Levetiracetam

Levetiracetam
Clinical data
Pronunciation/lɛvɪtɪˈræsɪtæm/
Trade namesKeppra, Elepsia, Spritam, others
AHFS/Drugs.comMonograph
MedlinePlusa699059
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous
Drug classRacetam anticonvulsant
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability≈100%
Protein binding<10%
MetabolismEnzymatic hydrolysis of acetamide group
Elimination half-life6–8 hrs
ExcretionKidney
Identifiers
  • (S)-2-(2-Oxopyrrolidin-1-yl)butanamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.121.571 Edit this at Wikidata
Chemical and physical data
FormulaC8H14N2O2
Molar mass170.212 g·mol−1
3D model (JSmol)
  • O=C1N([C@H](C(=O)N)CC)CCC1
  • InChI=1S/C8H14N2O2/c1-2-6(8(9)12)10-5-3-4-7(10)11/h6H,2-5H2,1H3,(H2,9,12)/t6-/m0/s1 checkY
  • Key:HPHUVLMMVZITSG-LURJTMIESA-N checkY
 ☒NcheckY (what is this?)  (verify)

Levetiracetam, sold under the brand name Keppra among others, is a novel antiepileptic drug[7] (medication) used to treat epilepsy.[8] It is used for partial-onset, myoclonic, or tonic–clonic seizures,[7] and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.[8]

"Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a approximately 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A."[9] "The discovery process identifying levetiracetam's antiepileptic potential was unique because it challenged several dogmas of antiepileptic drug discovery, and thereby encountered skepticism from the epilepsy community."[10]

Common side effects of levetiracetam include sleepiness, dizziness, feeling tired, and aggression.[8] Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens–Johnson syndrome or anaphylaxis.[8] Levetiracetam is the S-enantiomer of etiracetam.[11] It acts as a synaptic vesicle glycoprotein 2A (SV2A) ligand.[12]

Levetiracetam was approved for medical use in the United States in 1999[8] and is available as a generic medication.[13] In 2022, it was the 123rd most commonly prescribed medication in the United States, with more than 5 million prescriptions.[14][15] It is on the World Health Organization's List of Essential Medicines.[16]


Medical uses

Focal epilepsy

Levetiracetam is effective as single-drug treatment for newly diagnosed focal epilepsy in adults.[17][18] It reduces focal seizures by 50% or more as an add-on medication.[19]

Partial-complex epilepsy

Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.[20]

Generalized epilepsy

Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy.[18] It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures.[4] Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures or as an adjunctive therapy for partial, myoclonic, and tonic-clonic seizures.[21]

Levetiracetam is sometimes used off label to treat status epilepticus.[22][23]

Prevention of seizures

Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury.[24] It may be effective for prevention of seizures associated with subarachnoid hemorrhages.[25]

Other

Levetiracetam has not been found to be useful for treatment of neuropathic pain,[26] nor for treatment of essential tremors.[27] Levetiracetam has not been found to be useful for treating all developmental disorders within the autism spectrum;[28][29] studies have only proven to be an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.[30]

Special groups

Levetiracetam's efficacy and tolerability in individuals with intellectual disability is comparable to those without. [31]

Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.[medical citation needed]

Studies were conducted to look for increased adverse effects in the elderly population as compared to younger patients. One such study published in Epilepsy Research showed no significant increase in incidence of adverse symptoms experienced by young or elderly patients with disorders of the central nervous system.[medical citation needed]

Adverse effects

The most common adverse effects of levetiracetam treatment include effects on the central nervous system such as somnolence, decreased energy, headache, dizziness, mood swings and coordination difficulties. These adverse effects are most pronounced in the first month of therapy. About 4% of patients dropped out of pre-approval clinical trials due to these side effects.[4]

About 13% of people taking levetiracetam experience adverse neuropsychiatric symptoms, which are usually mild. These include agitation, hostility, apathy, anxiety, emotional lability, and depression. Serious psychiatric adverse side effects that are reversed by drug discontinuation occur in about 1%. These include hallucinations, suicidal thoughts, or psychosis. These occurred mostly within the first month of therapy, but they could develop at any time during treatment.[32]

