Zonisamide

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

Zonisamide Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R22:Gesundheitsschädlich beim Verschlucken.

• Beschreibung

  Zonisamide is a broad-spectrum antiepileptic effective in the treatment of refractory seizures. In cultured spinal cord neurons, zonisamide blocks the sustained firing of action potentials induced by depolarizing steps of current injected across the membrane.

• Chemische Eigenschaften

  Off-White Powder

• Originator

  Dainippon (Japan)

• Verwenden

  For use as adjunctive treatment of partial seizures in adults with epilepsy.

• Verwenden

  muscarinic antagonist used as an antispasmodic

• Verwenden

  anticonvulsant;carbonic anhydrase inhibitor, repetitive firing of voltage-gated sodium channels and reduction of T-type calcium channel currents blocker

• Verwenden

  Sulfonamide antiseizure agent; blocks repetitive firing of voltagesensitive sodium channels and reduces voltage-sensitive T-type calcium currents. Heterocyclic methanesulfonide with anticonvulsant pro perties. The compound is under investigation for potential therapeutic use as an antiepileptic drug. Anticonvulsant.

• Definition

  ChEBI: A 1,2-benzoxazole compound having a sulfamoylmethyl substituent at the 3-position.

• Manufacturing Process

  To a solution of 8.0 of 3-bromomethyl-1,2-benzisoxazole (m.p. 64-66°) in 130 ml of methanol was added a solution of 8.1 g of sodium sulfite in 130 ml of water. The mixture was heated with stirring at 50°C for 4 hours and concentrated under reduced pressure. The crystalline residue was dissolved in 250 ml of methanol with warming and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the crystalline residue of 1,2-benzisoxazole-3-methanesulfonyl chloride was washed with diethyl ether to give crude sodium 1,2-benzisoxazole-3-methanesulfonate (10.5 g).
  To 100 ml of phosphorus oxychloride was added 10.5 g of the above- mentioned sodium salt and the mixture was heated under reflux for 3 hours. The excess of phosphorus oxychloride was distilled off under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and the removal of the insoluble material by filtration gave the solution of the 1,2- benzisoxazole-3-methanesulfonyl chloride.
  The solution of 1,2-benzisoxazole-3-methanesulfonyl chloride in ethyl acetate, was cooled on an ice bath, saturated with dry ammonia gas, and allowed to stand at room temperature for one hour. After the removal of the insoluble material by filtration, the filtrate was concentrated to yield a crystalline solid, which was washed with a small amount of ethyl acetate and recrystallized from ethyl acetate to give the 3-sulfamoylmethyl-1,2-benzisoxazole (5.2 g), m.p. 160-163°C.

• Trademarks

  Zonegran (Dainippon Pharmaceutical Co., Japan);Exegran.

• Therapeutic Function

  Anticonvulsant; Antiepileptic

• Biologische Funktion

  Zonisamide has only recently been approved for use in the United States, although it has been available in Japan for several years. It is effective in partial complex and generalized tonic–clonic seizures and also appears to be beneficial in certain myoclonic seizures. It has a long half-life (about 60 hours) and requires about 2 weeks to achieve steady-state levels. It causes cerebellovestibular side effects similar to those of most other AEDs sharing its mechanism of action. In addition, it appears to cause an increased incidence of kidney stones.

• Allgemeine Beschreibung

  Zonisamide, a sulfonamide-type anticonvulsant was recentlyapproved for adjunctive therapy in the treatment ofpartial seizures in adults with epilepsy.Zonisamide isprimarily metabolized by reductive ring cleavage of the 1,2-benzisoxazole ring to 2-sulfamoyl-acetyl-phenol. This biotransformation is mainly carried out by theintestinal bacteria rather than the mammalian cytosolicaldehyde oxidase suggested earlier.Again, because ofthe presence of a sulfonamide moiety in zonisamide molecule,precaution should be given to patients who have ahistory of hypersensitivity reactions toward sulfonamidedrugs and concomitant use of zonisamide with other carbonicanhydrase inhibitors should also be avoided.

