Piracetam

Piracetam is a nootropic agent derived from the amino acid GABA. The way it works is yet to be discovered, but the substance seems to induce an improvement in cognitive functioning by causing important metabolic modifications. It is used in children for stimulating the ability to learn. It has neuroprotective properties and very low toxicity. It is used in the treatment of several mental syndromes caused by cerebral deficiency, for example psycho-organic senility syndrome. It is a useful aid in alcoholism treatment as well.

Piracetam, the generic name of which is Nootropil, is a nootropic agent, a derivative of the amino acid GABA. The way it works is not yet known, but it can be described as facilitating learning in ways that are hard to quantify. It seems to awaken a noticeable improvement in creativity and lucidity, but it is not a stimulant or sedative. Its neuro-protective properties and low toxicity are renowned.
It acts on the nerve cells to bring about important metabolic modifications, which in turn results in greater receptiveness and increased use of chemical energy by these cells. It treats mental syndromes caused by cerebral deficiency, disturbances in the mental performance of the elderly and with higher dosages psycho-organic senility syndrome and disturbances caused by alcohol withdrawal.
Piracetam has been proven to boost learning and memory in normal subjects as well as those who suffer cognitive deficits, and is also a cognitive enhancer under conditions of hypoxia or too little oxygen. Administering Piracetam also eases other conditions. These include alcoholism, stroke, vertigo, senile dementia or Alzheimer's, sickle cell anemia, dyslexia, vestibular migraine headaches, myoclonus, Raynaud's phenomenon, tinnitus, and numerous other health problems.

Epilepsia. 2005 May;46(5):775-7.
Levetiracetam concentrations in serum and in breast milk at birth and during lactation.
Johannessen SI, Helde G, Brodtkorb E.
The National Center for Epilepsy, Sandvika, Norway. svein.johannessen@epilepsy.no

PURPOSE: To study the pharmacokinetics of levetiracetam (LEV) at birth, during lactation, and in the nursed infant. METHODS: Eight consecutive breast-feeding women with epilepsy treated with LEV twice daily and their infants were studied. RESULTS: The mean umbilical cord serum/maternal serum ratio was 1.14 (range, 0.97-1.45) (n = 4). The mean milk/maternal serum concentration ratio was 1.00 (range, 0.76-1.33) at 3 to 5 days after delivery (n = 7). At sampling 2 weeks to 10 months after delivery (n = 5), it was similar (range, 0.85-1.38). At 3 to 5 days after delivery, the infants had very low LEV serum concentrations (<10-15 microM), a finding that persisted during continued breast-feeding. No malformations were detected, and in none of the infants did signs of adverse effects develop. CONCLUSIONS: Our data indicate an extensive transfer of LEV from mother to fetus and into breast milk. However, breast-fed infants had very low LEV serum concentrations, suggesting a rapid elimination of LEV.

Epilepsy Behav. 2005 May 2
Nonconvulsive status epilepticus on treatment with levetiracetam.
Atefy R, Tettenborn B.
Department of Neurology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.

In several studies the efficacy and tolerability of levetiracetam (LEV) have been demonstrated. We report two patients who developed nonconvulsive status epilepticus on treatment with LEV. Both patients never experienced status epilepticus before. One patient had a symptomatic epilepsy with complex partial seizures following radiotherapy of astrocytoma in 1985; the second patient had complex partial seizures due to mesial temporal sclerosis. Both patients received LEV 2000mg/day. We postulate a correlation between occurrence of nonconvulsive status and treatment with LEV. This has not been described before apart from a single report of mentally retarded patients with status epilepticus on high dosages of LEV.

Pharmacoeconomics. 2005;23(5):493-503.
Economic evaluation of levetiracetam as an add-on therapy in patients with refractory epilepsy.
Sheehy O, St-Hilaire JM, Bernier G, Godfroid P, Lelorier JJ.
Research Centre, University of Montreal Hospital, Montreal, Quebec, Canada.

