Topiramate

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P271：Nur im Freien oder in gut belüfteten Räumen verwenden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

Topiramate Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.

• Beschreibung

  Topiramate, a novel sulfamate-substituted D-fructose derivative, was launched in the United Kingdom as an adjunct therapy for use in partial seizures with or without secondary generalized seizures in adult patients inadequately controlled on conventional antiepileptics. Topiramate is structurally distinct from other available antiepileptics and functions through a unique combination of several mechanisms. It appears to act by blocking voltage-sensitive sodium channels to raise the action potential threshold and block the spread of seizure, enhancing GABA activity at postsynaptic GABA receptors and reducing glutamate activity at postsynaptic AMPAtype receptors, and is also a carbonic anhydrase inhibitor. Topiramate is orally active with rapid absorption, high bioavailability, and long duration of action. Excellent efficacy has been reported as an add-on therapy in epilepsy and it is also being evaluated as a monotherapy.

• Chemische Eigenschaften

  White-to-Off-White Crystalline Powder

• Originator

  Johnson & Johnson (U.S.A.)

• Verwenden

  Used for the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures and also for the prevention of migraine headaches. In children it is also used for treatment of Lennox-Gastaut syndrome. Qsymia? is indicated for the treat

• Verwenden

  Used as an anticonvulsant

• Verwenden

  Topiramate may be used as a pharmaceutical reference standard for the quantification of the analyte in pharmaceutical formulations using high-performance liquid chromatography technique and spectrophotometric technique.

• Verwenden

  anticonvulsant, antimigraine, GABA-A agonist, AMP/kinate glutamate receptor antagonist, carbonic anhydrase inhibitor

• Definition

  ChEBI: A hexose derivative that is 2,3:4,5-di-O-isopropylidene-beta-D-fructopyranose in which the hydroxy group has been converted to the corresponding sulfamate ester. It blocks voltage-dependent sodium channe s and is used as an antiepileptic and for the prevention of migraine.

• Manufacturing Process

  To a cold solution (-4°C) of 2,3:4,5-di-O-isopropylidene-β-fructopyranose (75 g, 0.29 mol) in DMF (725 ml) was added 50% oily sodium hydride (16.34 g,0.34 mol). After stirring for 90 min, sulfamoyl chloride (54.9 g, 0.48 mol) was added and the stirring continued for an additional 3.5 h at that temperature.
  The reaction mixture was poured into cold water and extracted with toluene.
  The organic layer was dried (Na2SO4) and the solvents removed under vacuum to give a syrup which crystallized immediately. Recrystallization from ethylacetate/hexane gave pure 2,3:4,5-bis-O-(1-methylethylidene)-β-D_x0002_fructopyranose sulfamate, melting point 125°-126°C.

• Trademarks

  Topamax

• Therapeutic Function

  Anticonvulsant

• Biologische Funktion

  Topiramate is most useful in patients with generalized tonic–clonic seizures and those with partial complex seizures. Topiramate causes a higher incidence of CNSrelated side effects (primarily cognitive slowing and confusion) than other AEDs. It does not appear to cause a significant incidence of rashes or other hypersensitivity reactions; however, a significantly higher incidence of kidney stones has been observed in persons receiving topiramate than in a similar untreated population.

• Allgemeine Beschreibung

  TPM is a sulphamate-substituted monosaccharide, a derivativeof the naturally occurring sugar D-fructose thatexhibits broad and potent AED actions at both glutamateand GABA receptors.19 It has good oral bioavailability of85% to 95%, most likely resulting from its structural similarityto D-glucose. Thus, it may be actively transportedinto the brain by the D-glucose transporter. (Recall thatD-fructose and D-glucose have identical stereochemistry atmany of their chiral centers.) Only about 20% of the drugis eliminated by hepatic metabolism (CYP2C19), the remainingdrug is excreted unchanged by the kidneys.57 Thesulphamate ester is hydrolyzed by sulfatases to the correspondingprimary alcohol, which is further oxidized to thecorresponding carboxylic acid. Even though there are noreports of significant interactions between TPM and otherAEDs, TPM is said to have a weak carbonic anhydrase inhibitoryactivity because of the presence of the sulphamatemoiety. Thus, concomitant use of TPM with other carbonicanhydrase inhibitors should be avoided.57 The exact mechanismof actions are still unknown, but TPM appears toblock glutamate release, antagonize glutamate kainicacid/AMPA receptors, and increase GABAergic transmissionby binding to a site distinct from BZDs or barbiturateson the GABAA receptor complex.

