Epc_262.tex

LEVITATING LEVETIRACETAM'S STATUS FOR STATUS EPILEPTICUS Intravenous Levetiracetam in the Treatment of Benzodiazepine Refractory Status Epilepticus. Knake S, Gruener J,
Hattemer K, Klein KM, Bauer S, Oertel WH, Hamer HM, Rosenow F. J Neurol Neurosurg Psychiatry 2008;79(5):588-589.
In 2006, levetiracetam was approved as the first of the newer anticonvulsive drugs as an intravenous formulation (ivLEV) for patients
with epileptic seizures who are unable to take oral medication. We report our experience with the use of ivLEV for the treatment of 18 episodes of benzodiazepine refractory focal status epilepticus (SE) in 16 patients, including four patients with secondary generalised SE. SE was controlled in all patients by the given combination of drugs; application of further antiepileptic medications after ivLEV was necessary in two episodes. No severe side effects occurred. Our data suggest that ivLEV may be an alternative for the treatment of SE in the future, even in patients that did not respond to benzodiazepines. A large prospective, randomised, controlled study is warranted to investigate the efficacy and safety of ivLEV for the treatment of SE.
COMMENTARY
levetiracetam; only one had failed IV phenytoin first. All pa-tients were discharged on oral levetiracetam, with a mean dose W hen the first intravenous (IV) medication (typically a ofjustover2,000mg/day.
benzodiazepine) does not stop status epilepticus (SE), The limitations of the study should be kept in mind. The administration of subsequent agents often is ineffective. In the group of patients was highly selective and received IV levetirac- landmark prospective, randomized clinical trial for the treat- etam for SE (rather than IV phenytoin or fosphenytoin) for a ment of SE, the second agent was successful in only 7% of particular, clinically relevant reason-most commonly because patients if the first agent failed (1). Although anesthetic doses of hepatic failure or to avoid interactions with anticoagulants of midazolam and propofol are quite effective in this situation, or chemotherapy. The study was open label and retrospective; they frequently require respiratory support and long-term crit- thus, the possibility of publication bias also must be considered.
ical care. Thus, there is a need for effective IV agents that do Perhapshundredsofcentershavereviewedtheirexperiencewith not result in prolonged sedation or respiratory compromise. IV IV levetiracetam, but only those with highly impressive results valproate has shown significant promise in this regard (2), and go on to submit for publication. Indeed, the outcomes seem al- now IV levetiracetam is demonstrating similar promise.
most too good to be true. Finally, four of the eight authors have In 2006, the United States Food and Drug Administration received speakers' honoraria or research grants from the manu- approved the IV formulation of levetiracetam for instances in facturer of levetiracetam, as has the author of this commentary.
which oral medication cannot be used: up to 1,500 mg in a Nonetheless, the report by Knake et al. is quite encouraging single dose, administered over 15 minutes after dilution (com- and provides justification for future prospective clinical trials.
patible with most or all diluents). IV levetiracetam was not How does levetiracetam stop seizure activity? The mecha- approved for higher doses or for use in status epilepticus. How- nism remains somewhat unclear, but its study has led to inter- ever, studies rapidly appeared showing that up to 2,500 mg esting new insights. Levetiracetam is not effective in some of the over 5 minutes and up to 4,000 mg over 15 minutes could be classic animal models of acute seizures, such as maximal elec- administered safely to normal volunteers (3).
troshock and pentylenetetrazol, but it is effective against several The current retrospective study by Knake et al. is the models of chronic epilepsy, such as kindling (4). This finding first report involving a reasonable number of patients with might suggest that it would not be effective in SE, and animal SE who were treated with IV levetiracetam. All patients had studies have been conflicting in this regard (4). Levetiracetam focal-onset SE and failed treatment with a benzodiazepine (usu- seems to desynchronize neuronal networks without affecting ally lorazepam) prior to receiving IV levetiracetam. The mean normal neuronal transmission, thereby preventing burst firing.
levetiracetam loading dose was 944 mg, usually given over It may prevent early changes in gene expression during kindling 30 minutes, followed by a mean maintenance dose of 2,166 and modulates effects of calcium and GABA. The most inter- mg/day. There were no serious adverse effects, and intubation esting discovery has been that levetiracetam binds to synaptic was avoided in 17/18 episodes. Efficacy was impressive, with vesicle protein 2A, a regulator of vesicular traffic and therefore, clinical seizure activity stopping in all patients and rarely recur- of neurotransmitter release, and the potency of binding seems ring. Five patients had failed IV valproate prior to receiving IV to correlate with antiseizure efficacy. SV2A knockout mice have growth retardation, progressive seizures, and premature death.
