トピラマート

危険有害性情報のコード(GHS)

• 絵表示(GHS)

  

• 注意喚起語

  Warning

• 危険有害性情報

  H315：皮膚刺激

  H319：強い眼刺激

  H335：呼吸器への刺激のおそれ

• 注意書き

  P261：粉じん/煙/ガス/ミスト/蒸気/スプレーの吸入を避ける こと。

  P264：取扱い後は皮膚をよく洗うこと。

  P264：取扱い後は手や顔をよく洗うこと。

  P271：屋外または換気の良い場所でのみ使用すること。

  P280：保護手袋/保護衣/保護眼鏡/保護面を着用するこ と。

  P302+P352：皮膚に付着した場合：多量の水と石鹸で洗うこと。

  P305+P351+P338：眼に入った場合：水で数分間注意深く洗うこと。次にコ ンタクトレンズを着用していて容易に外せる場合は外す こと。その後も洗浄を続けること。

トピラマート 価格

MSDS Information

• RWJ-17021

トピラマート 化学特性,用途語,生産方法

• 外観

  白色～ほとんど白色粉末～結晶

• 溶解性

  Soluble to 100 mM in DMSO and to 100 mM in Ethanol

• 用途

  医薬品 (抗てんかん剤) (JAPIC 医療医薬品集 2017)

• 効能

  抗けいれん薬, 抗てんかん薬, AMPA受容体拮抗薬

• 商品名

  トピナ (協和発酵キリン); トピナ (協和発酵キリン)

• 説明

  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.

• 化学的特性

  White-to-Off-White Crystalline Powder

• 来歴

  The development of topiramate originated from exploratory research conducted by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, in the late 1970s. Initially, the research focused on developing a fructose-1,6-bisphosphatase inhibitor for the treatment of diabetes. However, researchers unexpectedly discovered the compound's anticonvulsant properties during screening. This discovery led to a fundamental shift in research direction. Through the systematic work of a team of chemists (including principal inventors Harvey J. Klimish and Craig A. Marianov), the molecular structure of topiramate was eventually determined through continuous optimization of the compound's structure. Subsequent research gradually elucidated its unique multiple mechanisms of action, including blocking voltage-gated sodium channels, enhancing GABA-A receptor activity, and antagonizing AMPA/algal taurine receptors. After rigorous clinical evaluation, the drug was first approved by the U.S. Food and Drug Administration (FDA) in 1996 as an adjunct treatment for epilepsy. Subsequently, its indications expanded to include migraine prevention (approved in 2004) and its use in combination with other drugs for weight management.

• 使用

  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.

• 定義

  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.

• 生物学の機能

  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.

• 一般的な説明

  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.

• 生物活性

  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.

• 作用機序

  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.

• 薬物動態学

  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.

• 臨床応用

  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.

• 副作用

  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.

トピラマート 上流と下流の製品情報

トピラマート 生産企業

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トピラマート スペクトルデータ(¹HNMR、MS)

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