• Biologische Aktivität

  Anticonvulsant. Antagonizes GluR5 kainate receptors (IC 50 = 0.46 μ M), acts as a positive allosteric modulator of GABA A receptor-mediated currents, inhibits Na v channels (IC 50 = 48.9 μ M) and inhibits L-type Ca 2+ channels. Also inhibits carbonic anhydrase (CA) (K i values are 0.1 and 0.2 μ M at rat CA II and CA IV respectively), which lowers intracellular neuronal pH.

• Biochem/physiol Actions

  Kainate GluR5 receptor antagonist; anticonvulsant.

• Mechanism of action

  The mechanism of action for topiramate is unknown, but several actions are thought to contribute to its AED activity. It blocks repetitive firing by acting on sodium channels, may enhance GABAA-mediated chloride flux, and appears to be an antagonist at the AMPA and KA receptors, thus blocking the effect of glutamate. In addition, recent evidence suggests inhibition of L-type calcium currents.

• Pharmakokinetik

  Topiramate is rapidly absorbed, with at least an 80 to 95% oral bioavailability that is unaffected by food. Following an oral dose of topiramate, peak plasma concentration is reached in 1 to 4 hours, exhibiting linear pharmacokinetics. Protein binding is minimal (<20%), and the usual elimination half-life is 20 to 30 hours, allowing a twice-daily dosing regimen. In the absence of enzyme-inducing drugs, approximately 70 to 80% of the drug is excreted unchanged in the urine, with the remainder as metabolites resulting from oxidation and hydrolysis. Enzyme-inducing AEDs alter the pharmacokinetics of topiramate by reducing its plasma levels and increasing its rate of elimination.
  In children from 4 to 17 years of age, topiramate exhibits linear pharmacokinetics, with a 50% increase in clearance rate compared to adults. Topiramate may require up to a 50% dose reduction in patients with renal insufficiency, and a replacement dose may be needed after renal dialysis. Topiramate has demonstrated teratogenicity in animal studies.

• Clinical Use

  Topiramate is a sulfamate-substituted monosaccharide derived from fructose with a broad spectrum of AED activity. It is approved for monotherapy or as an adjunct drug for partial or primary generalized tonic-clonic seizures in patients older than 10 years, as adjunct therapy in children aged from 2 to 10 years with partial-onset seizures, and in persons older than 2 years with Lennox-Gastaut syndrome. Topiramate also is approved for the prophylaxis of migraine headaches.

• Nebenwirkungen

  Common CNS side effects associated with topiramate therapy include drowsiness, dizziness, impaired concentration and memory, speech and language difficulties, and confusion. These effects develop during the first weeks of therapy and may decline over time. Acute closed-angle glaucoma caused by topiramate requires immediate evaluation. Only rare hepatic or bone marrow effects have been noted thus far; however, an increased incidence of renal stones is troublesome and probably related to the drug's activity as a carbonic anhydrase inhibitor, reducing citrate excretion and increasing urinary pH. Use of additional carbonic anhydrase inhibitors, a ketogenic diet, or a family history of nephrolithiasis may be considered as contraindications for using topiramate.
  Topiramate is not devoid of potential interaction properties: It induces CYP3A4 and inhibits CYP2C19, thus significantly increasing plasma phenytoin levels. Topiramate also may decrease the effectiveness of oral contraceptives.

• Synthese

  Ziconitide is the synthetic form of the conotoxin ω-conopeptide MVIIA .

• Veterinary Drugs and Treatments

  Topiramate may be useful for treating seizures in dogs, particularly partial seizure activity. It may also be of benefit in treating cats, but little information is available.