OBJECTIVES: This study provides the results of a cost-effectiveness analysis of levetiracetam as an adjunctive treatment for refractory epilepsy from the Canadian Ministry of Health perspective. The main objective is to estimate the expected cost-effectiveness ratio expressed as the incremental cost per seizure-free day gained when using levetiracetam. In addition, this study examines the potential savings that might result by reducing the number of surgical evaluations and surgery when using levetiracetam. METHODS: A 1-year dose escalation decision-tree model comparing levetiracetam plus standard therapy with standard therapy alone was designed in order to combine probability, resource use and unit cost data (1999 Canadian dollars [$Can]). The short-term outcomes were derived from three phase III randomised, double-blind, placebo-controlled trials performed in 904 patients, aged 16-70 years, with at least 1 year history of epilepsy, two to four partial seizures per month, and receiving a maximum of two classic antiepileptic drugs. RESULTS: The average gain in seizure-free days attributed to levetiracetam was 19 days per patient per year and the incremental cost-effectiveness ratio (ICER) for levetiracetam add-on in the base-case scenario was $Can80.7 per seizure-free day gained per patient per year. Moreover, when surgical investigation and surgery are considered in the model, the use of levetiracetam may be dominant, with substantial savings to the overall healthcare budget. All univariate sensitivity analyses show that the model was robust to the assumptions made. CONCLUSIONS: The economic analysis presented in this paper suggests, given a wide range of assumptions, that the increased cost of treating patients (with refractory epilepsy) with levetiracetam may be partially offset by a reduction in other direct medical costs (from the Canadian Ministry of Health perspective), as a consequence of an increase in the number of seizure-free days. Moreover, potential cost savings may be foreseen when it is assumed that levetiracetam may reduce the number of candidates for surgical evaluation and surgery through a reduction of seizure frequency.

Drugs Aging. 2005;22(2):163-82.
Poststroke aphasia : epidemiology, pathophysiology and treatment.
Berthier ML.
Centro de Investigaciones Medico-Sanitarias (CIMES), University of Malaga, Malaga, Spain.

Aphasia, the loss or impairment of language caused by brain damage, is one of the most devastating cognitive impairments of stroke. Aphasia is present in 21-38% of acute stroke patients and is associated with high short- and long-term morbidity, mortality and expenditure. Recovery from aphasia is possible even in severe cases. While speech-language therapy remains the mainstay treatment of aphasia, the effectiveness of conventional therapies has not been conclusively proved. This has motivated attempts to integrate knowledge from several domains in an effort to plan more rational therapies and to introduce other therapeutic strategies, including the use of intensive language therapy and pharmacological agents.Several placebo-controlled trials suggest that piracetam is effective in recovery from aphasia when started soon after the stroke, but its efficacy vanishes in patients with chronic aphasia. Drugs acting on catecholamine systems (bromocriptine, dexamfetamine) have shown varying degrees of efficacy in case series, open-label studies and placebo-controlled trials. Bromocriptine is useful in acute and chronic aphasias, but its beneficial action appears restricted to nonfluent aphasias with reduced initiation of spontaneous verbal messages. Dexamfetamine improves language function in subacute aphasia and the beneficial effect is maintained in the long term, but its use is restricted to highly selected samples.Pharmacological agents operating on the cholinergic system (e.g. donepezil) have shown promise. Data from single-case studies, case series and an open-label study suggest that donepezil may have beneficial effects on chronic poststroke aphasia. Preliminary evidence suggests that donepezil is well tolerated and its efficacy is maintained in the long term. Randomised controlled trials of donepezil and other cholinergic agents in poststroke aphasia are warranted.

Epilepsia. 2005 Feb;46(2):324-6.
Rapid onset of action of levetiracetam in refractory epilepsy patients.
French J, Arrigo C.
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PURPOSE: To investigate whether rapid achievement of levetiracetam (LEV) steady state is translated into an immediate measurable efficacy. The time to onset of action of LEV immediately after its initiation in adult patients with refractory partial seizures was analyzed. METHODS: Treatment effect was assessed in a pooled analysis (n=883) from three randomized, double-blind, placebo-controlled add-on trials. RESULTS: The increase in the proportion of seizure-free patients over baseline was 15, 17, and 17% for the first, second, and third day, respectively, for the LEV 1,000-mg group (all differences statistically significant; McNemar p value<0.001), whereas the increase was 7, 9, and 9% for the 333-mg LEV group (differences not significant). No major changes were observed for the placebo group. For differences in proportion of seizure-free patients between groups, the probability of being seizure free in the LEV groups was twofold higher than in the placebo group. For the 1,000-mg LEV group, odds ratios were 2.3, 2.5, and 2.7 for the first, second, and third day of therapy, respectively; all differences versus placebo were statistically significant (logistic regression p values, all <0.001). The addition of LEV significantly increased the proportion of patients without a seizure as of the first day of therapy. Each of the first 3 days, seizure freedom was twice as likely to occur with LEV 1,000 mg than with placebo. CONCLUSIONS: Evidence of a rapid onset of action of LEV 1,000 mg was demonstrated through a significant increase in the proportion of seizure-free patients as of the first day of therapy.