Although rare, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which appears as a painful spreading rash with redness and blistering and/or peeling skin, have been reported in patients treated with levetiracetam.[33] The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.[34]

Levetiracetam should not be used in people who have previously shown hypersensitivity to levetiracetam or any of the inactive ingredients in the tablet or oral solution. Such hypersensitivity reactions include, but are not limited to, unexplained rash with redness or blistered skin, difficulty breathing, and tightness in the chest or airways.[4]

In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.[35]

Suicide

Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicidal behavior or thoughts. People taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.[4]

Kidney and liver

Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments. Kidney function can be estimated from the rate of creatinine clearance.[4]

Dose adjustment of levetiracetam is not necessary in liver impairment.[4]

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.[36] The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.[37]

Mechanism of action

The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. Levetiracetam does not exhibit pharmacologic actions similar to that of classical anticonvulsants. It does not inhibit voltage-dependent Na+ channels, does not affect GABAergic transmission, and does not bind to GABAergic or glutamatergic receptors.[38] However, the drug binds to SV2A,[39] a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels,[40] reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.[41] As of 2024, this is widely accepted to be its mechanism of action.[12] However, the molecular basis of this action remains unknown.[12]

Pharmacokinetics

FDA provides a detailed review of the pharmacology and biopharmaceutics of Levetiracetam in 2013.[42]

Absorption

The absorption of levetiracetam tablets and oral solution is rapid and essentially complete. The bioavailability of levetiracetam is close to 100 percent, and the effect of food on absorption is minor.[4]

Distribution

The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).[4]

Metabolism

Levetiracetam does not undergo extensive metabolism, and the metabolites formed are not active and do not exert pharmacological activity. Metabolism of levetiracetam is not by liver cytochrome P450 enzymes, but through other metabolic pathways such as hydrolysis and hydroxylation.[4]

Excretion

In persons with normal kidney function, levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours,[4] although the mean CSF half life of approx. 24 hours better reflects levels at site of action.[43]

Analogues

Brivaracetam, a chemical analogue to levetiracetam, is a racetam derivative with similar properties.

Society and culture

Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.[44]

The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011.[45][19] The patent for the extended release tablet will expire in 2028.[46]

The branded version Keppra is manufactured by UCB Pharmaceuticals S.A.[3][4][5][6]

In 2015, Aprecia's orally disintegrating tablet form of the drug manufactured using pharmaceutical 3D printing techniques was approved by the FDA, under the trade name Spritam.[47] Some have said that the drug has been improved by 3D printing, as the formula used now has improved disintegration properties.[48]

Australia

Levetiracetam is a Schedule 4 substance in Australia under the Poisons Standard (February 2020).[49] A Schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."[49]

Japan

Under Japanese law, levetiracetam and other racetams cannot be brought into the country except for personal use by a traveler for whom it has been prescribed.[50] Travelers who plan to bring more than a month's worth must apply for an import certificate, known as a Yakkan Shoumei (薬監証明, yakkan shōmei).[51]

Research

Levetiracetam has been studied in the past for treating symptoms of neurobiological conditions such as Tourette syndrome,[52] and anxiety disorder.[53] However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.[53]

Levetiracetam is being tested as a drug to reduce hyperactivity in the hippocampus in Alzheimer's disease.[54]

Additionally, Levetiracetam has been experimentally shown to reduce Levodopa-induced dyskinesia,[55] a type of movement disorder, or dyskinesia associated with the use of Levodopa, a medication used to treat Parkinson's disease.

