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Research Notes: Piracetam and LevetiracetamNote: Piracetam (2-oxo-1-pyrrolidine acetamide) is a cyclic derivative of GABA. The exact mechanism of action of piracetam is not known. It has been found to increase blood flow and oxygen consumption in parts of the brain and to protect against the effects of hypoxia. Piracetam may facilitate movement of information between the brain's two hemispheres via the corpus callosum, and improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors which are implicated in memory processes. It may also have an effect on NMDA glutamate receptors which are involved with learning and memory processes. Piracetam is also thought to increase cell membrane permeability and may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Ca2+, K+). Levetiracetam (Keppra) is basically piracetam tweaked by the addition of an ethyl group - (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide aka 2-(2-oxopyrrolidin-1-yl)butanamide. Abstracts about levetiracetam are included here because, as a structural analogue of piracetam, it may provide insight into piracetam's mode of action and side effects. Int Clin Psychopharmacol. 2006 Nov. The purpose of this study was to determine the safety and efficacy of the anticonvulsant levetiracetam in the treatment of children with autism. A previous open-label study in autistic children treated with levetiracetam demonstrated effectiveness in hyperactivity, impulsivity/aggression, and mood lability. Twenty patients with autism ranging from 5 to 17 years of age were entered into a 10-week, placebo-controlled, double-blind trial of levetiracetam versus placebo. The mean maximum dosage for levetiracetam was 862.50+/-279.19 mg/day. We evaluated global improvement of autism with the Clinical Global Impression-Improvement (CGI-I) Scale and aggression and affective instability with the Aberrant Behavior Checklist (ABC) parent and teacher ratings. We measured repetitive behaviors using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score and impulsivity and hyperactivity with the Conners' Rating Scale-Revised: Long Version for parent and teacher. No significant difference was found between levetiracetam and placebo groups comparing the change in CGI-I (t=0.350, d.f.=13.621, P=0.765), nor on change in ABC, CY-BOCS or Conners' scales. These findings suggest that levetiracetam does not improve behavioral disturbances of autism, but are limited by the small sample size and lack of stratification of the autistic sample at baseline. Epilepsy Behav. 2006 Nov. PURPOSE: The aim of this study was to evaluate the clinical effects of levetiracetam (LEV) in patients with partial epilepsy and disfluent speech. METHODS: Five consecutive patients with partial epilepsy and disfluent speech resulting from developmental or neurogenic stuttering were enrolled in a 9-week, open-label, prospective study. LEV was given in combination with carbamazepine (CBZ) or phenytoin (PHT) at dosages ranging from 500 to 1500mg twice daily. The severity of stuttering was assessed with the verbal fluency test (VFT), and with the patient global impression of improvement (PGI), at baseline and after 9weeks. Electroencephalography and serum monitoring of CBZ and PHT levels were done before and after the study. Seizure frequency was monitored. RESULTS: After LEV therapy, verbal fluency for all patients, as measured by the VFT, improved from 25% at baseline to 64%, as did the speed of oral reading, from 5 to 23%. On the PGI, all patients rated themselves as better and as having less disfluent speech after LEV therapy. For four patients with incomplete control of their seizures, the seizure count decreased by more than 50% after LEV therapy. The beneficial effect of LEV on verbal disfluency demonstrated on the PGI persisted for the entire period of observation, which ranged from 7 to 11 months. CONCLUSIONS: As an add-on therapy, LEV seems to improve verbal fluency in patients with partial epilepsy and disfluent speech. This effect seems unrelated to the antiepileptic activity of the drug. A placebo-controlled trial of LEV in patients with this kind of verbal disfluency is warranted. J Clin Psychiatry. 2006 Oct. OBJECTIVE: To examine the safety and efficacy of the anticonvulsant levetiracetam in the treatment of patients with panic disorder. METHOD: In an open-label, fixed-flexible dose study, 18 patients with panic disorder with or without agoraphobia (DSM-IV diagnostic criteria) were treated with levetiracetam for 12 weeks. Outcome was assessed with standard rating instruments (Clinical Global Impressions-Severity of Illness scale [CGI-S], Clinical Global Impressions-Improvement scale [CGI-I], and the 14-item Hamilton Rating Scale for Anxiety [HAM-A]) and by the number of panic attacks during the previous week. The study was conducted in 2 outpatient clinics in New York City from January 2004 through July 2005. RESULTS: Of the 13 patients completing the study, 11 were rated "very much" or "much" improved on the CGI-I. Panic attack frequency, anxiety (HAM-A), and global severity (CGI-S) ratings also demonstrated significant improvement (all p < .00). For most patients, clinical benefits were apparent after only 1 to 2 weeks of treatment. Levetiracetam was well tolerated with minimal side effects. CONCLUSION: Given its favorable pharmacokinetics, side effect profile, and, if confirmed, early onset of action and efficacy, levetiracetam might represent significant progress in the pharmacologic management of panic disorder. Neurology. 2006 Jun 13. OBJECTIVE: To evaluate the efficacy and tolerability of levetiracetam (LEV) as adjunctive therapy in children (4 to 16 years) with treatment-resistant partial-onset seizures. METHODS: This multicenter, randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 14-week double-blind treatment period. During the treatment period, patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day. RESULTS: One hundred ninety-eight patients (intent-to-treat population) provided evaluable data. The reduction in partial-onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy was significant (26.8%; p = 0.0002; 95% CI 14.0% to 37.6%). A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo (p = 0.0002). Seven (6.9%) LEV-treated patients were seizure-free during the entire double-blind treatment period, compared with one (1.0%) placebo-treated patient. One or more adverse events were reported by 88.1% of LEV-treated patients and 91.8% of placebo patients. The most common treatment-emergent adverse events were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, and pharyngitis. A similar number of patients in each group required a dose reduction or withdrew from the study as a result of an adverse event. CONCLUSION: Levetiracetam adjunctive therapy administered at 60 mg/kg/day is efficacious and well tolerated in children with treatment-resistant partial seizures. Epilepsia. 2006 Jun. Based on blood sampling in a formula-fed pair of twins, the estimated serum half-life of levetiracetam (LEV) at birth is 16-18 h. Ideggyogy Sz. 2006 May 20. OBJECTIVE: To evaluate the efficacy and tolerability of levetiracetam in children with drug resistant epilepsy from a retrospective study. METHODS: We report the result of a study of 85 pediatric patients (mean 10.5 years, range: 1-24) with refractory generalized and focal epilepsy, who received levetiracetam as add-on treatment. The average duration of epilepsy was eight years, and the patient were treated with mean of 6.0 antiepileptic drugs before levetiracetam was introduced. RESULTS: Ten patients (12%) became seizure-free, three (3%) responded with seizure reduction of more than 90%, 32 (38%) responded with seizure reduction of more than 50% following introduction of levetiracetam. No response to levetiracetam was reported in 34% (n: 29). Positive psychotropic effect was observed in 26 patient (30%). Mild to moderate side effects were reported in 11 patients (13%), consisting most frequently general behavioral changes, aggression, sleep disturbances, but they ceased after decreasing the dose of levetiracetam. Mental retardation was associated with poor response and associated with more side effects. CONCLUSION: Levetiracetam is a well tolerated new antiepileptic drug that may effectively improve seizures control as an add-on drug in resistant epilepsy in childhood with good tolerability. Eksp Klin Farmakol. 2006 May-Jun. It is established that bicuculline, picrotoxin, and flumazenil (agents blocking different sites of GABA receptor) decrease the anxiolytic effect of piracetam as manifested in the conflict situation test. The most pronounced interaction was observed between piracetam and flumazenyl. On the background of antagonist action, piracetam inhibited the effects of flumazenil (but not those of bicuculline and picrotoxin). Based on these data, it is assumed that the anxiolytic effect of piracetam is mediated to some extent by benzodiazepine site of the GABA-benzodiazepine receptor complex. Epilepsy Behav. 