J Pharm Biomed Anal. 2004 Sep 21;36(1):183-7.
Rapid quantitative analysis of oxiracetam in human plasma by liquid chromatography/electrospray tandem mass spectrometry.
Son J, Lee J, Lee M, Lee E, Lee KT, La S, Kim DH.
Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Chungryang, Seoul 130-650, South Korea.
A rapid and accurate reversed-phase liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantitative determination of oxiracetam in human plasma. After addition of internal standard (piracetam) plasma was precipitated with two volumes of acetonitrile and the supernatant was evaporated. The residues were dissolved in 0.1% acetic acid and analyzed by reversed-phase HPLC with the detection of the analyte in the multiple reaction monitoring (MRM) mode. This method for the determination of oxiracetam was accurate and reproducible, with a limit of quantitation of 0.2 microg/ml in human plasma. The standard calibration curve for oxiracetam was linear (r2 = 0.999) over the concentration range 0.2-40.0 microg/ml in human plasma. The intra- and inter-day precision over the concentration range of oxiracetam was lower than 8.3% (relative standard deviation, %R.S.D.), and accuracy was between 92.5-106.4%.

Farmaco. 2004 Sep;59(9):713-22.
Spectrophotometric and LC determination of two binary mixtures containing antihistamins.
El-Gindy A, Emara S, Mostafa A.
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt. ghhadad@hotmail.com
Several methods are developed for the determination of two binary mixtures containing cyclizine hydrochloride with pyridoxine HCl (mixture (mix.) 1); and cinnarizine with piracetam (mix. 2). The resolution of the two binary mixtures has been accomplished by using numerical spectrophotometric methods as partial least squares (PLS-1) and principal component regression applied to UV spectra of the mixture and graphical spectrophotometric method as second derivative of the ratio spectra (2DD). In addition, HPLC methods were developed depending on using RP18 column with mobile phase consisting of acetonitrile/0.05 M KH2PO4 (50:50, v/v, pH 4.0) with UV detection at 239 nm for mix. 1, and mobile phase consisting of acetonitrile/0.05 M KH2PO4/triethylamine (50:50:0.2, v/v/v, pH 3.0) with UV detection at 227 nm for mix. 2. The proposed methods were successfully applied for the determination of the two binary combinations in synthetic mixtures and commercial tablets.

Int J Neuropsychopharmacol. 2004 Sep;7(3):351-69. Epub 2004 Jul 01.
Evidence-based pharmacotherapy of Alzheimer's disease.
Evans JG, Wilcock G, Birks J.
Cochrane Dementia and Cognitive Improvement Group, University of Oxford, UK.
Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimer's disease. Descriptions of the clinical manifestations of Alzheimer's disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimer's disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimer's disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimer's disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimer's disease.

J Neural Transm. 2004 Sep;111(9):1121-39. Epub 2004 May 14.
Effects of piracetam alone and in combination with antiepileptic drugs in rodent seizure models.
Fischer W, Kittner H, Regenthal R, Russo E, De Sarro G.
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Germany.
The nootropic drug piracetam was investigated in various experimental models of epilepsy. Generally, piracetam exhibits no or only moderate anticonvulsant properties against generalized tonic or clonic seizures. However, in many cases it did increase the anticonvulsant effectiveness of conventional antiepileptics, as shown in the maximal electroshock seizure (MES) threshold test, the traditional MES test or in DBA/2 mice. A pharmacokinetic interaction does not seem to be responsible for this effect. In lethargic mice, a model of absence seizures, piracetam significantly decreased the incidence and duration of spike-wave discharges. Furthermore, in the cobalt-induced focal epilepsy model piracetam reduced the number of spikes/min and in the hippocampal stimulation model it increased the anticonvulsant potency of phenobarbital and phenytoin after single and repeated administration. In conclusion, the well tolerated piracetam itself did not show marked anticonvulsant effects in most screening tests, however, its co-medication with antiepileptic drugs improved seizure protection in various models which may bear potential clinical significance.

