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
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
原材料
準備製品