2006 May. An observational longitudinal design was employed to evaluate whether treatment with the antiepileptic drug levetiracetam (LEV) adversely impacts behavior in people with intellectual disabilities and/or acquired brain damage. Thirty-five adults were assessed once off the drug and once when on LEV therapy, with a 2-month interval between assessments. Behaviors were rated using an adaptation of the Yale-Brown Obsessive Compulsive Scale and the Challenging Behaviour Scale. Challenging behaviors were rated as more frequent and severe when individuals were taking LEV. Behavioral worsening was not related to better seizure control or increased levels of engagement in activities. Families and professionals need to be aware of the potential reversible adverse effects of this drug. J Neurol Sci. 2006 Apr 15. The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA should be used with caution in PME due to mitochondrial dysfunction, i.e. in MERRF (myoclonic epilepsy with ragged red fibers) syndrome, because of its interaction with mitochondrial respiration and metabolism. Levetiracetam (LEV) treatment was started in combination with VPA in a patient with typical clinical, histological, and biochemical features of MERRF due to a mutation on the tRNA of Phenilalanine gene. The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA. LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF. Epilepsy Res. 2006 Mar. PURPOSE: The aim of the present study is to verify whether patients with partial epilepsy receiving levetiracetam (LEV) as an add-on treatment show an improvement in cognitive function. METHODS: A neuropsychological battery of tests was administered to 35 patients with partial epilepsy before the assumption of LEV and after the achievement of the therapeutical dose of this drug, 7 weeks later. A control group of 35 patients with partial epilepsy was administered the same battery of tests twice, at the same time interval as the LEV group. The controls were administered the same pharmacological treatment, which did not include LEV in either of the two sessions. RESULTS: We found a statistically significant improvement in cognitive functioning, i.e. in attention and oral fluency, in patients receiving LEV compared to the controls. The responders to LEV were 28.6%. CONCLUSIONS: LEV as an add-on therapy improved attention level and verbal fluency in our sample of patients with partial epilepsy. It is reasonable to assume that LEV may influence the metabolism of attention and of language area, as already suggested for piracetam (PIR) from which LEV derives. Further studies are needed to confirm these findings. Epilepsy Behav. 2006 Feb. Levetiracetam (Keppra) is a novel antiepileptic drug approved as adjunctive treatment for adults with partial onset seizures. Although the drug is generally well tolerated, behavioral side effects have been reported in variable frequency. Most behavioral problems are mild in nature (agitation, hostility, anxiety, emotional lability, apathy, depression) and quickly resolve with discontinuation of medication. However, serious psychiatric adverse events may also occur with rare cases of psychosis and suicidal behavior. We report here the case of a 43-year-old woman who developed symptoms compatible with catatonia after being exposed to levetiracetam for the treatment of epilepsy. To our knowledge, it is the first reported case of catatonia induced by levetiracetam. We review the difficulties that may be encountered in the differential diagnosis of medical catatonia. J Clin Psychiatry. 2006 Feb. OBJECTIVE: To assess the use of levetiracetam, a novel anticonvulsant agent, in the treatment of refractory posttraumatic stress disorder (PTSD). METHOD: Retrospective analysis was conducted of 23 patients with DSM-IV diagnosis of PTSD who, after being deemed partial or nonresponders to antidepressant therapy, received levetiracetam in a naturalistic fashion. The primary outcome measure was the PTSD Checklist-Civilian Version (PCL-C). Secondary outcome measures included the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impressions-Severity of Illness scale (CGI-S), and Clinical Global Impressions-Improvement scale (CGI-I). RESULTS: Levetiracetam at a mean+/-SD dose of 1967+/-650 mg/day for 9.7+/-3.7 weeks was generally well tolerated. Nineteen patients (83%) were taking at least 1 concomitant medication. Patients were severely ill with a mean baseline PCL-C score of 67.2+/-9.4, CGI-S score of 6.0+/-0.7, and HAM-A score of 26.8+/-4.9. Patients improved significantly on all measures (p<.001). Thirteen patients (56%) met responder criteria at endpoint (PCL-C mean change=23.5, CGI-I score<or=2), and 6 (26%) met remission criteria (CGI-S score<or=2). Adverse events were generally mild, and no patients discontinued levetiracetam because of side effects. CONCLUSION: These preliminary data suggest that levetiracetam may be an effective treatment in combination with antidepressant therapy for patients with PTSD who remain symptomatic after initial intervention. Br J Pharmacol. 2006 Jan. 1. Mitochondrial dysfunction including decrease of mitochondrial membrane potential and reduced ATP production represents a common final pathway of many conditions associated with oxidative stress, for example, hypoxia, hypoglycemia, and aging. 2. Since the cognition-improving effects of the standard nootropic piracetam are usually more pronounced under such pathological conditions and young healthy animals usually benefit little by piracetam, the effect of piracetam on mitochondrial dysfunction following oxidative stress was investigated using PC12 cells and dissociated brain cells of animals treated with piracetam. 3. Piracetam treatment at concentrations between 100 and 1000 microM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside (SNP) and serum deprivation. Under conditions of mild serum deprivation, piracetam (500 microM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. 4. Piracetam treatment (100-500 mg kg(-1) daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Moreover, the same treatment reduced antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in aged mouse brain only, which are elevated as an adaptive response to the increased oxidative stress with aging. 5. In conclusion, therapeutically relevant in vitro and in vivo concentrations of piracetam are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of piracetam's beneficial effects in elderly patients. Pediatr Neurol. 2006 Jan. This report describes the first neonatal case of "malignant migrating partial seizures in infancy" with a positive therapeutic response to levetiracetam. This patient is the youngest reported infant with this rare syndrome, and the report provides the first documentation on levetiracetam treatment in a neonatal patient. Treatment with levetiracetam improved both ictal and interictal status. This observation also highlights the need to consider and include malignant migrating partial seizures in the differential diagnosis of early neonatal seizure disorders, even during the first hours of life. Epilepsia. 2006 Jan. PURPOSE: Individuals with epilepsy commonly report daytime sleepiness, attributed to sleep disruption (frequent arousals, awakenings, and stage shifts) induced by ictal and interictal activity or antiepileptic drugs (AEDs) or both. To study the effect of levetiracetam (LEV) on sleep, at full doses but without the interference of epilepsy, we investigated the sleep architecture and daytime vigilance in healthy adults after 3 weeks of treatment. METHODS: The study was of a double-blind crossover design with random allocation of multiple doses of two different treatments (randomly first LEV <or=2,000 mg/day or placebo for 3 weeks, washout for 4 weeks, and then the alternative treatment for another 3 weeks). Fourteen healthy volunteers were studied with polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT). Epworth Sleepiness Scale (ESS) and sleep log also were evaluated. RESULTS: After treatment with LEV, statistically significant increases were observed in total sleep time, sleep efficiency, and time spent in non-rapid eye movement (NREM) sleep stages 2 and 4. Stage shifts and wake after sleep onset were significantly decreased. Sleep latency was normal at PSG and MSLT in all subjects and did not statistically differ between placebo and LEV. No changes were found in the ESS. CONCLUSIONS: Our findings show that in healthy volunteers, LEV consolidates sleep and does not modify vigilance, two appreciated qualities in epilepsy patients with sleep disturbance and daytime sleepiness. Epilepsy Behav. 2005 Nov. BACKGROUND: Epilepsy patients commonly suffer from sleep disturbances, and these can exacerbate memory dysfunction and seizures. Sleep can be affected by seizures, independent sleep disorders, or anticonvulsant drugs. Levetiracetam is a novel anticonvulsant effective for the treatment of partial seizures. We studied the effects of levetiracetam (LEV) on sleep using polysomnography in normal subjects. METHODS: Subjects (aged 18-40) were screened for freedom from sleep disorders, excessive daytime sleepiness, and depression. Screening overnight polysomnography was performed, followed by baseline polysomnography. Subjects were randomized to placebo or LEV, titrated to 1000 mg twice daily over 9 days. Polysomnography was repeated on Treatment Day 28. Differences between baseline and treatment in the drug and placebo groups were compared using single-factor ANOVA. RESULTS: Seventeen subjects were enrolled; 14 completed the study (8 placebo, 6 LEV). All subjects who remained on LEV were able to tolerate the target dose. There were no significant differences between the placebo and drug groups with respect to baseline sleep characteristics. When baseline polysomnography was compared with treatment polysomnography, there were no differences in the change in sleep efficiency, sleep latency, total sleep time, REM latency, or percentages of REM, stage 1, stage 2, or slow wave sleep. There was an increase in the number of awakenings in the drug group that was significant compared with placebo. CONCLUSION: These results suggest that LEV does not have major effects on sleep structure. Seizure. 