クロザピン 化学特性,用途語,生産方法
外観
ごくうすい黄色〜黄色, 結晶〜粉末
溶解性
メタノールに溶ける。
用途
セロトニン5-HT2A 受容体阻
害作用を示します。ドーパミンD2 受容体に
対する親和性が低く、セロトニン5-HT2A 受
容体及びドーパミンD4 受容体に対して高い
親和性を示します。D2 受容体遮断作用に依存
せず、中脳辺縁系への選択的抑制作用を示す
と考えられています。
効能
統合失調症治療薬
商品名
クロザリル (ノバルティスファーマ)
化学的特性
Yellow Crystalline Solid
使用
Clozapine is a neuroleptic, which expresses antipsychotic and sedative action. It does not
cause general depression and extrapyramidal disorders. It is used for severe and chronic forms of schizophrenia, maniacal conditions, manic-depressive psychosis, psychomotor
excitement, and various other psychotic conditions.
定義
ChEBI: A benzodiazepine that is 5H-dibenzo[b,e][1,4]diazepine substituted by a chloro group at position 8 and a 4-methylpiperazin-1-yl group at position 11. It is a second generation antipsychotic used in the treatment of psychiatr
c disorders like schizophrenia.
世界保健機関（WHO）
Clozapine, a tricyclic neuroleptic, was introduced in 1972 for the
treatment of psychosis. In 1975 its use was associated with cases of
agranulocytosis, particularly in Finland. These cases, which included several
fatalities, resulted in the withdrawal of the drug in some countries. However,
clozapine remains available in at least 30 countries, in some cases only on special
request, for the treatment of severe psychotic disorders unresponsive to other
neuroleptics provided that close monitoring of the blood count is feasible. In 1989,
it was introduced in the United States for the treatment of severe schizophrenia.
Lately, the use of clozapine in the United Kingdom has been associated with
convulsions.
(Reference: (WHODIB) WHO Drug Information Bulletin, 2: 10, , 1977)
一般的な説明
Clozapine, 8-chloro-11-(4-methyl-1-piperazinyl)5H-dibenzo[b,e] [1,4] diazepine (Clozaril), is a yellowcrystalline powder that is only slightly soluble in water. Withthe introduction of clozapine, a different pharmacological antipsychotics.106 Unlike typical antipsychotics, clozapine is largelydevoid of EPS. The lack of EPS with this compound waspostulated to be caused by its preferential binding tomesolimbic rather than striatal DA receptors.Furthermore,clozapine was shown to exhibit potent affinity for 5-HT2Areceptors.
DMCZ shows partial agonism at D
2 and D
3 receptors andexhibits a distinctly different pharmacological profile comparedwith clozapine and other atypical antipsychotics.Unlike clozapine, which is a potent M
1 muscarinic antagonist,DMCZ is a potent M
1 agonist. Agonism at muscarinicreceptors has been proposed to be useful for impaired cognitionin schizophrenia. Burnstein et al.found thatDMCZ acted as a partial agonist at DA D
2 and D
3 receptors.These investigators suggested that the low incidence of EPSassociated with clozapine may be caused by the partial agonismof DMCZ at D
2 and D
3 receptors. Thus, DMCZ maybe of interest as an atypical antipsychotic with an improvedside effect profile compared with clozapine.
生物活性
Atypical antipsychotic drug, with a much lower tendency to cause extrapyramidal side effects than conventional neuroleptics. Displays a broad range of pharmacological actions; the antipsychotic effects are thought to be mediated principally by 5-HT 2A/2C and dopamine receptor blockade (K i values are 21, 170, 170, 230 and 330 nM for D 4 , D 3 , D 1 , D 2 and D 5 receptors respectively).
臨床応用
Although clozapine demonstrates a favorable pharmacologicalprofile compared with typical antipsychotics, its useis restricted by a relatively high incidence of agranulocytosis.The exact mechanism for the cause of agranulocytosishas not been confirmed, but a highly reactive nitrenium ionthat is formed by the action of hepatic enzymes appears tobe involved.The mean elimination half-life of clozapine following a single 75-mg dose is 8 hours. Because of severaladverse effects, clozapine is only used in refractory casesof schizophrenia. Individuals with a history of seizures orpredisposed to seizures should be cautioned when takingclozapine. Similar to other atypical antipsychotic agents,clozapine causes an increased risk of mortality in elderly individualswith dementia-related psychoses.
副作用
A serious drawback to the use of clozapine, however, is the potentially fatal agranulocytosis that
is reported to occur in 1 to 2% of unmonitored patients, necessitating weekly white blood cell counts for at
least the first 6 months of pharmacotherapy.
代謝
Clozapine is orally active and metabolized mainly by CYP3A4 to
inactive desmethyl, hydroxyl, and N-oxide derivatives, with a half-life of approximately 12 hours. Clozapine has relatively low affinity for brain dopamine D1 and D2 receptors (moderate affinity for D4) in comparison to its affinity
at adrenergic α1 and α2, histamine H1, muscarinic M1 and serotonin 5-HT2A receptors.
クロザピン 上流と下流の製品情報
原材料
準備製品