Pharmacol Biochem Behav. 2004 Sep;79(1):11-6.
Effect of leaves of Butea frondosa on stress, anxiety, and cognition in rats.
Soman I, Mengi SA, Kasture SB.
C.U. Shah College of Pharmacy, SNDT University Santacruz (W), Mumbai 400 049, Maharashtra, India.
The plant Butea frondosa has been indicated in the Indian system of medicine as a plant augmenting memory and as a rejuvenator. The effect of oral administration of the aqueous and alcoholic extracts of the leaves was assessed on stress, cognitive function, and anxiety in albino rats. The antistress activity was evaluated using cold restraint induced ulcers and leukocyte count after subcutaneous injection of milk. The aqueous extract provides protection against stress-induced gastric lesions while both the alcoholic as well as the aqueous extract normalizes the white blood cell count. Effect on cognitive function was evaluated using Cook and Weidley's pole apparatus. The results indicate that the aqueous extract and the alcoholic extract when administered at a dose of 300 mg/kg for a period of 7 days augment both the acquisition as well as the retention of memory of learned task. The absence of an increase in the occupancy of the open arm in the elevated plus maze and in the number of head dips in the hole-board paradigms indicates that both the extracts are devoid of anxiolytic activity. Nootropic activity was compared using piracetam (100 mg/kg po) as the standard, while for anxiolytic and antistress activity, diazepam (1.0 mg/kg ip) was employed as the standard drug. It is concluded that the aqueous and alcoholic extract of B. frondosa possesses antistress and weak nootropic activity.

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004 Aug;24(8):694-7.
Clinical study of shuizhitong capsule in treating senile vascular dementia
Fan XZ, Yang BL.
The Third Affiliated Hospital of Henan TCM College, Zhengzhou (450000). xifenli@yahoo.com
OBJECTIVE: To observe the clinical therapeutic effect of Shuizhitong capsule (SZT) in treating senile vascular dementia (VD) and on changes of related physio-chemical criteria. METHODS: Eighty-five patients with VD were randomly divided into the treated group (n = 51) and the control group (n = 34) in the ratio of 3:2, treated with SZT and Piracetam respectively. Before and after treatment, the Zhang's Dementia Scoring (HDS) and Function of Social Activity Questionnaire (FAQ) scoring, cerebral blood flow and hemorrheologic properties were determined. RESULTS: SZT could significantly improve the patients' clinical symptoms, intracranial hemodynamic condition and the hyperviscosity, hypercoagulation and hyperaggregation status, lower the whole blood and plasma specific viscosity, raise the living standard of partial patients, with significant difference between before and after treatment (P < 0.05). CONCLUSION: The therapeutic effect of SZT in treating senile VD is definite.

Epilepsia. 2004 Jul;45(7):737-44.
The activity of antiepileptic drugs as histone deacetylase inhibitors.
Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M, Bialer M.
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Ein Karem, Hebrew University of Jerusalem, Israel.
PURPOSE: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors. METHODS: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate. RESULTS: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent Ki values of 2.22 +/- 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinone-n-butyric acid (PBA), inhibited HDACs with Ki values of 2.25 +/- 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively. CONCLUSIONS: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA. Copyright 2004 International League Against Epilepsy

Epilepsia. 2004 Jul;45(7):719-28.
Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine.
Pisani A, Bonsi P, Martella G, De Persis C, Costa C, Pisani F, Bernardi G, Calabresi P.
Clinica Neurologica, Dipartimento di Neuroscienze, Universita di Roma "Tor Vergata,", Rome, Italy. pisani@uniroma2.it
PURPOSE: Alterations in neuronal calcium (Ca2+) homeostasis are believed to play an essential role in the generation and propagation of epileptiform events. Levetiracetam (LEV) and lamotrigine (LTG), novel antiepileptic drugs (AEDs), were tested on epileptiform events and the corresponding elevations in intracellular Ca2+ concentration ([Ca2+]i) recorded from rat neocortical slices. METHODS: Electrophysiological recordings were performed from single pyramidal neurons from a slice preparation. Spontaneous epileptiform events consisting of long-lasting, repetitive paroxysmal depolarization shifts (PDSs) and interictal spike activity were induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. Simultaneously, microfluorimetric measurements of [Ca2+]i were performed. Optical imaging with Ca2+ indicators revealed a close correlation between Ca2+ transients and epileptiform events. RESULTS: Both LEV and LTG were able to reduce both amplitude and duration of PDSs, as well as the concomitant elevation in [Ca2+]i, in a dose-dependent fashion. Whole-cell patch-clamp recordings from isolated neocortical neurons revealed that LEV significantly reduced N-, and partially P/Q-type high-voltage-activated (HVA) Ca2+ currents, whereas sodium currents were unaffected. Interestingly, the inhibitory effects of LEV were mimicked and occluded by LTG or by a combination of omega-conotoxin GVIA and omega-agatoxin IVA, selective blockers of N- and P/Q-type HVA channels, respectively, suggesting a common site of action for these AEDs. CONCLUSIONS: These results demonstrate that large, transient elevations in neuronal [Ca2+]i correlate to epileptiform discharges. The antagonistic effects of LEV and LTG on [Ca2+]i overload might represent the basis for their anticonvulsant efficacy and could preserve neuronal viability. Copyright 2004 International League Against Epilepsy