2005 Oct. PURPOSE: To evaluate the efficacy and tolerability of Levetiracetam (LEV) in a large pediatric cohort with drug-resistant epilepsy from a prospective multicenter observational study. METHODS: We report the results of a multicenter observational survey of a cohort of 285 pediatric patients (mean: 9.9 years, range: 0; 6-17; 11) with refractory generalized and focal epilepsy who received Levetiracetam as an add-on open label treatment trial. The average duration of epilepsy was 6.0 years and the patients were treated with a mean of 7.0 antiepileptic drugs (AED) before LEV was introduced. RESULTS: No serious persistent adverse events were reported. Reversible colitis and an apnoea syndrome in a child with phosphorylase-A-kinase-deficiency were noted. Mild to moderate side effects were reported in 128 patients (44.9%), consisting most frequently of somnolence (23.9%), general behavioral changes (15.4%), aggression (10.5%) and sleep disturbances (3.2%). In 209 patients, efficacy was analyzed over a treatment period of at least 12 weeks compared to a baseline of 2 weeks. Thirteen patients (6.2%) became seizure free, 39 (18.7%) responded with a seizure reduction of more than 50% following introduction of LEV. No response to LEV was reported in 65.1% (n=136). A decrease of initial treatment effect was seen in 37 patients (17.8%) while in 6.7% the seizure frequency doubled to the baseline (n=14). In seven patients (3.3%), the effect of LEV on seizure frequency could not be evaluated. A positive psychotropic effect was observed in 18 patients (8.6%). Mental retardation was associated with poor response and associated with more side effects and earlier discontinuation of LEV therapy. CONCLUSION: LEV is a well-tolerated new AED that may effectively improve seizure control as an add-on drug in resistant epilepsy in childhood with good tolerability. However, neurologically handicapped children appear at increased risk for reversible neurocognitive side effects and have a poorer treatment response. Acta Pol Pharm. 2005 Sep-Oct. Piracetam (2-oxo-1-pyrrolidine-acetamide), the most common of the nootropic drugs, is a cyclic derivative of gamma-aminobutyric acid. The treatment with piracetam improves learning, memory, brain metabolism, and capacity. Piracetam has been shown to alter the physical properties of the plasma membrane by increasing its fluidity and by protecting the cell against hypoxia. It increases red cell deformability and normalizes aggregation of hyperactive platelets. Piracetam is an agent with antithrombotic, neuroprotective and rheological properties. The interaction of this molecule with the membrane phospholipids restores membrane fluidity and could explain the efficacy of piracetam in various disorders ranging from dementia and vertigo to myoclonus and stroke. CNS Drug Rev. 2005 Summer. Piracetam, a derivative of the neurotransmitter gamma-aminobutyric acid (GABA), has a variety of physiological effects that may result, at least in part, from the restoration of cell membrane fluidity. At a neuronal level, piracetam modulates neurotransmission in a range of transmitter systems (including cholinergic and glutamatergic), has neuroprotective and anticonvulsant properties, and improves neuroplasticity. At a vascular level, it appears to reduce erythrocyte adhesion to vascular endothelium, hinder vasospasm, and facilitate microcirculation. This diverse range of physiological effects is consistent with its use in a range of clinical indications. Its efficacy is documented in cognitive disorders and dementia, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia. While high doses are sometimes necessary, piracetam is well tolerated. Mov Disord. 2005 Jun. Some drugs currently used to treat tics in pediatric patients have drawbacks, including the risk of side effects. New therapeutic options with better safety profiles are needed. Levetiracetam is an antiepileptic drug with atypical mechanisms of action that might be beneficial for this indication. We evaluated the effects of levetiracetam on motor and vocal tics, behavior, and school performance in children and adolescents with tics and Tourette syndrome (TS). Sixty patients, < or =18 years of age, with tics and TS were enrolled in this prospective, open-label study. The initial starting dose of levetiracetam was 250 mg/day. The dosage was titrated over 3 weeks to 1,000 to 2,000 mg/day. Clinical outcomes were assessed with the Clinical Global Impression Scale, Yale Global Tic Severity Scale, and Revised Conners' Parent Rating Scale. Behavior and school performance were also recorded. All 60 patients showed improvements based on all of the scales used, and 43 patients improved with regard to behavior and school performance. Levetiracetam was generally well tolerated. Three patients discontinued treatment because of exaggeration of preexisting behavioral problems. Levetiracetam may be useful in treating tics in children and adolescents. Given its established safety profile, levetiracetam is a candidate for evaluation in a well-controlled trial. J Child Neurol. 2005 Feb. Levetiracetam is a new antiepileptic drug whose efficacy and tolerability are already well known in adults. Few studies are available in children. This review, based on the international literature, aims to identify and make known the possible indications for levetiracetam in childhood. Most studies suggest that levetiracetam is effective against partial and generalized epilepsy. In resistant partial epilepsy, the percentage of responders reaches 64%, with 8 to 23% seizure free. Levetiracetam is used to treat symptomatic and idiopathic epilepsies. The drug has also proven effective against photosensitivity and epileptic and nonepileptic myoclonus. The most frequent side effects involve the behavioral sphere and manifest mostly in patients with a history of behavioral problems. In some patients, levetiracetam increases the number of seizures, but this adverse reaction can be partially avoided with slow titration. Doses for children should be 130 to 140% of those advised for adults. Levetiracetam seems to have a broad spectrum of action and is, on the whole, well tolerated. Its efficacy against generalized epilepsy is particularly promising in childhood. Eur J Paediatr Neurol. 2005. An 11-month-old infant with a 5-month history of seizures and a 3-month history of infantile spasms is described. EEG showed epileptic encephalopathy. The infantile spasms were resistant to treatment with clobazam. Following the introduction of levetiracetam, there was clinical cessation of seizures with resolution of seizure activity on the EEG. This is the second report in the literature of effective treatment of infantile spasms with levetiracetam. Drug Saf. 2005. Levetiracetam is a novel antiepileptic drug that has been demonstrated as being effective in the management of partial seizures. It is rapidly and completely absorbed after oral administration and it is predominantly eliminated as unchanged drug in the urine. Its metabolism is independent of the cytochrome P450 enzyme system, nor does it induce cytochrome P450 enzymes. As a result of its pharmacokinetic features, levetiracetam has not been demonstrated to interact with other drugs in either direction. In double-blind, placebo-controlled trials, all the levetiracetam dosages tested were effective, including 1000 mg/day, 2000 mg/day and 3000 mg/day. The ineffective dose is not known. Efficacy seemed to be maintained in long-term studies, with no evidence of tolerance. In major double-blind, placebo-controlled trials discontinuation rates because of adverse events were 6.9-10.9% for levetiracetam-treated patients (all doses) compared with 5.3-8.6% for placebo-treated patients. The most common adverse events that differed between treatment groups and placebo control groups were somnolence, asthenia, dizziness and, in the US study, infection. Since levetiracetam was marketed, behavioural effects have been reported, namely irritability, agitation, anger and aggressive behaviour. These adverse effects are more likely in learning disabled individuals, those with prior psychiatric history and those with symptomatic generalised epilepsy. Overall, the risk has been estimated at 12-15%. Laboratory parameters overall seem to be not significantly affected by levetiracetam, although slight trends to lower white and red blood cell counts were detected in the studies. No organ toxicity has been described so far, with patient exposures exceeding 500,000. In summary, levetiracetam exhibits a very favourable safety profile in patients with partial onset seizures. Whereas somnolence, asthenia and dizziness were the most prominent adverse effects in clinical trials, behavioural adverse effects have generally been the most common reason for drug discontinuation in clinical practice. J Pharm Belg. 2005. Piracetam preparations formulated as capsules, tablets and granules were evaluated with different tests including in vitro dissolution and assay with previously validated methods according to the guideline of the European network of official medicines control laboratories (OMCLs). All examined products complied with the requirements as described here and in the European Pharmacopoeia except for the dissolution test where 3 products did not meet the USP acceptance criteria applied on the established specification. Epilepsy Behav. 2004 Dec. Levetiracetam (LEV) is a novel antiepileptic drug (AED) with efficacy against a wide range of seizures types. The aim of this observational study was to assess its effectiveness in patients with mental retardation and refractory epilepsy. Sixty-four patients were started on adjunctive LEV after a 3-month baseline. LEV was initially dosed at 250 mg daily and increased by 250 mg every 2 weeks thereafter according to clinical response. Caregivers rated the patient's sleep, appetite, alertness, and behavior as poor (1), reasonable (2), or good (3) at each clinic visit. Patients were reviewed until one of four endpoints was reached: seizure freedom for at least 6 months, > or = 50% reduction in seizure frequency (responder) over a 6-month period, <50% reduction in seizure frequency (marginal effect) over a 6-month period, or LEV withdrawal due to lack of efficacy, adverse effects, or both. Twenty-four (38%) patients became seizure-free, 10 of whom were controlled on LEV 250 mg twice daily. An additional 18 (28%) patients were classified as responders, and 8 (12%) reported only marginal benefit from adjunctive LEV. Fourteen (22%) patients discontinued LEV (6 worsening seizures, 1 lack of efficacy, 7 adverse effects). Caregivers rated combined sleep, appetite, alertness, and behavior scores as "improved" at the end of follow-up (P<0.001). LEV improved seizure control in the majority of patients with mental retardation and may also have enhanced their quality of life. J Child Neurol. 