Of the ten medications evaluated in a 2023 systematic review of the literature, levetiracetam was found to be the only medication with sufficient evidence showing that it may cause seizure freedom in some infants.[56] Further, adverse effects from levetiracetam were rarely severe enough for the medication to be discontinued in this age group. Because available research included only 2 published studies reporting seizure freedom rates, however, the strength of the evidence was judged to be low.[56]

References

  1. ^ "Levetiracetam Use During Pregnancy". Drugs.com. Archived from the original on 6 March 2019. Retrieved 5 March 2019.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ^ a b "Keppra 100 mg/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). Archived from the original on 24 October 2021. Retrieved 9 September 2020.
  4. ^ a b c d e f g h i j k l "Keppra- levetiracetam tablet, film coated Keppra- levetiracetam solution". DailyMed. 5 November 2019. Archived from the original on 7 August 2020. Retrieved 9 September 2020.
  5. ^ a b "Keppra XR- levetiracetam tablet, film coated, extended release". DailyMed. 4 November 2019. Archived from the original on 29 July 2021. Retrieved 9 September 2020.
  6. ^ a b "Keppra- levetiracetam injection, solution, concentrate". DailyMed. 4 November 2019. Archived from the original on 21 January 2016. Retrieved 9 September 2020.
  7. ^ a b Kumar A, et al. (2024), Levetiracetam, National Library of Medicine, National Institute of Health, PMID 29763065, archived from the original on 2 September 2024. Internet Archive 2024.12.05.
  8. ^ a b c d e "Levetiracetam Monograph for Professionals". Drugs.com. AHFS. Archived from the original on 24 March 2019. Retrieved 14 January 2019.
  9. ^ Rogawski M (2008), "Brivaracetam: a rational drug discovery success story", Br J Pharmacol 154(8):1555-7, 154 (8): 1555–1557, doi:10.1038/bjp.2008.221, PMC 2518467, PMID 18552880, Aug.
  10. ^ Klitgaard H, et al. (2007), "Levetiracetam: the first SV2A ligand for the treatment of epilepsy", Expert Opin Drug Discov 2(11):1537-45, 2 (11): 1537–1545, doi:10.1517/17460441.2.11.1537, PMID 23484603, Nov.
  11. ^ Cavanna AE (2018). Behavioural Neurology of Anti-Epileptic Drugs: A Practical Guide. Oxford University Press. p. 17. ISBN 9780198791577.
  12. ^ a b c Wu PP, Cao BR, Tian FY, Gao ZB (May 2024). "Development of SV2A Ligands for Epilepsy Treatment: A Review of Levetiracetam, Brivaracetam, and Padsevonil". Neurosci Bull. 40 (5): 594–608. doi:10.1007/s12264-023-01138-2. PMID 37897555.
  13. ^ British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 319. ISBN 9780857113382.
  14. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  15. ^ "Levetiracetam Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  16. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  17. ^ Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, et al. (January 2019). "Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis". Acta Neurologica Scandinavica. 139 (1): 33–41. doi:10.1111/ane.13025. PMID 30194755. S2CID 52174058.
  18. ^ a b Nevitt SJ, Sudell M, Cividini S, Marson AG, Tudur Smith C (April 2022). "Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data". The Cochrane Database of Systematic Reviews. 2022 (4): CD011412. doi:10.1002/14651858.CD011412.pub4. PMC 8974892. PMID 35363878.
  19. ^ a b Mbizvo GK, Dixon P, Hutton JL, Marson AG (September 2012). "Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review". The Cochrane Database of Systematic Reviews. 2012 (9): CD001901. doi:10.1002/14651858.cd001901.pub2. PMC 7061650. PMID 22972056.
  20. ^ Slater J, Chung S, Huynh L, Duh MS, Gorin B, McMicken C, et al. (July 2018). "Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials". Epilepsy Research. 143: 120–129. doi:10.1016/j.eplepsyres.2017.10.004. PMID 29784458.
  21. ^ BNF 59. BMA & RPSGB. 2010.
  22. ^ Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. (Neurocritical Care Society Status Epilepticus Guideline Writing Committee) (August 2012). "Guidelines for the evaluation and management of status epilepticus". Neurocritical Care. 17 (1): 3–23. doi:10.1007/s12028-012-9695-z. PMID 22528274. S2CID 4675838.