J Pharmacol Exp Ther. 2004 Jul;310(1):386-94. Epub 2004 Mar 05.
The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B.
Department of Molecular and Cellular Biology, UCB Research Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. berkley.lynch@ucb-group.com
Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding. LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies.

Ann N Y Acad Sci. 2004 Jun;1019:401-5.
Prolongevity medicine: Antagonic-Stress drug in distress, geriatrics, and related diseases. II. Clinical review--2003.
Riga S, Riga D, Schneider F.
Department of Stress Research and Prophylaxis, Al. Obregia Clinical Hospital of Psychiatry, 10 Berceni Road, Sector 4, RO-041914 Bucharest 8, Romania. d_s_riga@yahoo.com
Distress and senescence, their reciprocal aggravating-quickening connections, and their related pathologies have a large worldwide impact on healthcare systems in this new millennium. For this reason, Antagonic-Stress (AS)--an advanced integrative therapy, with specific synergistic composition, and patented internationally--represents a significant strategy in health, aging, and longevity. Clinical research with AS proves the drug's efficacy in the management of distress (neurotic, stress-related, and affective disorders; behavioral syndromes associated with physiological disturbances and physical factors; mental and behavioral disorders due to psychoactive substance uses) and psychogeriatrics [organic, including symptomatic, mental disorders (OMD)]. Specific multiaxial psychopathological instruments and psychometric tests in multiple assessments used for gerontopsychiatry demonstrated strong improvements after AS administration in early-moderate stages of Alzheimer or vascular dementia, as well as in other OMD. In addition, comparative clinical studies evinced the superiority of AS (synergistic multitherapy) versus monotherapy [meclofenoxate (MF), piracetam (PA), pyritinol (PT), and nicergoline (NE), respectively]. These comparative clinical trials agreed closely with comparative preclinical research and confirmed AS synergistic homeostatic, adaptogenic, antioxidative, cerebrovascular, neurometabolic, and nootropic actions. Also, the AS protective actions against oxidative stress recommend this orthomolecular therapy in stress, aging, and free radical pathology.

Ann N Y Acad Sci. 2004 Jun;1019:64-9.
Antiaging treatments have been legally prescribed for approximately thirty years.
Ukraintseva SV, Arbeev KG, Michalsky AI, Yashin AI.
Max Planck Institute for Demographic Research, 18057 Rostock, Germany. ukraintseva@cds.duke.edu
There is an interesting divergence between the achievements of geriatrics and gerontology. On the one hand, during the last 30 years physicians in many developed countries have successfully prescribed several medicines to cure various symptoms of senescence. On the other hand, the influence of such medicines on human life span practically has not been studied. The most common of the relevant medicines are nootropic piracetam, gamma-aminobutyric acid (GABA), selegiline, Ginkgo biloba, pentoxifylline, cerebrolysin, solcoseryl, ergoloid, vinpocetin, sertraline, and estrogens, among others. Available data from human clinical practices and experimental animal studies indicate that treatments with these drugs improve learning, memory, brain metabolism, and capacity. Some of these drugs increase tolerance to various stresses such as oxygen deficit and exercise, stimulate the regeneration of neurons in the old brain, and speed up the performance of mental and physical tasks. This means that modern medicine already has "antiaging" treatments at its disposal. However, the influence of such treatments on the mean and maximal life span of humans, and on the age trajectory of a human survival curve has been poorly studied. The increase in human life expectancy at birth in the second half of the last century was mostly caused by the better survival at the old and oldest old rather than at the young ages. In parallel, the consumption of brain protective and regenerative drugs has been expanding in the elderly population. We provide evidence in support of the idea that the consumption of medicines exerting antiaging properties may contribute to the increase in human longevity.

Br J Pharmacol. 2004 Jun;142(3):594-608. Epub 2004 May 17.
Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport.
Naftalin RJ, Cunningham P, Afzal-Ahmed I.
Physiology Division, Centre for Vascular Biology and Medicine, King's College London, Guy's Campus, New Hunt's House, London SE1 1UL. Richard.Naftalin@kcl.ac.uk
1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (P<0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (P<0.001). 3 Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis.