2004 Dec. The purpose of this study was to assess the efficacy and safety of levetiracetam in a diverse pediatric epilepsy population. A retrospective chart review of 52 consecutive children age 8 months to 16 years who were treated with levetiracetam was performed. The data include patients with partial and generalized seizures, monotherapy, and concomitant antiepileptic drug use. Levetiracetam was dosed to efficacy or unacceptable side effects, with a range of 8 to 315 mg/kg/day. Two patients discontinued levetiracetam prior to assessment of efficacy owing to side effects. Of the remaining 50 patients, 12 had > or =75% seizure reduction, 3 had > or =50% and <75% seizure reduction, 8 had > or =25% and <50% seizure reduction, and 27 had < 25% seizure reduction. A variety of pediatric epilepsy syndromes and seizure types were represented. Adverse events, seen in 17 patients, were determined to be tolerable or resolved over time with continued dosing, dosage reduction, or discontinuation. This open-label, retrospective study of 52 consecutive pediatric patients treated with levetiracetam indicates at least partial efficacy in a variety of pediatric epilepsy syndromes. Tolerability was surprisingly favorable, even at doses far exceeding 40 mg/kg/day. Epilepsia. 2004 Jun. PURPOSE: Disabling myoclonus is the main symptom in long-standing Unverricht-Lundborg disease (ULD), and levetiracetam (LEV) appears to be an effective anticonvulsant with promising short-term antimyoclonic properties. METHODS: LEV was prescribed to 13 patients with ULD. We retrospectively analyzed the efficacy of LEV on seizure frequency and on myoclonus, by using a simplified myoclonus rating score, and compared the patients' status before LEV and at the last follow-up. They were two women and 11 men, aged 14 to 52 years (mean, 36.5 years), with a disease duration of 4 to 40 years (mean, 24.3 years). LEV was given at 2,000 to 4,000 mg/d for 0.5 to 26 months (mean, 13.8 months). RESULTS: One patient stopped LEV within 2 weeks because of side effects and lack of efficacy. None of the other 12 patients reported side effects. The average myoclonus score significantly changed from 3.1 to 2.4 (p = 0.01), but only eight had a measurable improvement. CONCLUSIONS: The best effects were noted in the younger patients. In patients previously treated with high-dose piracetam (PIR), discontinuation of PIR was not always well tolerated, and a combination of PIR at lower doses and LEV appeared to be a practical solution. LEV should probably be considered as a major treatment option early in the course of ULD. Seizure. 2004 Apr. Levetiracetam is a new anti-epileptic drug that is currently not licensed for use in children. Studies in adults suggest that it may be a useful adjunctive treatment both in partial onset and generalised epilepsy. A retrospective case notes review of 26 children age 10 years and under with refractory epilepsy was undertaken to evaluate the efficacy and safety of the drug. The drug appeared to be most effective in children with partial onset seizures and least effective in those with myoclonic seizures. Sixty-one percent of patients showed a good response to levetiracetam with at least a 50% reduction in seizure frequency with two of these 26 children with previously refractory epilepsy becoming seizure-free. Levetiracetam was also found to be well-tolerated with very few reported side-effects. J Med Chem. 2004 Jan 29. (S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003. Clin Pharmacokinet. 2004. Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs.Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours.The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment.To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward. Epilepsy Behav. 2003 Oct. Levetiracetam (LEV) was shown to be very efficacious and well tolerated as add-on therapy for refractory epilepsy. Here we report 33 patients with longstanding histories of epilepsy who experienced aggressive episodes during LEV therapy. This corresponds to 3.5% of LEV-treated patients as compared with less than 1% of patients not on LEV. Among these cases, 24 showed only moderate, partly transient irritability, with 10 patients requiring reduction or discontinuation of LEV. More strikingly, 9 patients displayed severe symptoms of aggression with physical violence and, in 2 cases, the need for psychiatric emergency treatment. One patient developed additional psychotic symptoms. We suggest that, specifically in patients with a previous history of aggression, behavioral tolerability of LEV should be carefully monitored. Epileptic Disord. 2003 Jun. A twelve year-old-girl with idiopathic partial epilepsy with secondary generalization, developed acute psychosis 10 days after the administration of levetiracetam. The patient was already on sodium valproate, and levetiracetam was given as add on therapy. A final dosage of 60 mg/kg was used. Complete seizure control was achieved but the patient developed hallucinations, agitation and self-harming behaviour, as well as poor social contact.The psychotic behavior resolved completely soon after the discontinuation of levetiracetam. Epileptic Disord. 2003 May. Treatment of seizures in pediatric patients is complicated by the fact that the etiology of the disorder and the pharmacokinetics, efficacy, and safety of antiepileptic drugs (AEDs) may differ from that in adults. With few controlled clinical trials of AEDs in children, the selection of agents to treat pediatric patients must be made on the basis of information from small uncontrolled studies or the extrapolation of clinical trial results in adults. Data from a large number of children with a wide range of seizure disorders who were treated in small-scale prospective studies, or whose records were retrospectively evaluated, indicate that levetiracetam reduces the frequency of seizures in pediatric patients. Available data also indicate that levetiracetam is well tolerated in pediatric patients, with a safety profile similar to that in adults, a low potential for behavioral disturbances, and no reported idiosyncratic adverse reactions. As with other AEDs, children metabolize and clear levetiracetam more rapidly than adults, and somewhat higher doses (based on body weight) are needed to achieve desired plasma concentrations. Several ongoing studies will provide further information on the pharmacokinetics, efficacy, and safety of levetiracetam in this patient population. Eur J Paediatr Neurol. 2003. In this open-label add-on study of levetiracetam in refractory childhood epilepsy syndromes, we studied the effect of a rapid introduction of levetiracetam on the total seizure frequency in 21 children, known to have partial and generalized seizures. Starting dosage was 10 mg/kg/day, increased every 4th day by 10 mg/kg up to a maximum of 60 mg/kg/day, depending on efficacy and tolerability. In this highly refractory population, 47% showed a seizure frequency reduction of more than 50%. Levetiracetam was effective both in partial and generalized seizures, with a significant effect on myoclonic seizures. Only mild side-effects were observed in four of 21 children, at a dosage of more than 40 mg/kg/day. J Sleep Res. 2002 Sep. Levetiracetam is a novel antiepileptic drug which has recently been released as an adjunctive treatment for partial epilepsy. In the two studies reported here we examined the objective and subjective effects of levetiracetam on sleep in 12 healthy volunteers and 17 patients [16 who could be evaluated for electroencephalogram (EEG) recordings] with a history of partial epilepsy on stable carbamazepine monotherapy. The studies were of a similar double-blind crossover placebo-controlled design with subjects' sleep being recorded in their own homes. The results from the two studies showed considerable similarities. In both, levetiracetam produced an increase in the time spent in stage 2 sleep, which in the patient study was accompanied by a decrease in the time spent in stage 4 sleep and in the volunteer study an increase in rapid eye movement (REM) latency. The subjective changes included reports that sleep was of a better quality with fewer awakenings and patients also reported that their sleep was more restful. Volunteers and patients did, however, feel less alert on waking in the morning. Therefore, both groups reported a decrease in awakenings after levetiracetam despite the finding from the EEG of no change in the actual number of awakenings. It may be concluded from both studies that levetiracetam does affect some indicators of subjective sleep perception, but does not influence objective sleep measures of sleep continuity. The results from the patient study during placebo add-on treatment also showed that patients on carbamazepine had a marked increase in SWS, an increase in stage 2 sleep and an increase in REM latency compared with healthy volunteers. Interestingly, levetiracetam also reduced bilateral epileptiform EEG activity, particularly in patients with more discharges. Rev Neurol. 2002 Sep. J Dev Behav Pediatr. 