  23. ^ Meierkord H, Boon P, Engelsen B, Göcke K, Shorvon S, Tinuper P, et al. (March 2010). "EFNS guideline on the management of status epilepticus in adults". European Journal of Neurology. 17 (3): 348–355. doi:10.1111/j.1468-1331.2009.02917.x. PMID 20050893. S2CID 1032139.
  24. ^ Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, et al. (December 2016). "Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis". Neurosurgery. 79 (6): 775–782. doi:10.1227/NEU.0000000000001445. PMID 27749510.
  25. ^ Shah D, Husain AM (December 2009). "Utility of levetiracetam in patients with subarachnoid hemorrhage". Seizure. 18 (10): 676–679. doi:10.1016/j.seizure.2009.09.003. PMID 19864168. S2CID 7555384.
  26. ^ Crawford-Faucher A, Huijon RM (July 2015). "The Role of Levetiracetam in Treating Chronic Neuropathic Pain Symptoms". American Family Physician. 92 (1): 23–24. PMID 26132123. Archived from the original on 29 August 2021. Retrieved 1 September 2017.
  27. ^ Zesiewicz TA, Elble RJ, Louis ED, Gronseth GS, Ondo WG, Dewey RB, et al. (November 2011). "Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology". Neurology. 77 (19): 1752–1755. doi:10.1212/WNL.0b013e318236f0fd. PMC 3208950. PMID 22013182.
  28. ^ Volkmar F, Siegel M, Woodbury-Smith M, King B, McCracken J, State M (February 2014). "Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 53 (2): 237–257. doi:10.1016/j.jaac.2013.10.013. PMID 24472258.
  29. ^ Hirota T, Veenstra-Vanderweele J, Hollander E, Kishi T (April 2014). "Antiepileptic medications in autism spectrum disorder: a systematic review and meta-analysis". Journal of Autism and Developmental Disorders. 44 (4): 948–957. doi:10.1007/s10803-013-1952-2. PMID 24077782. S2CID 36509998.
  30. ^ Frye RE, Rossignol D, Casanova MF, Brown GL, Martin V, Edelson S, et al. (September 2013). "A review of traditional and novel treatments for seizures in autism spectrum disorder: findings from a systematic review and expert panel". Frontiers in Public Health. 1: 31. doi:10.3389/fpubh.2013.00031. PMC 3859980. PMID 24350200.
  31. ^ Allard J, Sellers A, Henley W, McLean B, Parrett M, Rajakulendran S, et al. (August 2024). "Efficacy and tolerability of levetiracetam in people with and without intellectual disabilities: A naturalistic case control study". Seizure. 120: 25–32. doi:10.1016/j.seizure.2024.05.010. PMID 38897161.
  32. ^ Gambardella A, Labate A, Colosimo E, Ambrosio R, Quattrone A (February 2008). "Monotherapy for partial epilepsy: focus on levetiracetam". Neuropsychiatric Disease and Treatment. 4 (1): 33–38. doi:10.2147/NDT.S1655. PMC 2515905. PMID 18728811.
  33. ^ Zou LP, Ding CH, Song ZJ, Li XF (December 2012). "Stevens-Johnson syndrome induced by levetiracetam". Seizure. 21 (10): 823–825. doi:10.1016/j.seizure.2012.09.005. PMID 23036769.
  34. ^ Griebel ML (1998). "Acute management of hypersensitivity reactions and seizures". Epilepsia. 39 (Suppl 7): S17 – S21. doi:10.1111/j.1528-1157.1998.tb01680.x. PMID 9798757. S2CID 10305861.
  35. ^ Beniczky SA, Viken J, Jensen LT, Andersen NB (July 2012). "Bone mineral density in adult patients treated with various antiepileptic drugs". Seizure. 21 (6): 471–472. doi:10.1016/j.seizure.2012.04.002. PMID 22541979.
  36. ^ Browne TR, Szabo GK, Leppik IE, Josephs E, Paz J, Baltes E, et al. (June 2000). "Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique". Journal of Clinical Pharmacology. 40 (6): 590–595. doi:10.1002/j.1552-4604.2000.tb05984.x. PMID 10868309. S2CID 35576679.
  37. ^ Gidal BE, Baltès E, Otoul C, Perucca E (2005). "Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: a pooled analysis of data from randomized clinical trials". Epilepsy Research. 64 (1–2): 1–11. doi:10.1016/j.eplepsyres.2005.01.005. PMID 15823510. S2CID 13555324.
  38. ^ Deshpande LS, Delorenzo RJ (2014). "Mechanisms of levetiracetam in the control of status epilepticus and epilepsy". Frontiers in Neurology. 5: 11. doi:10.3389/fneur.2014.00011. PMC 3907711. PMID 24550884.