Curr Drug Targets CNS Neurol Disord. 2004 Jun;3(3):181-94.
AMPA receptor potentiators for the treatment of CNS disorders.
O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES.
Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. Oneill_Michael_J@Lilly.com
Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.

Epilepsia. 2004 Jun;45(6):678-81.
Antimyoclonic effect of levetiracetam in 13 patients with Unverricht-Lundborg disease: clinical observations.
Magaudda A, Gelisse P, Genton P.
Center for Diagnosis and Care of Epilepsy, University of Messina, Italy. adriana.magaudda@libero.it
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.

Infection. 2004 Jun;32(3):176-8.
Trimethoprim-sulfamethoxazole exacerbates posthypoxic action myoclonus in a patient with suspicion of Pneumocystis jiroveci infection.
Jundt F, Lempert T, Dorken B, Pezzutto A.
Dept. of Hematology and Oncology, Charite, Campus Virchow-Klinikum, Humboldt University of Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. franziska.jundt@charite.de
We describe a 58-year-old patient with relapsing high-grade non-Hodgkin's lymphoma who exhibited exacerbation of posthypoxic action myoclonus during high-dose intravenous trimethoprim-sulfamethoxazole (TMP-SMX) treatment for highly suspicious Pneumocystis jiroveci pneumonia (PCP). Three months previously the patient had experienced a hypoxic insult caused by respiratory arrest due to an anaphylactic reaction to antibiotic therapy. He had developed posthypoxic action myoclonus (Lance-Adams syndrome), which was well controlled by oral treatment with piracetam. However, after TMP-SMX therapy (115 mg/kg daily) was started for suspicion of newly developed PCP, posthypoxic action myoclonus worsened dramatically resulting in complete disability. Anti-myoclonic therapy with increased doses of piracetam and valproic acid did not significantly improve his clinical condition. Only when TMPSMX doses were reduced (38 mg/kg daily) on day 12 did action myoclonus cease within 2 to 3 days. We suggest that TMP-SMX can exacerbate posthypoxic action myoclonus. Copyright Urban and Vogel

MMW Fortschr Med. 2004 May 24;146 Spec No 2:53-6.
Current antidementive therapy
Perneczky R, Kurz A.
Klinik und Poliklinik fur Psychiatrie und Psychotherapie der TU Munchen. robert.perneczky@lrz.tu-muenchen.de
Current antidementive treatment can delay further progress of the symptoms of dementia and should therefore be initiated as early as possible and be of adequate duration. Wherever possible, maximum permissible doses should be given. The efficacy of current antidementive drugs in Alzheimer's disease has been sufficiently documented by relevant studies. The acetylcholinesterase inhibitors, donepezil, galantamine and rivastigmine have been approved for the treatment of mild-to-moderate Alzheimer's dementia, the NMDA inhibitor memantine is approved for moderate-to-severe Alzheimer's disease. Ginkgo biloba or piracetam are alternatives for patients with mild-to-moderate dementia, in whom acetylcholinesterase inhibitors cannot be used.

Epilepsia. 2004 May;45(5):410-23.
Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA; American Academy of Neurology Therapeutics and Technology Assessment Subcommittee; American Academy of Neurology Quality Standards Subcommittee; American Epilepsy Society Therapeutics and Technology Assessment Subcommittee; American Epilepsy Society Quality Standards Subcommittee.
Neurological Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. jfrench@mail.med.upenn.edu
PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) [gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS)] in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 to March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. GBP can be effective for the treatment of mixed seizure disorders, and GBP, LTG, OXC, and TPM for the treatment of refractory partial seizures in children. Limited evidence suggests that LTG and TPM also are effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox-Gastaut syndrome. CONCLUSIONS: The choice of AED depends on seizure and/or syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Epilepsia. 2004 May;45(5):401-9.
Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA; American Academy of Neurology Therapeutics and Technology Assessment Subcommittee; American Academy of Neurology Quality Standards Subcommittee; American Epilepsy Society Quality Standards Subcommittee; American Epilepsy Society Therapeutics and Technology Assessment Subcommittee.
Neurological Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. frenchj@mail.med.upenn.edu
PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 until September 2002, with selected manual searches up to 2003. RESULTS: Evidence exists, either from comparative or dose-controlled trials, that GBP, LTG, TPM, and OXC have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. Evidence also shows that LTG is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

