HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Levetiracetam
KEPPRA · LEVETIRACETAM USP · LEVITIRACETAM · (2R)-2-(2-oxopyrrolidin-1-yl)butanaMide · MFCD00 · SIB-S1 · UCB-L059 · 103833-73-4
Identifikatoren & physikalische Daten
| CAS No. | 102767-28-2 |
|---|---|
| Summenformel | C8H14N2O2 |
| Durchschnittliche Molmasse | 170,21 g/mol |
| Monoisotopische Masse | 170,10552769 g/mol |
| SMILES | CC[C@@H](C(N)=O)N1CCCC1=O |
| InChIKey | HPHUVLMMVZITSG-LURJTMIESA-N |
| PubChem CID | 5284583 |
| ChEMBL | CHEMBL1286 |
| ChEBI | CHEBI:6437 |
| EC No. | 600-348-9 |
| DTXSID | DTXSID9023207 |
Chemische & physikalische Eigenschaften
| XLogP | -0,3 |
|---|---|
| Polarare Oberfläche (TPSA) | 63,4 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 2 |
| Frei drehbare Bindungen | 3 |
| Schwere Atome | 12 |
| Formalladung | 0 |
| Komplexität | 203 |
| Arzneimittel | Pharmaceuticals -> Used in SwitzerlandPharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Antiepileptic |
| Geruch | Faint |
| Geschmack | Bitter |
| Color/Form | Crystals from ethyl acetateWhite to off-white crystalline powder |
| Löslichkeit | 104g/100mLVery soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/mL), soluble in ethanol (16.5 g/mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent)H2O: >5mg/mL |
| Human Drugs | Breast FeedingLactationMilk, HumanAnticonvulsantsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine |
| Schmelzpunkt | 115-119C117 °C118-119°C |
| Dampfdruck | 3.5X10-6 mm Hg at 25 °C |
| Optical Rotation | Specific optical rotation: -90 deg at 25 °C/D (c = 1 in acetone) |
| Flammpunkt | 9℃ |
| Lagerbedingungen | 2-8°C |
| Aggregatzustand | powder |
| Farbe | white |
| BCS Class | 3 |
| Stabilität | Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month. |
| Hauptanwendungen | clinical testing |
| InChI | InChI=1/C8H14N2O2/c1-2-6(8(9)12)10-5-3-4-7(10)11/h6H,2-5H2,1H3,(H2,9,12)/t6-/s3 |
| InChIKey | HPHUVLMMVZITSG-UHFFFAOYSA-N |
| SMILES | C(N)(=O)[C@@H](N1CCCC1=O)CC |&1:3,r| |
| CAS Datenbank | 102767-28-2(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | This chemical does not meet GHS hazard criteria for 1.7% (2 of 119) of reports.WarningH302 (89.1%): Harmful if swallowed [Warning Acute toxicity, oral]P264, P264+P265, P270, P280, P301+P317, P305+P351+P338, P330, P337+P317, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 119 reports by companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl levetiracetam, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Hazard Classes and Categories | Acute Tox. 4 (89.1%) |
| Lagerbedingungen | Store at 25 °C (77 °F)excursions permitted to 15-30 °C (59-86 °F) |
| Entsorgungsverfahren | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. |
| Treatment | There is no specific antidote for overdose with Levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavageusual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient's clinical status. |
| Wechselwirkungen | No interaction between probenecid and levetiracetam was observedhowever, probenecid decreased the renal clearance of ucb L057 (inactive metabolite of levetiracetam) by 60%./Levetiracetam/ had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.Levetiracetam did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Potential drug interactions between /levetiracetam/ and other Antiepileptic Drugs (AEDs) (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam./Levetiracetam/ did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.For more Interactions (Complete) data for LEVETIRACETAM (7 total), please visit the HSDB record page. |
| Gesundheitliche Auswirkungen | May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. |
| Hepatotoxicity | Prospective studies reported that chronic levetiracetam therapy was not accompanied by significant elevations in serum aminotransferase levels and clinically apparent liver injury was not observed. Since its approval for use and wide spread availability, however, levetiracetam has been linked to rare instances of serum enzyme elevations and occasional cases of clinically apparent liver injury. The time to onset of liver injury after starting levetiracetam has ranged from 1 week to 5 months and the usual pattern of injury has been hepatocellular. Immunoallergic features and autoantibodies were rare. At least one case of acute liver failure attributed to levetiracetam has been published, but the number of reported cases clinically apparent cases of liver injury has been few. In addition, levetiracetam is usually considered a reasonable alternative therapy in patients who develop anticonvulsant hypersensitivity (DRESS) syndrome after aromatic anticonvulsant use despite the fact that it has been implicated in rare instances of DRESS and Stevens Johnson syndrome. |
| Unerwünschte Wirkungen | Central nervous system (CNS): Most common adverse effects are neurobehavioral, like sedation, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, a decline in cognition, and increased suicide risk. Most of the time, the side effects are mild. About 1% of patients experience serious side effects like psychosis, hallucinations, and suicidal thoughts. These side effects are more common in the first month of treatment but can develop during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems. A systematic review suggests that pyridoxine supplementation might be of benefit in relieving levetiracetam-induced neuropsychiatric adverse events. |
| Expositionspfade | Rapidly and almost completely absorbed after oral administration (99%). Peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. |