  39. ^ Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. (June 2004). "The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam". Proceedings of the National Academy of Sciences of the United States of America. 101 (26): 9861–9866. Bibcode:2004PNAS..101.9861L. doi:10.1073/pnas.0308208101. PMC 470764. PMID 15210974.
  40. ^ Vogl C, Mochida S, Wolff C, Whalley BJ, Stephens GJ (August 2012). "The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an intracellular pathway". Molecular Pharmacology. 82 (2): 199–208. doi:10.1124/mol.111.076687. PMID 22554805. S2CID 8333373.
  41. ^ Rogawski MA (June 2006). "Diverse mechanisms of antiepileptic drugs in the development pipeline". Epilepsy Research. 69 (3): 273–294. doi:10.1016/j.eplepsyres.2006.02.004. PMC 1562526. PMID 16621450.
  42. ^ Dimova H, et al. (3 October 2013), Clinical Pharmacology/Biopharmaceutics Review, US Food & Drug Administration (FDA).
  43. ^ Steinhoff BJ, Staack AM (January 2019). "Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience". Therapeutic Advances in Neurological Disorders. 12: 1756286419873518. doi:10.1177/1756286419873518. PMC 6734620. PMID 31523280.
  44. ^ "Levetiracetam Injection Prescribing Information" (PDF). Archived (PDF) from the original on 1 November 2018. Retrieved 4 November 2015.
  45. ^ Branch Website Management. "Patent Terms Extended Under 35 USC §156". www.uspto.gov. Archived from the original on 15 November 2015. Retrieved 5 November 2015.
  46. ^ Webber K (12 September 2011). "FDA Access Data" (PDF). ANDA 091291. Department of Health and Human Services. Archived (PDF) from the original on 4 March 2016. Retrieved 4 November 2015.
  47. ^ "FDA approves the first 3D-printed drug product". KurzweilAI. 13 October 2015. Archived from the original on 16 October 2015. Retrieved 14 October 2015.
  48. ^ Mohammed AA, Algahtani MS, Ahmad MZ, Ahmad J, Kotta S (1 December 2021). "3D Printing in medicine: Technology overview and drug delivery applications". Annals of 3D Printed Medicine. 3D-Printed Medicine: From today's accomplishments to tomorrow's promises. 4: 100037. doi:10.1016/j.stlm.2021.100037. ISSN 2666-9641. S2CID 244421616.
  49. ^ a b Poisons Standard February 2020 Archived 2 March 2020 at the Wayback Machine. comlaw.gov.au
  50. ^ "Information for those who are bringing medicines for personal use into Japan". Japanese Ministry of Health, Labour and Welfare. Archived from the original on 12 November 2020. Retrieved 10 November 2020.
  51. ^ "Q&A for those who are importing medicines into Japan" (PDF). Archived from the original (PDF) on 11 November 2020. Retrieved 10 November 2020.
  52. ^ Martínez-Granero MA, García-Pérez A, Montañes F (June 2010). "Levetiracetam as an alternative therapy for Tourette syndrome". Neuropsychiatric Disease and Treatment. 6: 309–316. doi:10.2147/ndt.s6371. PMC 2898169. PMID 20628631.
  53. ^ a b Farooq MU, Bhatt A, Majid A, Gupta R, Khasnis A, Kassab MY (March 2009). "Levetiracetam for managing neurologic and psychiatric disorders". American Journal of Health-System Pharmacy. 66 (6): 541–561. doi:10.2146/ajhp070607. PMID 19265183.
  54. ^ Haberman RP, Branch A, Gallagher M (July 2017). "Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease". Neurotherapeutics. 14 (3): 662–676. doi:10.1007/s13311-017-0541-z. PMC 5509635. PMID 28560709.
  55. ^ Du H, Nie S, Chen G, Ma K, Xu Y, Zhang Z, et al. (27 January 2015). Reichmann H, Alves da Costa C (eds.). "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease. 2015 (1). London, England, United Kingdom: Hindawi Publishing Corporation: 253878. doi:10.1155/2015/253878. LCCN 2010247839. PMC 4322303. PMID 25692070.
  56. ^ a b Treadwell JR, Wu M, Tsou AY (October 2022). Management of Infantile Epilepsies (Report). Rockville (MD): Agency for Healthcare Research and Quality (AHRQ) (US). doi:10.23970/ahrqepccer252. PMID 36383706. 22(23)-EHC004 Report No.: 2021-SR-01. Archived from the original on 5 July 2023. Retrieved 12 July 2023.