2002 Aug. The objectives of this study were to determine whether autistic children taking levetiracetam (1) showed improvement in the areas of aggression, impulsivity, hyperkinesis, and mood instability, and (2) showed a nootropic response. Ten white autistic boys ranging from 4 to 10 years were compared pretreatment and while taking levetiracetam for an average of 4.1 weeks. Inattention, hyperkinesis, and impulsivity were evaluated using the Achenbach Attention Problems scale, Conners DSM-IV Total scale, and the Conners Attention-Deficit Hyperactivity Disorder Index scale, all of which showed statistically significant improvements. Mood instability was measured with the Conners Global Index (CGI) Emotional Lability and CGI Total scales, both of which showed statistically significant improvements. Aggressive behavior, as measured with the Achenbach Aggression scale, showed statistically significant improvement only for subjects who were not recently weaned from medications that reduce aggression (e.g., risperidone, carbamazepine, desipramine). Levetiracetam may reduce hyperactivity, impulsivity, mood instability, and aggression in autistic children with these problems. No nootropic effect was observed. Ned Tijdschr Geneeskd. 2002 Jun 29. Levetiracetam is a new anticonvulsant for adjunctive treatment of partial epilepsy. It is well tolerated, with no significant risks, at a dose of 1000-3000 mg/day in adults. The efficacy (> 50% reduction in attacks) in refractory partial epilepsy is 22-40%, depending on the dose. Efficacy was also seen with levetiracetam monotherapy in more than half of the positive responders. Levetiracetam does not cause induction or inhibition of the P450 enzyme system or other enzyme systems, there is no active metabolite and it exhibits almost no protein binding. These factors mean that this drug undergoes no significant interactions with other medication and appears suitable for elderly patients and for conditions requiring complex pharmacotherapy. Compared with other recently registered anti-epilepsy drugs, levetiracetam appears promising in terms of efficacy, tolerability and pharmacokinetics. The simple dosing schedule is an additional benefit. J Child Neurol. 2002 Jun. Levetiracetam, one of the newer-generation antiepilepsy drugs, is not currently approved for use in children. Given its favorable efficacy, pharmacokinetic, and, particularly, safety profile in adults, we felt that it may be a useful antiepilepsy drug for children with refractory epilepsy. We treated 39 patients (mean age 8.6 years) with open-label levetiracetam for up to 9 months. Seizure frequency, drug dosages, adverse events, and neurologic examinations were documented at baseline and routine follow-up visits. Levetiracetam, as add-on therapy, was effective in reducing seizure frequency in a variety of seizure types but was most effective for partial-onset seizures. Fourteen patients were discontinued for lack of efficacy or adverse events. Ten patients reported improvements in cognition or behavior. Levetiracetam was generally effective and well tolerated in this open-label study. Its apparent positive effects on cognition in some patients are encouraging. Large, well-controlled studies are needed to fully define levetiracetam's potential in children with refractory epilepsy. Epilepsia. 2002 May. PURPOSE: To assess the efficacy and safety of levetiracetam (LEV) as adjunctive therapy in children with treatment-resistant partial-onset seizures. METHODS: Children (aged 6-12 years) with treatment-resistant partial-onset seizures receiving one standard antiepileptic drug (AED) were eligible. After a 4-week baseline period, children received LEV in a 6-week titration phase (target dose, 40 mg/kg/day) followed by an 8-week evaluation phase. Seizure frequency during the evaluation period with individualized LEV doses (20-40 mg/kg/day) were compared with the 4-week baseline seizure frequency. Plasma concentrations of LEV and other AEDs were determined to evaluate potential drug interactions. RESULTS: Twenty-four subjects enrolled and received LEV; 23 entered the evaluation phase, and 22 completed the evaluation phase. Compared with their baseline seizure frequency, 12 (52%) of 23 subjects entering the evaluation phase had their seizure frequency decrease by >50%. Two subjects remained seizure free during the entire evaluation period. LEV did not significantly affect plasma concentrations of any concomitant AED during this study, and no alteration of mean clinical laboratory values was observed. The most commonly reported adverse events were headache, infection, anorexia, and somnolence. CONCLUSIONS: This open-label study of adjunctive LEV therapy (at 20-40 mg/kg/day) suggests that LEV is effective, safe, and well tolerated in children ages 6-12 years with treatment-resistant partial-onset seizures. A randomized, placebo-controlled, double-blind trial of LEV adjunctive therapy in children with treatment-resistant partial-onset seizures is needed and ongoing to confirm these open-label findings. Cochrane Database Syst Rev. 2002. BACKGROUND: Piracetam is thought to promote the metabolism of brain cells when they are hypoxic. It has been used to prevent adverse effects of fetal distress. OBJECTIVES: The objective of this review was to assess the effects of piracetam for suspected fetal distress in labour on method of delivery and perinatal morbidity. SEARCH STRATEGY: The Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001) were searched. Date of last search: September 2001. SELECTION CRITERIA: Randomised trials of piracetam compared with placebo or no treatment for suspected fetal distress in labour. DATA COLLECTION AND ANALYSIS: Both reviewers assessed eligibility and trial quality. MAIN RESULTS: One study of 96 women was included. Piracetam compared with placebo was associated with a trend to reduced need for caesarean section (relative risk 0.57, 95% confidence interval 0.32 to 1.03). There were no statistically significant differences in relative risk between the piracetam and placebo group for neonatal morbidity (measured by neonatal respiratory distress) or Apgar score. REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate the use of piracetam for fetal distress in labour. Lancet. 2001 Dec 1. The pyrrolidone (2-oxopyrrolidine) family of chemicals has been the subject of research for more than three decades. Experimental and clinical work first focused on their so-called nootropic effects; later came the possibilities for neuroprotection after stroke and use as antiepileptic agents. Piracetam, the first of the class, was developed by pioneering research by C Giurgea in the late 1960s, and it was he who coined the term "nootropic", to mean enhancement of learning and memory. The term is sometimes extended to include other actions such as neuroprotection. These properties, together with the lack of other generally adverse psychopharmacological actions (eg, sedation, analgesia, or motor or behavioural changes), distinguish the pyrrolidones from other psychoactive drug classes. The mechanisms of action of these drugs are still not fully established; indeed, different compounds in this class may have different modes of action. Interest in this drug class has recently been reawakened by the licensing of levetiracetam as a potentially major new antiepileptic drug and of piracetam for its antimyoclonic action and effects after stroke and in mild cognitive impairment. Other drugs in this class are currently at an advanced stage of development, and the renewal of interest in this therapeutic area is likely to mean not only that more pyrrolidones will enter clinical practice in the next few years but also that the clinical indications of drugs already licensed will widen. Epilepsia. 2001 Dec. PURPOSE: Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children. METHODS: In four young patients, acute psychosis developed within days to months of initiation of levetiracetam for seizures. RESULTS: A 5-year-old girl began having visual hallucinations of spiders in her room 14 days after starting levetiracetam. A 13-year-old boy began having auditory hallucinations, insomnia, and screaming behavior 3 months after initiation of levetiracetam. A 16-year-old girl became acutely agitated, hyperreligious, and had persecutory delusions within 7 days of starting levetiracetam. A 17-year-old girl had auditory hallucinations telling her to sing and yell after 30 days of taking the drug. All four children had dramatic improvement within days of either discontinuing or decreasing the dose of levetiracetam. The three adolescents had historical findings consistent with mild behavioral problems before initiating levetiracetam, and all four patients had prior cognitive deficits. CONCLUSIONS: Reversible treatment-emergent psychosis associated with levetiracetam therapy was observed in four children and adolescents. Whether rapid initiation or prior neurobehavioral problems predispose to this side effect is not established. Arch Neurol. 2001 May. BACKGROUND: Piracetam has been proven to be effective and well tolerated in the treatment of myoclonus in short-term studies. OBJECTIVE: To assess its long-term clinical efficacy, 11 patients with disabling myoclonus due to progressive myoclonus epilepsy were treated with piracetam in an open-label study. METHODS: Neurologic outcome (at the 1st, 6th, 12th, and 18th month of treatment) was assessed by an adjusted sum score of the following 3 indices: motor impairment, functional disability, and global assessment of disability due to myoclonus. Severity of other neurologic symptoms (seizure frequency and severity, dysarthria, and gait ataxia) also was assessed. Treatment with piracetam was initiated at a dose of 3.2 g/d that was gradually increased until stable benefit was noted (maximal dose in the trial was 20 g/d). Concomitant antiepileptic drugs were maintained at their previous dose. RESULTS: Statistically significant improvement in the total rating score was observed after introduction of piracetam at the 1st, 6th, and 12th month of treatment. Severity of other neurologic symptom scores did not improve significantly. Two patients reported drowsiness during the first 2 weeks of treatment. CONCLUSIONS: Piracetam given as add-on therapy seems to be an effective, sustained, and well-tolerated treatment of myoclonus. In patients with progressive myoclonus epilepsy, the efficacy of the drug increased during the first 12 months of treatment and then stabilized. Epilepsia. 