| Milk Concentrations | To study the pharmacokinetics of levetiracetam (LEV) at birth, during lactation, and in the nursed infant. Eight consecutive breast-feeding women with epilepsy treated with LEV twice daily and their infants were studied. 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. ...Levetiracetam is distributed into milk. |
| Toxizitätsübersicht | There are few known cases of overdose with levetiracetam in clinical trials. Drowsiness, somnolence, agitation, respiratory depression, and coma have been observed with levetiracetam overdose. There is no antidote for levetiracetam. General supportive measures, airway protection, and monitoring of vital signs are done on overdose patients. Clinicians should contact poison control. Hemodialysis may be needed in patients with significant renal impairment. A four-hour hemodialysis session can remove almost 50% of the drug.The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain. Levetiracetam is thought to stimulate synaptic vesicle protein 2A (SV2A), inhibiting neurotransmitter release. |
| Signs and Symptoms | Side effects include aggression, agitation, coma, drowsiness, reduced consciousness, slowed breathing. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Other than drowsiness, there were no adverse events in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with /levetiracetam/ overdoses in postmarketing use./CASE REPORTS/ A twelve year-old-girl with idiopathic partial epilepsy with secondary generalization, developed acute psychosis 10 days after the administration of levetiracetam. The patient was already on sodium valproate, and levetiracetam was given as add on therapy. A final dosage of 60 mg/kg was used. Complete seizure control was achieved but the patient developed hallucinations, agitation and self-harming behavior, as well as poor social contact. The psychotic behavior resolved completely soon after the discontinuation of levetiracetam./CASE REPORTS/ I In two patients Levetiracetam (LEV) was initiated to control refractory complex partial seizures (CPS). The first patient was treated with 1500 mg/day and complained of abdominal pain and weight loss 6 months later. Internal examination and colonoscopy revealed a punctate colitis. The second patient presented with bloody stool 1 month after LEV initiation. Colonoscopy showed punctate colitis. In both patients gastrointestinal symptoms disappeared following tapering of LEV. Three possible mechanisms of action are discussed. Colitis may be part of a hypersensitivity syndrome caused by LEV. Pharmacodynamic interactions with other anti-epileptic drugs, for example, carbamazepine may play a role. .../CASE REPORTS/ /Investigators/ report here the case of a 43-year-old woman who developed symptoms compatible with catatonia after being exposed to levetiracetam for the treatment of epilepsy. /Investigators/ review the difficulties that may be encountered in the differential diagnosis of medical catatonia.For more Human Toxicity Excerpts (Complete) data for LEVETIRACETAM (8 total), please visit the HSDB record page. |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)LevetiracetamvLess-DILI-concern8Adverse reactionsDOI:10.1016/j.drudis.2016.02.015 |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | UN1230 - class 3 - PG 2 - Methanol, solution |
| Zollcode | 29337900 |
| RTECS-Nr. | UX9656166 |
| R-Sätze (R) | 22-36-39/23/24/25-23/24/25-11 |
| Toxizität | LD50 in male mice, male rats (mg/kg): 1081, 1038 i.v. (Gobert, 1990) |
| Gefahrensymbole | Xn,T,F |
| Sicherheitshinweise (S) | 26-45-36/37-16-7 |
| Lagerklasse | 3 - Flammable liquids |
| Gefahrstoffdaten | 102767-28-2(Hazardous Substances Data) |
| Gefahrenklasse | Acute Tox. 3 DermalAcute Tox. 3 InhalationAcute Tox. 3 OralFlam. Liq. 2STOT SE 1 |
Anwendungen & Verwendung
Beschreibung
Levetiracetam was first introduced in the US as an adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. This second-generation analog of piracetam can be prepared by condensation of (S)-2-aminobutyramide with 4-chlorobutyryl chloride. Although its mechanism of action is not well established, it was shown that [3H]-levetiracetam reversibly binds to a specific site predominantly present in the membranes of the brain. Unlike conventional anticonvulsants such as phenytoin, carbamazepine, valproic acid, phenobarbital, diazepam and clonazepam, compounds structurally-related to levetiracetam, such as piracetam and aniracetam, also have affinity for this site. Levetiracetam reveals a broad and unique profile in animal seizure models, including promising antiepileptogenic properties. Besides being rapidly and almost completely absorbed in man (oral bioavailability>95%), it possesses a favorable pharmacokinetic profile since it is not hepatically metabolized but only partly hydrolized into the inactive carboxylic acid by enzymes in a number of tissues including blood cells, it is minimally bound to plasma proteins (
History
Levetiracetam was originally discovered by UCB and is now marketed as Keppra® in over 90 countries worldwide. It was discovered in 1992 through screening in audiogenic seizure susceptible mice. It is available as regular and extended release oral formulations and as intravenous formulations. The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011. The patent for the extended release tablet will expire in 2028. 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.
Verwenden
The (S)-enantiomer of the ethyl analog of Piracetam. Used as an anticonvulsant.