ラモトリギン 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
効能
双極性障害治療薬, 抗けいれん薬, 抗てんかん薬
商品名
ラミクタール (グラクソ・スミスクライン)
説明
Lamotrigine, also known by the brand name Lamictal®, is a second-generation antiepileptic drug (AED) manufactured by GlaxoSmithKline in the UK and USA. Lamotrigine is a new mazine, glutamate inhibitor anticonvulsant that significantly reduces the incidence of refractory partial seizures. The drug is reported to produce fewer CNS side effects than diazepam or sodium phenytoin. It is also indicated as add-on therapy for the treatment of generalized seizures not satisfactorily controlled by other anti-epileptics.
化学的特性
It is a white to cream coloured powder that is soluble in isopropanol and somewhat soluble in water. It has a melting point of 216-218°C and readily dissolves in organic solvents like benzene, toluene, and hot ethanol.
使用
Lamotrigine is an anticonvulsant that works by Inhibits glutamate release, possibly through inhibition of Sodium, Potassium, and Calcium currents. Used in the treatment of bipolar depression, partial seizures in epilepsy, and generalized seizures of Lennox-Gastaut syndrome. Additionally, it is used for the maintenance treatment of bipolar I disorder and depression.
定義
ChEBI: Lamotrigine is a member of the class of 1,2,4-triazines in which the triazene skeleton is substituted by amino groups at positions 3 and 5, and by a 2,3-dichlorophenyl group at position 6. It has a role as an anticonvulsant, an antimanic drug, an antidepressant, a non-narcotic analgesic, a calcium channel blocker, an excitatory amino acid antagonist, an EC 3.4.21.26 (prolyl oligopeptidase) inhibitor, an environmental contaminant, a xenobiotic and a geroprotector. It is a member of 1,2,4-triazines, a primary arylamine and a dichlorobenzene.
製造方法
The preparation method of Lamotrigine involves several steps. 2,3-dichlorobenzoic acid is chlorinated to 2,3-dichlorobenzoyl chloride, then reacted with cuprous cyanide, condensed with aminoguanidine, and finally cyclized under the action of potassium hydroxide Lamotrigine.
Two key methods for the synthesis of lamotrigine have been reported.
https://www.sciencedirect.com/topics/chemistry/lamotrigine A novel process for the synthesis of lamotrigine and its intermediate
https://patents.google.com/patent/WO2007069265A1/en
世界保健機関（WHO）
Lamotrigine is a relatively new antiepilepsy agent acting through
stabilization of neuronal membranes and preventing liberation of neurotransmitters.
生物学の機能
Lamotrigine has a broad spectrum of action and is effective in generalized and partial epilepsies. Its primary mechanism of action appears to be blockage of voltagedependent sodium channels, although its effectiveness against absence seizures indicates that additional mechanisms may be active. Lamotrigine is almost completely absorbed from the gastrointestinal tract, and peak plasma levels are achieved in about 2 to 5 hours. The plasma half-life after a single dose is about 24 hours. Unlike most drugs, lamotrigine is metabolized primarily by glucuronidation. Therefore, it appears likely that lamotrigine will not induce or inhibit cytochrome P450 isozymes, in contrast to most AEDs.
一般的な説明
Lamotrigine is an antiepileptic drug belonging in the phenyltriazine class. It is used in the treatment of both epilepsy and as a mood stabilizer in bipolar disorder. Lamotrigine is the first medication since lithium granted Food and Drug Administration (FDA) approval for the maintenance treatment of bipolar type I. It is approved for use in more than 30 countries.
生物活性
Anticonvulsant. Inhibits glutamate release, possibly through inhibition of Na + , K + and Ca 2+ currents.
作用機序
Lamotrigine has been found effective against refractory partial seizures. Like phenytoin and CBZ, its main mechanism of action appears to be a blockade of sodium channels that is both voltage- and used-dependent. It also inhibits the high-threshold calcium channel, possibly through inhibition of presynaptic N-type calcium channels, and also blocks glutamate release. The most probable explanation for lamotrigine's efficacy is its ability to produce a blockade of sodium channel repetitive firing. In addition, lamotrigine appears to reduce glutaminergic excitatory transmission, although the mechanism for this action remains unclear.
薬物動態学
Following oral administration, lamotrigine is absorbed rapidly and completely, exhibiting linear pharmacokinetics and modest
protein binding (55%). Lamotrigine is metabolized predominantly by N-glucuronidation and subsequent urinary elimination of its
major metabolite, the quaternary 2-N-glucuronide (80–90%), the minor 5-amino-N-glucuronide (8–10%), and unchanged drug
(8–10%). Lamotrigine's usual elimination half-life of 24–35 hours is reduced to 13–15 hours in patients taking enzymeinducing AEDs. The presence of valproate increases the lamotrigine half-life substantially by inhibiting N-glucuronidation,
necessitating a reduction in dose to avoid toxicity. Hepatic disease patients may demonstrate a reduced capacity to for
lamotrigine glucuronidation, thus reducing its rate of clearance.
臨床応用
Lamotrigine is a 5-phenyl-1,2,4-triazine derivative indicated as monotherapy or as an adjunct for partial seizures in adults, as
adjunct in patients with Lennox-Gastaut syndrome, and as adjunct for partial seizures in children 2 years of age and older.
Lamotrigine may have additional benefit in combating myoclonic and typical absence seizures. It is approved for use in the
maintenance treatment of bipolar disorder.
副作用
The usefulness of lamotrigine is limited by the increased incidence of serious rashes, particularly in children or patients taking
valproate. This increase, however, may be attenuated by very slow dose escalation, because most rashes appear within
the first 8 weeks of treatment. The drug should be discontinued if a rash appears at any time. Additionally, lamotrigine may be
associated with development of myoclonus after 2 to 3 years of drug treatment. Additional common side effects associated
with lamotrigine therapy include dizziness, diplopia, headache, ataxia, blurred vision, somnolence, and nausea.
代謝
Lamotrigine is extensively metabolised in the liver by
UDP-glucuronyl transferases and excreted almost entirely
in urine, principally as an inactive glucuronide conjugate.
It slightly induces its own metabolism. Only about 2% of
lamotrigine-related material is excreted in faeces.
参考文献
https://my.clevelandclinic.org/health/drugs/20217-lamotrigine-tabletshttps://pubchem.ncbi.nlm.nih.gov/compound/Lamotriginehttps://go.drugbank.com/drugs/DB00555The_Renal_Drug_Handbook_The_Ultimate
ラモトリギン 上流と下流の製品情報
原材料
準備製品