• Mechanism of action

  Zonisamide is a sulfonamide derivative that is indicated as an adjunct for partial seizures in patients older than 16 years whose seizures are not controlled by first-line drugs. In Japan, it is used for myoclonic seizures as well. Apparently, it has more than one mechanism of action—all as yet unidentified. It is known to produce blockade of both sodium and T-type calcium channels. Because it also affects dopaminergic transmission, bipolar or schizoaffective disorder patients may improve.

• Pharmakokinetik

  The absorption for orally administered zonisamide is slow but nearly complete. Its pharmacokinetics are nonlinear, with a half life of 50 to 70 hours when administered alone or 27 to 46 hours when administered concurrently with enzyme-inducing AEDs. Protein binding is moderate (<50%). An oral dose of zonisamide is completely absorbed, with peak plasma concentration occurring in 2 to 6 hours. Although the presence of food will delay the attainment of its peak plasma concentration, oral bioavailability does not appear to be altered. More than one-third of each oral dose is excreted in the urine in an unchanged form. The routes of metabolism for zonisamide include acetylation to form its N-acetyl metabolite, reduction by CYP3A4/CYP2D6, and the formation of an open-ring metabolite, 2-sulfamoylacetyl phenol. These metabolites subsequently are eliminated unconjugated or glucuronidated in the urine, with an elimination half-life of 63 hours. Its coadministration with enzyme-inducing AEDs, such as phenytoin, CBZ, or phenobarbital, and with valproate will alter its pharmacokinetics by reducing its half-life and serum concentration. The half-life for zonisamide is decreased to 27 hours in the presence of phenytoin, to 38 hours in the presence of either CBZ or phenobarbital, and to 46 hours with valproate. Other drugs that inhibit or induce CYP3A4 could affect the metabolism of zonisamide.
  Zonisamide should be used with caution in patients with hepatic or renal disease. It also has shown to be teratogenic in animal studies.

• Clinical Use

  Antiepileptic

• Nebenwirkungen

  Zonisamide is contraindicated in patients with a history of allergy to sulfonamides. The most frequent side effects include somnolence, anorexia, dizziness, agitation, confusion, headache, cognitive impairment, and memory loss. In addition, an incidence of drug-induced psychosis has been noted. Reports from both the United States and Europe have indicated that development of renal stones may occur with use of this drug. A family history of nephrolithiasis may be a contraindication, and urinary monitoring for hypercalciuria may be warranted in bedridden patients or those receiving multiple AEDs. Although the incidence of severe rashes attributable to zonisamide is low, sulfonamides are associated with Stevens-Johnson syndrome. Thus, it is recommended to discontinue the drug immediately should a rash occur.

• Sicherheitsprofil

  Moderately toxic by ingestion,intraperitoneal, subcutaneous, and intravenous routes. Anexperimental teratogen. Other experimental reproductiveeffects. When heated to decomposition it emits very toxicfumes of SOx and NOx. An anticonvulsant.

• Veterinary Drugs and Treatments

  Zonisamide may be useful as an “add-on” drug for refractory epilepsy in dogs.

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antidepressants: anticonvulsant effect antagonised; avoid with St John’s wort.
  Antimalarials: anticonvulsant effect antagonised by mefloquine.
  Antipsychotics: anticonvulsant effect antagonised.
  Orlistat: increased risk of convulsions.

• Stoffwechsel

  Zonisamide is metabolised mainly by reductive cleavage of the benzisoxazole ring of the parent drug by CYP3A4 to form 2-sulphamoylacetylphenol (SMAP) and also by N-acetylation. Parent drug and SMAP can also be glucuronidated.
  The metabolites, which could not be detected in plasma, are inactive. Excretion is mainly in the urine; about 15 to 30
  % appearing as unchanged drug, 15
  % as N-acetylzonisamide, and 50
  % as the glucuronide of SMAP.

• Lager

  Store at +4°C

Zonisamide Upstream-Materialien And Downstream Produkte

Zonisamide Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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