2001. Levetiracetam was approved in November 1999 as add-on therapy for the treatment of partial-onset seizures in adults (age 16 years and older). This review focuses on recently published data from four well-controlled studies in patients with partial-onset seizures with or without secondary generalization. When levetiracetam was given along with other antiepileptic drugs (AEDs), the most frequently reported adverse events were central nervous system related. Adverse events were usually mild to moderate in intensity, with the most frequently reported events occurring predominantly during the first 4 weeks of treatment. No relationship was apparent between the dose of levetiracetam and the most commonly reported adverse events in well-controlled clinical trials within the recommended dose range of 1,000-3,000 mg/day. Levetiracetam is a Pregnancy Category C drug. Overall, when used in combination with other AEDs, levetiracetam was generally well tolerated as add-on treatment for partial-onset seizures. Nippon Yakurigaku Zasshi. 2000 Oct. Myoclonus is defined as shock-like, brief involuntary abnormal movements in muscle jerking caused by external stimuli; and it arises from progressive myoclonus epilepsy, post-anoxic encephalopathy and Alzheimer's disease, causing disabling symptoms. It is a rare syndrome but very difficult to control. Piracetam (2-oxo-1-pyrrolidineacetamide, Myocalm) was developed more than 30 years ago as a cyclic derivative of gamma-aminobutyric acid (GABA); it has been used in European countries for the treatment of memory loss and other cognitive defects in patients. Some reports have suggested that piracetam has anti-myoclonus activities, but the mechanisms of myoclonus are not well-identified, and thus there have been few preclinical studies on piracetam for the treatment of myoclonus. We investigated the effect of piracetam and clonazepam, an anti-epileptic drug, on high dosage urea-induced myoclonus using an electromyogram in rats. The incidence of myoclonus induced by urea 4.5 g/kg (i.p.) was significantly reduced by piracetam at 300 mg/kg (i.p.) and by clonazepam at 0.3 mg/kg (p.o.). The coadministration of piracetam 100 mg/kg (i.p.) and clonazepam at 0.03-0.1 mg/kg (p.o.) significantly reduced the incidence of myoclonus, although separate administration was not effective. After oral administration of piracetam, it is rapidly and completely absorbed and excreted almost unchanged in the urine; however, it does show a little binding to human serum protein. Repeated oral administration of piracetam for 7 days in phase-I trials did not show any accumulation of the drug. In the placebo-controlled double-blind crossover trial of piracetam conducted in the UK, there was a significant improvement in cortical myoclonus. In phase-II trials, piracetam inhibited myoclonus and showed an improvement in the quality of life (QOL) of the patients. These results show that piracetam has a beneficial use in clinics for severe myoclonus patients when it is combined with anti-epileptic drugs, demonstrating an improvement in the myoclonus and QOL of patients. Epileptic Disord. 2000 Jun. Piracetam (PIR) and levetiracetam (LEV), an S-enantiomer, are pyrrolidone derivatives that share similar chemical structures but have distinct pharmacological profiles and consequently different clinical uses. Although the mode of action of neither drug has been fully elucidated, they do not interact with inhibitory or excitatory neurotransmission or alter membrane excitability. A brain-specific stereoselective binding site has been identified for which LEV and other S-enantiomers, but not PIR, have high affinity. In preclinical studies, PIR significantly improves learning and memory; in contrast, LEV has less effect but is much more active in preventing seizures. Both drugs have a high therapeutic index and are well tolerated. PIR, a nootropic drug, is used in the therapy of age-related cognitive disturbances and poststroke aphasia. Clinical experience has also shown that at high doses it is effective against cortical myoclonus. LEV is an antiepileptic drug. Clinical trials have confirmed its efficacy in partial seizures and preliminary findings suggest that it is also effective in generalized seizures and myoclonus. Eur J Pharmacol. 2000 Mar 17. The effects of the nootropic drug piracetam and its analogue, the antiepileptic drug levetiracetam (ucb L059) on severity of dystonic attacks were studied in a mutant hamster model of idiopathic generalized dystonia. Both drugs significantly decreased the severity of dystonia. In contrast to seizure models, in which levetiracetam is much more potent as an anticonvulsant than piracetam, the antidystonic potency of levetiracetam was only moderately higher than that of piracetam. The antidystonic activity of piracetam and levetiracetam was not associated with any behavioral side effects. The data indicate that piracetam and levetiracetam are interesting novel treatments for idiopathic dystonia. Pharmacopsychiatry. 1999 Mar. This paper reviews existing publications on the use of piracetam for the treatment of cortical myoclonus of various etiologies and includes the personal experience of the authors in progressive myoclonus epilepsy. Two double-blind comparisons with placebo provided results which allow recommendations for the dosage and usage of piracetam in cortical myoclonus. Wide individual variation (7-24g daily) exists in dosage requirements but responses are dose-related so that dosage should be increased until an optimum effect is obtained. Tolerability after long-term use of piracetam in high dosage has been very good and without toxicity or serious adverse effects. Side effects have been occasional, mild and transient. The authors present their experience of 12 patients with progressive myoclonus epilepsy in whom the administration of up to 45 g piracetam daily, when added to existing anti-epileptic treatment, caused marked and sometimes spectacular improvement and was without significant adverse effects. Improvement was maintained for up to 7 years. The use of piracetam for disabling cortical myoclonus of any etiology, either as an addition to existing antimyoclonic drugs or as monotherapy, may bring about profound improvement in disability and quality of life. Piracetam should be considered a first-line drug for the treatment of cortical myoclonus. Pharmacopsychiatry. 1999 Mar.\\
Piracetam: novelty in a unique mode of action. Extensive research of the recent years has demonstrated that piracetam is effective in the treatment of cognitive decline in aging and dementia. It is usually much more active in situations of impaired brain function. Accordingly, its mechanism of action has been associated with neurochemical deficits of the aged brain relevant to cognitive dysfunctions. Since many of these neurochemical deficits depend on changes of membrane properties, including fluidity, it is of special importance that piracetam not only modifies membrane properties by interacting with the polar head moieties of the phospholipid bilayer, but also that this effect is more pronounced in membranes of aged as opposed to young animal and human brains, and that this mechanism also has specific relevance for brain membranes of Alzheimer's disease patients. Altering membrane properties might also be involved in vascular effects of piracetam such as improved erythrocyte deformability and normalization of hyperactive platelet aggregation. This novel mechanism of piracetam thus combines a rather non-specific physico-chemical mode of action with the pharmacological and clinical experience with this unique drug - effects are always much more pronounced when function is impaired. Pediatr Neurol. 1998 Jan. To evaluate the efficacy of piracetam therapy, 76 children with breath-holding spells admitted to the Outpatient Clinic of Dicle University Medical Faculty Paediatrics Department and Bakirkoy State Hospital, Paediatrics Department between 1988 and 1990 and 1991 and 1996, respectively, were included in this placebo-controlled trial. Diagnosis of breath-holding spells was made for all cases by medical history, pediatric physical examination, electroencephalogram, and laboratory findings. Placebo or piracetam as suspension was administered to patients on a randomized basis; piracetam was administered to children in suspension 40 mg/kg/day in 2 divided doses for a period of 2 months. Of the 76 children enrolled, 39 received piracetam and 37 received placebo. Overall, control of breath-holding spells was observed in 92.3% of the patients in the group taking piracetam as compared with 29.7% in the group taking placebo (P < .05). No differences between the 2 groups in adverse events or side effects were observed. Complete blood count, biochemical profile, and urine analysis taken before and after treatment revealed no change from beginning to end and no difference between the 2 groups. It is suggested that piracetam is a safe and effective drug, with an incidence of side effects no different from that of placebo, for the treatment of breath-holding spells. Brain Res Brain Res Rev. 1994 May. Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible. Eksp Klin Farmakol. 1992 Jan-Feb. Overall 30 women in childbirth with preeclampsia and fetoplacental dysfunction received piracetam solution which was given initially in a dose of 5 g by intravenous drip, rapidly since the onset of labour and then every 2 hours till the end of labour in a dose of 2 g by jet injection. This made it possible to increase fetus resistance to hypoxic conditions. The concentrations of piracetam within the range of 60-80 g/l in the blood of women in childbirth should be viewed as minimum therapeutic. A single daily intramuscular injection of piracetam (50 mg/kg) into neonates with encephalopathies may build up blood concentrations equal to 25-60 mg/l after 2 hours. The drug is not detectable in the blood by the moment the next injection is given. Psychopharmacology (Berl). 