Read other articles:

Đau buồn ở động vật

Cảm xúc buồn bã của một con tinh tinh bị giam cầm trong sở thú Tâm trạng của những con thỏ trước khi bị làm thịt Đau buồn ở động vật là những trải nghiệm cảm giác đau thương, buồn bã của động vật, thường là những động vật bậc cao trong tự nhiên thông qua các nguyên nhân như bệnh tật, thương tích, đói, thiên tai và bị giết bởi những động vật khác. Đau buồn ở động vật cần...

 

Ricardo I de Normandía

Para el rey de Inglaterra del siglo XII, véase Ricardo I. Ricardo I de Normandía Información personalNombre en francés Richard Ier de Normandie Nacimiento 28 de agosto de 933 Fécamp (Francia) Fallecimiento 20 de noviembre de 996jul. Fécamp (Francia) FamiliaFamilia Casa de Normandía Padres Guillermo I de Normandía Sprota Cónyuge Emma de Francia (desde 960, desde 960, hasta 968juliano)Gunnora de Crepon (969-996, desde 962) Pareja NN Hijos Ricardo II de NormandíaRoberto IIEmm...

 

Paraíso (República Dominicana)

Paraíso   Cidade   Localização ParaísoLocalização de Paraíso na República Dominicana Coordenadas 18° N 71° 10' O País República Dominicana Província Barahona Paraíso é uma pequena cidade da República Dominicana pertencente à província de Barahona. Sua população estimada em 2012 era de 6 888 habitantes.[1] Referências ↑ «Dominican Republic: largest cities and towns and statistics of their population» (em inglês). World-Gazetteer.com. 2010....

甘國亮

  提示：此条目的主题不是甘國衛。 本條目存在以下問題，請協助改善本條目或在討論頁針對議題發表看法。 此條目閱讀起來类似新聞稿，或包含過度的宣傳性語調。 (2022年10月17日)請協助以中立的觀點來撰寫本條目，非常明显的广告内容请加入{{Delete|G11}}來提请删除。 此生者传记条目需要补充更多可供查證的来源。 (2022年10月17日)请协助補充可靠来源，无法查证...

 

Islam in Pakistan

Overview of the role and impact of Islam in Pakistan Pakistani Muslims پاکستانی مسلمانEid Prayers at the Badshahi Mosque in LahoreTotal populationc. 242.5 Million (2023 Census estimation)[1][2][3] (97% of the population) Regions with significant populationsThroughout PakistanReligionsMajority: 90% Sunni Muslims, Minority: 10% Shia Muslims[4] LanguagesLiturgicalQuranic Arabic[5] CommonUrdu, Punjabi, Pashto, Sindhi, Saraiki, Balochi, K...

