Potential in Senile Cognitive Disorders
  • C. Rhoda Lee
  • Paul Benfield
Drug Evaluation

Summary

Synopsis

Aniracetam is a member of the nootropic class of drugs, which have possible cognition enhancing effects. It appears to positively modulate metabotropic glutamate receptors and α-amino-3-hydroxy- 5- methyl- 4- isoxazolepropionic acid (AMPA)- sensitive glutamate receptors, and may facilitate cholinergic transmission, effects which are possibly related to its mechanism of action.

Results from trials in elderly patients with mild to moderate cognitive impairment due to senile dementia of the Alzheimer type suggest that aniracetam may be of benefit, with further trials required to confirm its efficacy profile and to define more precisely those patients most likely to respond to treatment. Aniracetam 1500 mg/day was significantly more effective than placebo in all tests at 4 and 6 months, and in a further 6- month trial was more effective than piracetam 2400 mg/day in 8 of 18 tests. Preliminary evidence in the treatment of patients with cognitive impairment of cerebrovascular origin suggests aniracetam may also be of benefit in this condition.

Whilst incidence rates of adverse effects are not yet available, data from trials suggest aniracetam is well tolerated. In particular, aniracetam does not appear to cause increases in liver enzyme levels.

The evaluation of drugs for patients with senile cognitive disorders is a difficult area and therapeutic options are currently limited. Preliminary evidence of the potential benefits and good tolerability profile of aniracetam support continued evaluation of its use in patients with mild to moderate senile dementia of the Alzheimer type.

Pharmacodynamic Properties

Aniracetam is a pyrrolidinone derivative which has demonstrated memory enhancing effects in animals. In animal models it also reduces the memory and learning impairment caused by various agents and traumas such as cholinergic antagonists, cerebral ischaemia and electroconvulsive shock. In healthy volunteers, a single oral dose of aniracetam 500 to 2000mg significantly reduced electroencephalogram changes induced by hypoxic hypoxidosis and 1000mg was more active than piracetam 2000mg. Aniracetam 1500mg also reduced cognitive impairment caused by scopolamine in healthy young volunteers and was more active than piracetam 2400mg in this model.

The mechanism of action of aniracetam is not fully understood. It is a positive modulator of metabotropic glutamate receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive ionotropic glutamate receptors. In addition, it increases release of acetylcholine from the rat hippocampus and thus may facilitate cholinergic transmission.

Pharmacokinetic Properties

Peak plasma aniracetam concentrations of 2.3 and 14.1 µg/L occurred after oral doses of 300 and 1200mg, respectively, were administered as tablets to healthy volunteers. After intravenous administration of aniracetam 100mg the volume of distribution at steady state was calculated as 2.5 L/kg. Plasma protein binding was 66%. Only 0.2% of the parent drug reached the systemic circulation after administration of an oral dose due to marked first-pass hepatic metabolism. The plasma elimination half-life was 35 minutes.

The main metabolites of aniracetam are N-anisoyl-γ-aminobutyric acid (N-anisoyl-GABA), 2-pyrrolidinone and anisic acid. After oral and intravenous administration of [14C]-labelled aniracetam, approximately 84% of the dose was recovered in the urine, 0.8% in the faeces and 11% as carbon dioxide in expired air within 48 hours.

Therapeutic Potential

The efficacy of orally administered aniracetam in improving cognition and various other subjective symptoms in elderly patients with senile dementia of the Alzheimer type (SDAT) has been evaluated in a few comparative trials. Aniracetam 1500 mg/day was more effective than placebo at 4 and 6 months in 1 study in 109 patients fulfilling the clinical criteria guidelines of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) for probable SDAT of mild to moderate severity. Aniracetam recipients showed a 12 to 35% improvement in items assessed from the Sandoz Clinical Assessment Geriatric (SCAG) scale, whereas placebo recipients showed a 9 to 19% deterioration. In a further 6-month extension phase in 32 patients from this study, aniracetam continued to be more effective than placebo. However, in a smaller 3-month study which included some patients with severe SDAT, aniracetam at the lower dosage of 1000 mg/day was equivalent to placebo. In a further non-placebo controlled trial, aniracetam 1500 mg/day was more effective than piracetam 2400 mg/day in 8 of 18 variables in patients with mild to moderate SDAT, with aniracetam recipients showing a 17 to 29% improvement, and piracetam recipients a 9 to 20% improvement in all items assessed from the SCAG scale except the interpersonal relationship item.

In patients with impairment of mental function due to cerebrovascular disease, aniracetam 1000 and 1500 mg/day administered for 1 and 4 months, respectively, were more effective than placebo. In 2 further 3-month studies at a lower dosage, aniracetam 600 mg/day was significantly more effective than placebo in a small proportion of patients and was equivalent to calcium hopantenate 1500 mg/day. Aniracetam 1500 mg/day was slightly, but not statistically, superior to oxiracetam 1600 mg/day in a non-placebo controlled trial in elderly patients with mild senile cognitive decline due to various unspecified conditions.

Tolerability

Incidence rates of the adverse effects of aniracetam are not known; however, on available evidence the drug appears to be generally well tolerated with the most commonly reported effects being unrest, anxiety, uneasiness and insomnia. Other adverse effects include headache, somnolence, vertigo, mild epigastric pain, nausea, diarrhoea and rash. These effects were all considered mild and did not necessitate withdrawal of the drug. Increases in liver enzyme levels have not been detected in patients treated with aniracetam.

Dosage and Administration

Orally administered aniracetam has been used in clinical trials at daily doses of 1000 to 1500 mg for the treatment of cognitive impairment in patients with SDAT, and at doses of 600mg to 1500mg for the treatment of various symptoms including memory disorders in elderly patients with cerebrovascular disease. The recommended daily dose of aniracetam in the treatment of elderly patients with memory and attention disturbances of degenerative or vascular origin is 1500mg taken as a single dose or as 750mg twice daily. In Japan aniracetam 200mg 3 times daily is recommended in patients with anxiety and/or depression after cerebral infarction.

Keywords

Tacrine Metabotropic Glutamate Receptor Piracetam Senile Dementia Aniracetam 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • C. Rhoda Lee
    • 1
  • Paul Benfield
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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