1992. Oral pretreatment of mice with aldosterone or corticosterone blocked the memory-enhancing effects of piracetam, pramiracetam, aniracetam and oxiracetam in a dose-related manner, without, however, impairing the animals' learning performance. The improvement of memory induced by physostigmine, arecoline, and tacrine (THA) was similarly inhibited. The fact that elevated steroid levels suppress the memory-enhancing effects of entirely different substances could indicate that these substances have a common site of action. In the light of new observations showing increased cortisol concentrations in Alzheimer patients, this steroid dependency of the effects of memory enhancers might explain why only a limited number of these patients respond to therapy with nootropics or cholinomimetics. Drugs Aging. 1991 Jan. Piracetam is the first of the so-called 'nootropic' drugs, a unique class of drugs which affect mental function. In animal models and in healthy volunteers, the drug improves the efficiency of the higher telencephalic functions of the brain involved in cognitive processes such as learning and memory. The pharmacology of piracetam is unusual because it protects against various physical and chemical insults applied to the brain. It facilitates learning and memory in healthy animals and in animals whose brain function has been compromised, and it enhances interhemispheric transfer of information via callosal transmission. At the same time, even in relatively high dosages it is devoid of any sedative, analeptic or autonomic activities. How piracetam exerts its effects on memory disorders is still under investigation, although among other proposed mechanisms of action it is thought to facilitate central nervous system efficiency of cholinergic neurotransmission. Results from trials involving elderly patients with senile cognitive disorders have been equivocal, as have the results obtained when piracetam has been combined with acetylcholine precursors. Piracetam seems to be almost completely devoid of adverse effects, and is extremely well tolerated. In conclusion, opinion is divided as to the benefits of piracetam in the treatment of senile cognitive decline. Although double-blind studies in the elderly have produced mixed results, some such trials (particularly those involving larger numbers of patients) have reported favourable findings, thus offering some reason for cautious optimism in a notoriously difficult area of therapeutics. However, further investigations of piracetam alone and in combination therapy are required before any absolute conclusions can be drawn. Brain Res. 1990 Aug 6. The blockade of the memory-enhancing effects of piracetam resulting from adrenalectomy can be abolished by substitution with either corticosterone or aldosterone. However, corticosterone substitution does not reinstate these effects if the aldosterone receptors are blocked by the aldosterone antagonist epoxymexrenon. Brain Res. 1990 Jan 1. Since adrenalectomy abolishes the memory-enhancing effects of piracetam and its derivatives, oxiracetam, aniracetam and pramiracetam, the question arises whether endogenous steroids play a role in their mechanism of action. We show that inhibition of steroid biosynthesis by aminoglutethimide and blockade of the aldosterone receptors by epoxymexrenone completely suppress the memory-improving effects of the nootropics. These results indicate that steroids, or, more precisely, activities mediated by the aldosterone receptors, might be involved in the mechanism of action of this class of nootropics. Blockade of aldosterone receptors, however, does not block the effects of cholinomimetics on memory, indicating the involvement of another mechanism of action. Behav Brain Res. 1989 Aug 1. The present experiments demonstrate that the absence of any memory-improving action of nootropics in adrenalectomized animals cannot be ascribed to an effect of dosage. Doses of 1, 10, 100, 1000 and 3000 mg/kg p.o. of piracetam, oxiracetam, aniracetam or pramiracetam are ineffective in adrenalectomized mice. J Clin Psychopharmacol. 1987 Aug. Previous research has suggested that dyslexics treated with piracetam have shown improvements in reading skills, verbal memory and verbal conceptualizing ability, feature analysis, and processing of letter-like stimuli. Two hundred twenty-five dyslexic children between the ages of 7 years 6 months and 12 years 11 months whose reading skills were significantly below their intellectual capacity were enrolled in a multicenter, 36-week, double-blind, placebo-controlled study. Children of below average intelligence, with abnormal findings on audiologic, ophthalmologic, neurologic, psychiatric, and physical examinations, who were emotionally disturbed or educationally deprived and who had recently been treated with psychoactive medication were excluded from the trial. Piracetam was well tolerated, with no serious adverse clinical or laboratory effects reported. Piracetam-treated children showed significant improvements in reading ability (Gray Oral Reading Test) and reading comprehension (Gilmore Oral Reading Test). Treatment effects were evident after 12 weeks and were sustained for the total period (36 weeks). Int J Psychophysiol. 1986 May. Studies of 60 dyslexic boys age 8-14, carefully selected for exclusion of intellectual, sensory, psychiatric and neurological impairment and educational deprivation, were conducted to determine the efficacy of Piracetam, over a 12-week period, in improving reading and other related skills. There were no changes at the end of 12 weeks to distinguish the groups in accuracy or comprehension of prose-reading. Short-term memory gains, however, were recorded for the treated group on two different tests, digit span, and a test (Neimark) of immediate and delayed recall. The mean digit span scaled score for the entire group was one S.D. below their mean IQ. Considering only the performance of children whose digit span scaled scores were one S.D. or below the mean (7 or less), the treated group made a significant gain at the end of 12 weeks. On the Neimark test the treated group was significantly superior to the untreated group on first trial learning and they also lost significantly fewer object names after a delay. Improved retrieval from long-term storage could be demonstrated for the treated group on the rapid automatized naming test. Although there was no significant difference between the group at screening, the treated group was significantly faster on letter naming at the end of the drug trial. The treated group also improved their single word reading on the WRAT. Int J Psychophysiol. 1986 May. The effect of piracetam on visual event-related potentials (ERP) was investigated in a double-blind placebo-controlled study. Eight- to 12-year-old dyslexic males were randomly assigned to 3.3 g/day of piracetam or matching placebo in two divided doses over a 12-week period. Children performed a vigilance task in which they pressed a key when two alphabetic letters or shapes occurred in sequence. ERPs to letters and shapes, for active and passive responses, were recorded at the vertex and left and right parietal areas of the scalp. Performance measures included letter- and form-hits, misses, commission errors and reaction times. Piracetam increased the amplitude of a late positive component (believed to correspond to P300) at the vertex for letter-hits. Piracetam also increased the latency of this component in both hemispheres, but only for active responses (letter-hits) in the left hemisphere and passive responses (correct rejections and misses) in the right hemisphere. Although piracetam did not significantly affect performance, reaction time to letter-hits was significantly correlated with the latency of the P300 component, suggesting that letters created increased effort or attentional demand on the subjects compared with forms. An early ERP component (P225) also showed increased amplitude to piracetam in both hemispheres and effects were limited to form-hits. These effects were thought to possibly reflect slow negative potentials arising from stimulus anticipation in the CNV-like paradigm. In view of the small sample size, the results were cautiously interpreted as indicating a facilitation of verbal processing mechanisms responsible for analyzing the verbal significance of visual stimuli. Int J Psychophysiol. 1986 May. A new class of drugs (nootropics) are viewed from the perspective of their neuropsychological effect upon developmental dyslexia. Evidence from both the preclinical and clinical work conducted on Piracetam is briefly reviewed. The latest research on the effects of Piracetam in dyslexia shows a convergence of results. Attempts to replicate these results with dyslexia have only met with success in the areas of reading rate. In an attempt to find an independent replication of the Chase et al. (1984) finding, the author provides additional evidence on the effects of Piracetam on reading Rate X Accuracy in dyslexics. Int J Psychophysiol. 