 

Naturschutzgebiet Spielwigge

Naturschutzgebiet Spielwigge IUCN-Kategorie IV – Habitat/Species Management Area Bild gesucht BWf1 Lage Lüdenscheid, Märkischer Kreis, Nordrhein-Westfalen, Deutschland Fläche 6,5 ha Kennung MK-044 WDPA-ID 165612 Geographische Lage 51° 11′ N, 7° 40′ O51.1872222222227.6641666666667Koordinaten: 51° 11′ 14″ N, 7° 39′ 51″ O Naturschutzgebiet Spielwigge (Nordrhein-Westfalen) Einrichtungsdatum 1994 Rahmenplan ...

石州 (西夏)

石州，西夏时设置的州。 石州开始是为石堡镇，夏景宗广运三年（1036年）升置为石州。治所在今陕西省榆林市横山区东北。同时设石州祥祐军司于此。大致位于银州、夏州二州之间，地当今陕西省榆林市西南，元朝废除石州。 参考文献 《丝绸之路大辞典》 《中国历史地名大辞典》 查论编西夏行政区划河西兴州（兴庆府） | 定州 | 怀州 | 永州&#...

 

إيثانال

إيثانال إيثانال إيثانال إيثانال إيثانال الاسم النظامي (IUPAC) Acetaldehyde تسمية الاتحاد الدولي للكيمياء Ethanal أسماء أخرى Acetic aldehydeEthyl aldehyde[1] المعرفات رقم CAS 75-07-0 بوب كيم (PubChem) 177 مواصفات الإدخال النصي المبسط للجزيئات CC=O[2]  المعرف الكيميائي الدولي InChI=1S/C2H4O/c1-2-3/h2H,1H3[2]  I...

 

List of Ohio State Buckeyes head football coaches

Urban Meyer, head coach of the Ohio State Buckeyes from 2012 to 2018 The Ohio State Buckeyes college football team represents the Ohio State University in the East Division of the Big Ten Conference. The Buckeyes compete as part of the NCAA Division I Football Bowl Subdivision. The program has had 25 coaches since it began play during the 1890 season.[1] The Buckeyes have played over 1,200 games over 125 seasons. In those seasons, nine head coaches have led the Buckeyes to postseason ...

Control activo de ruido

Representación gráfica de la cancelación activa del ruido El control activo de ruido o cancelación activa de ruido (abreviado: CAR) es un sistema que permite anular el ruido no deseado mediante la adición de un segundo sonido específicamente diseñado para cancelar el primero. Fundamentos El sonido es una onda de presión que consiste en periodos alternos de compresión y rarefacción. Un altavoz con cancelación de ruido emite una onda sonora con la misma amplitud, pero con fase invert...

 

Amber Mafia

Criminal enterprise in Ukraine This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (April 2023) The Amber Mafia is the criminal network in north-west Ukraine composed of those who illegally dig up amber on government land and smuggle it out for sale on the black market with the aid of armed gangs and corrupt politicians.[1] 300 officers searched 123 homes in 2016 for amber.[2...

 

منظور بن زبان الفزاري

منظور بن زبان الفزاري معلومات شخصية تاريخ الوفاة سنة 645  الحياة العملية المهنة شاعر  بوابة الأدب تعديل مصدري - تعديل   منظور بن زبان بن سيار بن عمرو بن عقيل بن هلال الفزاري، صحابي، وشاعر . كان من سادات قومه، ويقال: طال حمله فولدته أمه أربع سنين .[1] نسبه هو منظور بن ز...

Gedung Ibu Pejabat Stasiun Kereta Api Tanah Melayu

Artikel ini sebatang kara, artinya tidak ada artikel lain yang memiliki pranala balik ke halaman ini.Bantulah menambah pranala ke artikel ini dari artikel yang berhubungan atau coba peralatan pencari pranala.Tag ini diberikan pada Oktober 2022. Gedung Ibu Pejabat Stasiun Kereta Api Tanah Melayu adalah salah satu gedung stasiun kereta api di Malaysia. Pembangunannya untuk pelengkap dalam Program Bangunan Tersergam. Program ini berlangsung antara tahun 1894 hingga tahun 1912. Gedung ini memakai...