Neurology. 2004 Apr 27;62(8):1261-73.
Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society.
University of Pennsylvania, Philadelphia, USA.
OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Clin EEG Neurosci. 2004 Apr;35(2):84-7.
"Mu rhythm status" and clinical correlates.
Niedermeyer E, Goldszmidt A, Ryan D.
Division of Neurology, Department of Internal Medicine, The Sinai Hospital, Baltimore, Maryland, USA.
Rolandic mu rhythm is usually limited to brief stretches of 0.5 to 2 sec duration. Two observations of status-like enhancement of mu rhythm have prompted this report. In both cases, 4-hour EEG-Video-Monitoring was used. Clinically, the reported cases differed considerably. Case 1 showed nearly continuous mu activity associated with general motionlessness: akinesia/amimia but without rigidity, caused by frontal lobe impairment due to multiple sclerosis. In Case 2, an impressive mu-status started in drowsiness and was presumably attributable to levitiracetam (which had rendered seizure-free the patient's formerly severe case of temporal lobe epilepsy). Mu rhythm status, thus far, is an unknown EEG entity. It can be caused by impaired fronto-motor input and may also constitute a medication-effect (levitiracetam).

Epilepsy Behav. 2004 Apr;5(2):260-3.
Aromatase inhibition, testosterone, and seizures.
Harden C, MacLusky NJ.
Department of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College of Cornell University, New York, NY, USA. clharden@med.cornell.edu
The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosterone's action in the brain may be due to its conversion to estrogen via aromatase. We report herein a 61-year-old man with temporal lobe epilepsy and sexual dysfunction due to low testosterone levels. Use of an aromatase inhibitor, letrozole, normalized his testosterone level and improved his sexual functioning. Letrozole, in addition to standard antiseizure medication, was also associated with improved seizure control. This was sustained and, further, was associated with seizure exacerbation after withdrawing letrozole, and subsequent seizure improvement after restarting it. During the course of treatment, his serum testosterone level increased, sex hormone-binding globulin decreased (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels increased, while serum estradiol levels remained undetectable. Letrozole may, therefore, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. This experience suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy

Nutrition. 2003 Nov;19(11-12):957-75.
"Brain-specific" nutrients: a memory cure?
McDaniel MA, Maier SF, Einstein GO.
Department of Psychology, University of New Mexico, Albuquerque, New Mexico, USA
We review the experimental evaluations of several widely marketed nonprescription compounds claimed to be memory enhancers and treatments for age-related memory decline. We generally limit our review to double-blind placebo-controlled studies. The compounds examined are phosphatidylserine (PS), phosphatidylcholine (PC), citicoline, piracetam, vinpocetine, acetyl-L-carnitine (ALC), and antioxidants (particularly vitamin E).In animals, PS has been shown to attenuate many neuronal effects of aging, and to restore normal memory on a variety of tasks. Preliminary findings with humans, though, are limited. For older adults with probable Alzheimer's disease, a single study failed to demonstrate positive effects of PS on memory performance. For older adults with moderate cognitive impairment, PS has produced consistently modest increases in recall of word lists. Positive effects have not been as consistently reported for other memory tests. There is one report of consistent benefits across a number of memory tests for a subset of normal adults who performed more poorly than their peers at baseline.The choline compounds PC and citicoline are thought to promote synthesis and transmission of neurotransmitters important to memory. PC has not proven effective for improving memory in patients with probable Alzheimer's disease. The issue remains open for older adults without serious degenerative neural disease. Research on citicoline is practically nonexistent, but one study reported a robust improvement in story recall for a small sample of normally aging older adults who scored lower than their peers in baseline testing.Animal studies suggest that piracetam may improve neuronal efficiency, facilitate activity in neurotransmitter systems, and combat the age-related decrease in receptors on the neuronal membrane. However, for patients with probable Alzheimer's disease, as well as for adults with age-associated memory impairment, there is no clear-cut support for a mnemonic benefit of piracetam.Vinpocetine increases blood circulation and metabolism in the brain. Animal studies have shown that vinpocetine can reduce the loss of neurons due to decreased blood flow. In three studies of older adults with memory problems associated with poor brain circulation or dementia-related disease, vinpocetine produced significantly more improvement than a placebo in performance on global cognitive tests reflecting attention, concentration, and memory. Effects on episodic memory per se have been tested minimally, if at all.ALC participates in cellular energy production, a process especially important in neurons, and in removal of toxic accumulation of fatty acids. Animal studies show that ALC reverses the age-related decline in the number of neuron membrane receptors. Studies of patients with probable Alzheimer's disease have reported nominal advantages over a range of memory tests for ALC-treated patients relative to placebo groups. Significant differences have been reported rarely, however. Whether ALC would have mnemonic benefits for aging adults without brain disease is untested as far as we know.Antioxidants help neutralize tissue-damaging free radicals, which become more prevalent as organisms age. It is hypothesized that increasing antioxidant levels in the organism might retard or reverse the damaging effects of free radicals on neurons. Thus far, however, studies have found that vitamin E does not significantly slow down memory decline for Alzheimer's patients and does not produce significant memory benefits among early Parkinson's patients. Neither did a combination of vitamins E and C significantly improve college students' performance on several cognitive tasks.In sum, for most of the "brain-specific" nutrients we review, some mildly suggestive effects have been found in preliminary controlled studies using standard psychometric memory assessments or more general tests designed to reveal cognitive impairment. We suggest that future evaluations of the possible memory benefits of these supplements might fruitfully focus on memory processes rpplements might fruitfully focus on memory processes rather than on memory tests per se.