1986 May. Piracetam, a new class of drug (nootropil) thought to enhance specific cognitive skills, was given in a 3300 mg daily dose to half of a group of fifty-five dyslexic boys aged 8-13 years, in a 12-week, double-blind, placebo-controlled study. The other half of the subjects received placebo. All subjects met the following criteria: normal intelligence, normal educational opportunities, no severe emotional problems, no neurological handicaps, good physical health, not taking other psychotropic medication, and scoring at least one and one half years below their mental age equivalent on the Gilmore Oral Reading Test. Non-verbal (auditory and visual) and verbal perceptual, and memory skills were examined, and reading, spelling, language and writing abilities were measured using standardized instruments. Compared to the placebo control group, individuals treated with Piracetam did not show statistically significant improvements above their baseline scores on measures of perception, memory, language, reading accuracy or comprehension, or writing accuracy. However, reading speed and numbers of words written in a timed period were significantly enhanced in subjects treated with Piracetam as compared to placebo. Effective reading and writing ability, taking both rate and accuracy into consideration, were also significantly improved in the Piracetam as compared to the placebo treatment group. The medication was well-tolerated and medical examinations showed no significant adverse reactions. These results encourage further study of Piracetam to determine more precisely the mechanism of action by which specific cognitive skills are affected. J Clin Psychopharmacol. 1985 Oct. Following previous research which suggests that piracetam improves performance on tasks associated with the left hemisphere, a 12-week, double-blind, placebo-controlled study of developmental dyslexics was conducted. Six study sites treated 257 dyslexic boys between the ages of 8 and 13 years who were significantly below their potential in reading performance. Children were of at least normal intelligence, had normal findings on audiologic, ophthalmologic, neurologic, and physical examination, and were neither educationally deprived nor emotionally disturbed. Piracetam was found to be well tolerated in this study population. Children treated with piracetam showed improvements in reading speed. No other effects on reading were observed. In addition, improvement in auditory sequential short-term memory was observed in those piracetam-treated patients who showed relatively poor memory at baseline. It is suggested that longer term treatment with piracetam may result in additional improvements. Clin Immunol Immunopathol. 1983 Aug. By the use of immunobeads, a convenient clinical laboratory test is available which detects, in metabolically stressed leukocytes, failing or absent phagocytosis and/or impaired to absent oxidative metabolic activity. Furthermore, it has been demonstrated that Piracetam, 2-oxo-pyrrolidine acetamide, will restore such compromised neutrophils to normal functional status. In 4 of 19 patients, all with a variety of serious diseases, a range from impaired to total failure of neutrophilic phagocytic and metabolic oxidative activities was detected by the test. Piracetam, as shown by qualitative methods, restored to optimal activity the two impaired neutrophil functions in these 4 patients. Quantitative techniques are available currently to establish the beneficial effect of Piracetam on such defective neutrophils. Piracetam merits additional study to determine its efficacy in enhancement of restorative effects on compromised neutrophils which have been observed. The clinical promise of this investigation offers benefit to some patients now jeopardized by certain stressful diseases in part due to agonal failure of neutrophils. J Int Med Res. 1983. A double-blind study was performed on ninety-six parturients of the Lima Maternity Hospital, Peru, with some evidence of foetal distress who were given indistinguishably piracetam or a placebo at random in order to investigate the effects of the drug on the foetus. The conditions of the new-born babies who had received piracetam were superior to those of the babies treated with the placebo, as evaluated with the Apgar at 1, 5 and 10 minutes after birth and on the basis of the neurological and clinical examination as from 24 hours until they were released. In addition, the reduction of the duration of the labour in the patients treated with piracetam as compared with the control group was obvious. Zh Nevropatol Psikhiatr Im S S Korsakova. 1983. It was shown that a marked therapeutic effect or its absence in the piracetam and nootropil treatment of children with different degrees of mental retardation is largely determined by the presence in patients' metabolism (before treatment) of certain combined changes in the general activity of lactate dehydrogenase (LDH) and its isoenzymic spectrum with regard to the ratio between aerobic and anaerobic subunits. Experimental studies on rats support the necessity of taking into account patients' metabolism when prescribing nootropic agents. It is suggested that considering LDH changes (along with the clinical condition of patients) may be of prognostic significance in the efficacy assessment of treatment with nootropic drugs. Fortschr Med. 1979 Dec 6. It was evaluated by continuous cardiotocogram-, tcpO2-and EEG-registration sub partu to what extent these parameters are influenced by application of Piracetam (10 g i.v./h) to the mother. A group of 26 primigravida between 18 and 23 years of age with normal course of delivery at term was analyzed. Piracetam was applicated to 17 patients in the beginning of cervix dilatation, whereas the other patients got Laevulose as a placebo infusion. The results permit the conclusion that Piracetam provides a stabilization of cerebral functions with a certain resistence against transient hypoxia during the expulsion period. The EEG-registration demonstrates after application of Piracetam an activation of alpha-waves with simultaneous reduction of delta-waves, the CTG shows a reduced quantity of decelerations during the expulsion period. The data obtained by computerization correlate with the Apgar-Index (fetal outcome) after application of Piracetam, which was better than 9 in all cases. Psychopharmacology (Berl). 1979 Sep. Sixteen male dyslexic children were seen again when adults and matched with 14 student volunteers for a 21-day trial of piracetam. It was found, using a double-blind cross-over technique, that dyslexics significantly increased their verbal learning by 15.0% and students by 8.6% (over and above their placebo increase). Psychopharmacology (Berl). 1979 Sep. A study is described of effects of a nootropic drug on chronic schizophrenia. The nootropic drugs act on the central nervous system with the cerebral cortex as their target. Chronic schizophrenic patients on the drug showed improvement in object naming and in tests where the patient was required to indicate the number of times he had been tapped. Improvements were also noted in learning and memory tasks. In dichotic listening the patients showed a reduction in the amount of incorrect verbal responses produced. There were no improvements in symptom rating or social behaviour rating. These results suggest some cognitive improvement but little if any change in the disease state of the patient. J Int Med Res. 1979. The purpose of this controlled clinical trial was to demonstrate possible correlations between changes in bioenergetic metabolism and psychotropic drug administration in the treatment of functional psychosis. The study included twenty-six patients, eleven with schizophrenia, three with chronic atypical depression and twelve with drug-resistant endogenous depressions. All patients were kept on continuous psychotropic medication for at least 3 weeks before starting the trial, and piracetam was given additionally in a fixed dosage of 2400 mg daily; the same number of identical capsules was given during the pre- and post-treatment placebo periods. Psycho-pathological evaluation of the patients was by the BPRS; clinical and biochemical data were evaluated statistically by the analysis of regression. The results show that in schizophrenic patients an improvement was observed in those cases who had improved biochemically, i.e. where the ATP values had increased. In drug-resistant depressions there was a rapid and significant clinical improvement after piracetam co-administration, and this went in step with a significant rise in ATP levels. Fortschr Med. 1978 Oct 5. The excretion of Piracetam was monitored by measuring the concentrations in maternal and fetal substrates during labor in nine volunteers. Piracetam was tolerated without side-effects and injected in the maternal cubital vein. Consecutively, maternal plasma and urine samples as well as amniotic fluid portions were collected during labor. at delivery, fetal blood from placenta and the first fetal urines were collected. Biostatistical methods showed that approximately 50% of Piracetam were eliminated 80 minutes after the injection of the drug. In amniotic fluid a continuous rise of Piracetam concentrations was monitored until delivery. In fetal plasma and urines the substance could be detected. The rapid excretion of Piracetam during labor was obviously typical for the situation sub partu; reasons are discussed. Med Klin. 1976 Apr 23. Piracetam, 1-pyrrolidone acetamid, was tested in 40 chronic alcoholics with a more or less marked psycho-organic syndrome by means of psychological tests. It was a double-blind-cross-over study. Statistical analysis of the results showed that Piracetam improves the energo-functional capacity of the cortex i.e. the basal functions of the cortical cells such as activating capacity, vital dynamic, flexibility, intellectual reactivity and stress tolerance. Apart from the overall improvement we also observed an improvement of specific cerebral performances which is however unimportant in comparison with the greneralized effect. Pharmakopsychiatr Neuropsychopharmakol. 1975 Mar. Ten chronic schizophrenics were tested by clinical observations, psychological tests (FPI, LEV, d 2) and ratings with the Wittenborn-Psychiatric-Ratings-Scales (WPRS) before and after taking 2-pyrrolidon-acetamid. The improvement of obstructive, apathy, withdrawal and affective flatness in seven patients justify a double-blind psychometric evaluation concerning the effect of Piracetam on the schizophrenic deficiency states. |