 

Futuro Beach

2014 film by Karim Aïnouz Futuro BeachTheatrical release posterPortuguesePraia do Futuro Directed byKarim AïnouzWritten by Felipe Bragança Karim Aïnouz Produced by Geórgia Costa Araújo Hank Levine Starring Wagner Moura Clemens Schick Jesuíta Barbosa CinematographyAli Olay GözkayaEdited byIsabela Monteiro de CastroMusic byHauschkaProductioncompanies Coração da Selva Hank Levine Film Detailfilm Watchmen Productions Distributed by California Filmes (Brazil) Real Fiction (Germany) Relea...

 

Roderic D. M. Page

New Zealand-born evolutionary biologist Rod PageRod PageBornRoderic Dugald Morton Page1962 (age 60–61)Auckland, New ZealandNationalityNew ZealandCitizenshipNew ZealandAlma materUniversity of Auckland (PhD)Known forMolecular evolution : a phylogenetic approach[3]AwardsBicentenary Medal of the Linnean Society 1998Scientific careerFields Biodiversity informatics Phyloinformatics[1] Institutions University of Glasgow University of Oxford University of Auc...

President of Iraq

Head of state of the Republic of Iraq You can help expand this article with text translated from the corresponding article in Arabic. (November 2016) Click [show] for important translation instructions. View a machine-translated version of the Arabic article. Machine translation, like DeepL or Google Translate, is a useful starting point for translations, but translators must revise errors as necessary and confirm that the translation is accurate, rather than simply copy-pasting machine-...

 

Aliaguilla

Questa voce o sezione sull'argomento centri abitati della Spagna non cita le fonti necessarie o quelle presenti sono insufficienti. Puoi migliorare questa voce aggiungendo citazioni da fonti attendibili secondo le linee guida sull'uso delle fonti. Segui i suggerimenti del progetto di riferimento. Aliaguillacomune Aliaguilla – Veduta LocalizzazioneStato Spagna Comunità autonoma Castiglia-La Mancia Provincia Cuenca TerritorioCoordinate39°43′59.88″N 1°19′00.12″W&#x...

 

Alex Christensen

German composer, producer, and DJ (born 1967) This biography of a living person needs additional citations for verification. Please help by adding reliable sources. Contentious material about living persons that is unsourced or poorly sourced must be removed immediately from the article and its talk page, especially if potentially libelous.Find sources: Alex Christensen – news · newspapers · books · scholar · JSTOR (March 2021) (Learn how and when to r...

Maesaan, Minahasa Selatan

Artikel ini tidak memiliki referensi atau sumber tepercaya sehingga isinya tidak bisa dipastikan. Tolong bantu perbaiki artikel ini dengan menambahkan referensi yang layak. Tulisan tanpa sumber dapat dipertanyakan dan dihapus sewaktu-waktu.Cari sumber: Maesaan, Minahasa Selatan – berita · surat kabar · buku · cendekiawan · JSTOR MaesaanKecamatanPeta lokasi Kecamatan MaesaanNegara IndonesiaProvinsiSulawesi UtaraKabupatenMinahasa SelatanKode Kemenda...

 

Shuttle America

Shuttle America IATA-Code: S5 ICAO-Code: TCF Rufzeichen: MERCURY Gründung: 1995 Betrieb eingestellt: 2017 Fusioniert mit: Republic Airline Sitz: Indianapolis, Vereinigte Staaten Vereinigte Staaten Unternehmensform: Corporation Allianz: SkyTeam (als Delta Connection) Star Alliance (als United Express) Vielfliegerprogramm: SkyMiles (als Delta Connection) Mileage Plus (als United Express) Flottenstärke: 111 Ziele: national und kontinental Website: www.shuttleamerica.com Shuttle America i...

 

Strategi Solo vs Squad di Free Fire: Cara Menang Mudah!