Epilepsy Currents, Vol. 8, No. 5 (September/October) 2008 pp. 125-126 Exactly how levetiracetam binding to SV2A leads to decreased seizures is unclear. Some investigators have argued that IV levetiracetam is neuroprotective or antiepileptogenic, and there shares these features. The current report provides justificationis some evidence that this is the case in models of epilepsy, stroke, for continued use of IV levetiracetam for critically ill patientstrauma, and subarachnoid hemorrhage. However, there is also with seizures (including SE in carefully selected cases) and forevidence to the contrary, as recently reviewed in this journal (5). assessing it in future clinical trials on the treatment of SE.
Does levetiracetam need to be given intravenously? The answer to this question is not clear, as oral absorption is typi- by Lawrence J. Hirsch, MD cally excellent. However, it has not been studied in critically ill
patients or those under sedation. Until the pharmacokinetics
in the acute setting is known, it may be preferable to utilize References
IV administration during acute seizure circumstances. Having
1. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, promptly available serum level determination may allow for Rowan AJ, Handforth A, Faught E, Calabrese VP, Uthman a more rapid, yet safe switch to oral administration. There are BM, Ramsay RE, Mamdani MB. A comparison of four treat- several studies that have found oral levetiracetam (via a nasogas- ments for generalized convulsive status epilepticus. Veterans Af-fairs Status Epilepticus Cooperative Study Group. N Engl J Med tric tube) to be effective in acute, refractory seizures, including 2. Hirsch LJ. The status of intravenous valproate for status. Epilepsy Shortly after the current study was published, a similar study reported on the use of IV levetiracetam in 50 criti- 3. Ramael S, Daoust A, Otoul C, Toublanc N, Troenaru M, Lu cally ill patients, including 24 with SE (9). SE ceased in two- ZS, Stockis A. Levetiracetam intravenous infusion: a randomized,placebo-controlled safety and pharmacokinetic study. Epilepsia thirds of the cases at a mean dose of 1,780 mg, typically given over 15-30 minutes, with seizure cessation confirmed by EEG.
4. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: the profile Two of the 50 patients given IV levetiracetam developed tran- of a novel anticonvulsant drug-part I: preclinical data. CNS Drug sient thrombocytopenia (dropping from normal to 55,000 and 82,000); no serious adverse effects were noted.
5. Dudek FE, Bertram EH, Staley KJ. Antiepileptogenesis therapy Is IV levetiracetam ready to be used routinely for the man- with levetiracetam: data from kindling versus status epilepticusmodels. Epilepsy Curr 2008;8(1):28-30.
agement of SE? The answer to this question is: probably not 6. Falip M, Carreno M, Amaro S, Donaire A, Delgado R, Toledo M, quite yet, as there have been no comparative, prospective, or Maestro I. Use of levetiracetam in hospitalized patients. Epilepsia randomized trials. In addition to determining its efficacy more definitively, it will be important to follow the incidence of agita- 7. Rossetti AO, Bromfield EB. Determinants of success in the tion and infections in patients administered levetiracetam (IV use of oral levetiracetam in status epilepticus. Epilepsy Behav2006;8(3):651-654.
or enterally), as both of these adverse effects are consistently 8. Rupprecht S, Franke K, Fitzek S, Witte OW, Hagemann G. Lev- more frequent for individuals on levetiracetam than on placebo etiracetam as a treatment option in non-convulsive status epilep- in clinical trials (10), and critically ill patients are at particu- ticus. Epilepsy Res 2007;73(3):238-244.
larly high risk for these issues. Nonetheless, IV levetiracetam 9. Ruegg S, Naegelin Y, Hardmeier M, Winkler DT, Marsch S, has many attractive features that will ensure its common use in Fuhr P. Intravenous levetiracetam: treatment experience with the the inpatient setting, including: mostly renal clearance, virtu- first 50 critically ill patients. Epilepsy Behav 2008;12(3):477-480.
ally no interactions, rare allergic reactions, minimal respiratory 10. De Smedt T, Raedt R, Vonck K, Boon P. Levetiracetam: part II, and cardiovascular effects with IV loading, broad-spectrum ef- the clinical profile of a novel anticonvulsant drug. CNS Drug Rev ficacy, and ease of use. No other IV medication for seizures

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