J Clin Psychiatry. 2003 Jul;64(7):781-4.
Levetiracetam in the treatment of acute mania: an open add-on study with an on-off-on design.
Grunze H, Langosch J, Born C, Schaub G, Walden J.
Department of Psychiatry at the University of Munich, Germany.
BACKGROUND: Levetiracetam is a novel antiepileptic drug with a broad spectrum of efficacy in epilepsy. We have tested the antimanic properties of the drug as an add-on to haloperidol in an open trial. METHOD: After giving informed written consent, 10 bipolar I acutely manic (DSM-IV) inpatients were investigated in an on-off-on study design. All patients were treated with 5 to 10 mg/day of haloperidol, depending on tolerability, throughout the investigation. Levetiracetam (up to 4000 mg/day) was added until day 14, then discontinued and reintroduced at day 21. The psychopathologic changes were assessed with the Young Mania Rating Scale (YMRS). RESULTS: After a mean decrease of the YMRS scores from 29.6 to 17.2 during the first "on" phase, manic symptoms worsened during the "off" period (YMRS score 20.9) and ameliorated again during the second "on" phase, with a decrease of the mean YMRS score to 14.7 at the end of the study. The mean dose of levetiracetam was 3125 mg/day. At day 14, only 2 (20%) of 10 patients were responders (defined as a decrease in YMRS scores of 50%) compared with 7 (70%) of 10 responders at the end of the study at day 28. CONCLUSION: The results from this open on-off-on add-on study suggest that levetiracetam exhibited additional antimanic effects. Controlled studies are clearly required.

Epileptic Disord. 2003 May;5 Suppl 1:S57-63.
Safety profile of levetiracetam.
Arroyo S, Crawford P.
Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
A good balance between safety and tolerability is necessary for an antiepileptic drug (AED) to be successful in the management of patients with epilepsy. Levetiracetam is one of the new generation of AEDs licensed as an add-on therapy for the treatment of patients with partial-onset seizures. Leveti-racetam's mechanisms of action are not fully understood. Controlled clinical trials, open-label studies, and postmarketing surveillance indicate that leveti-racetam has a favorable safety profile characterized by little effect on vital signs or clinical laboratory values, reported adverse events that are mild to moderate, and no known drug-drug interactions. The tolerability of levetiracetam may extend to both pediatric and elderly patients based on analyses of small numbers of patients. Tolerability is maintained over the long term. Levetirac-etam does not appear to have a different safety profile in learning-disabled patients. Levetiracetam appears to have a good balance between tolerability and efficacy in the treatment of a wide variety of patients with partial epilepsy.
Epileptic Disord. 2003 May;5 Suppl 1:S33-7.
Long-term experience with levetiracetam.
Abou-Khalil B, Lazenby B.
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-3375, United States.
Although short-term clinical trials provide important data regard-ing efficacy and tolerability, long-term studies are needed to address important aspects of clinical practice, such as long-term efficacy and safety. Long-term studies and post-marketing data show that the efficacy of levetiracetam is sustained over the long term and that this antiepileptic drug continues to be well tolerated, with low withdrawal rates and high retention rates. Patients continue to achieve significant reductions in seizure frequency and may achieve seizure freedom. Levetiracetam may allow patients to decrease the number of concomi-tant antiepileptic medications or withdraw to monotherapy. Add-on therapy with levetiracetam should be considered when additional control of seizures is needed.