• in vitro

  in principal neurons of the rat basolateral amygdala, low concentrations of topiramate selectively inhibited pharmacologically isolated excitatory synaptic currents mediated by kainate receptors with the glur5 subunit with an ic50 value of 0.5 μm. topiramate also partially depressed predominantly ampa-receptor-mediated epscs with lower efficacy [1]. in dissociated neocortical slices, low concentrations of tpm (25–30 μm) slightly inhibited the persistent fraction of na+ current and reduced the na+-dependent long-lasting action potential shoulders evoked in layer v pyramidal neurons after ca2+ and k+ current blockade. tpm (100 μm) had no effects on the voltage dependence of activation but induced a leftward shift of the steady-state inaf inactivation curve [3].

• in vivo

  tpm treatment significantly improved the 24-h neurological deficit scores (high dose, 1.17 ± 0.41; low dose, 1.75 ± 0.5; p < 0.05 for both doses). the percentage of infarct volume (low dose, 22.9 ± 8.9%, p = 0.002; high dose 7.6 ± 3.4%, p < 0.001) reduced when compared with the controls (infarct size, 54.2 ± 9.0%; neurobehavior score, 2. 67 ± 0.52). higher dose of tpm induced more neuroprotection than that of lower dose (p < 0.05). in a rat model of focal ischemia, treatment with tpm 2 h after mca embolization resulted in neuroprotective effect in a dose- and use-dependent manner [2]. topiramate (25-100 mg/kg, i.p.) dose-dependently elevated the threshold for clonic seizures induced by infusion of a selective agonist of glur5 kainate receptors atpa [4]. topiramate (i.p) effectively suppressed acute seizures induced by perinatal hypoxia in a dose-dependent manner with an ed50 of 2.1 mg/kg [5]. topiramate (20 and 40 mg/kg i.p.) dose-dependently inhibited both tonic and absence-like seizures. in dba/2 mice, topiramate inhibited sound-induced seizures with ed50 of 8.6 mg/kg (p.o) [6].

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antidepressants: antagonism of anticonvulsant effect; avoid with St John’s wort.
  Antiepileptics: concentration reduced by fosphenytoin, phenytoin, carbamazepine and possibly phenobarbital; increases fosphenytoin and phenytoin concentration; reduces concentration of perampanel; hyperammonaemia and CNS toxicity reported with valproate.
  Antimalarials: mefloquine antagonises anticonvulsant effect.
  Antipsychotics: anticonvulsant effect antagonised.
  Oestrogens and progestogens: reduced contraceptive effect.
  Orlistat: possibly increased risk of convulsions.
  Ulipristal: reduced contraceptive effect - avoid.

• Stoffwechsel

  Topiramate is not extensively metabolised (~20
  %) in healthy volunteers. It is metabolised up to 50
  % in patients receiving enzyme-inducing drugs. Six metabolites formed through hydroxylation, hydrolysis and glucuronidation have been identified but have little activity. It is eliminated chiefly in urine, as unchanged drug and metabolites.

• Lager

  +4°C

• Einzelnachweise

  [1] gryder d s, rogawski m a. selective antagonism of glur5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons[j]. the journal of neuroscience, 2003, 23(18): 7069-7074.
  [2] yang y, shuaib a, li q, et al. neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization[j]. brain research, 1998, 804(2): 169-176.
  [3] taverna s, sancini g, mantegazza m, et al. inhibition of transient and persistent na+ current fractions by the new anticonvulsant topiramate[j]. journal of pharmacology and experimental therapeutics, 1999, 288(3): 960-968.
  [4] kaminski r m, banerjee m, rogawski m a. topiramate selectively protects against seizures induced by atpa, a glur5 kainate receptor agonist[j]. neuropharmacology, 2004, 46(8): 1097-1104.
  [5] koh s, jensen f e. topiramate blocks perinatal hypoxia‐induced seizures in rat pups[j]. annals of neurology, 2001, 50(3): 366-372.
  [6] nakamura j, tamura s, kanda t, et al. inhibition by topiramate of seizures in spontaneously epileptic rats and dba/2 mice[j]. european journal of pharmacology, 1994, 254(1-2): 83-89.

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