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an antipsychotic drug (trade name Clozaril) used as a sedative and for treatment-resistant schizophrenia; know to have few side effects (同)Clozaril
tending to discourage (especially of prices); "the price was prohibitive" (同)prohibitory

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/06/09 16:52:42」(JST)

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Clozapine is an atypical antipsychotic medication used in the treatment of schizophrenia, and is also sometimes used off-label for the treatment of bipolar disorder. The first of the atypical antipsychotics to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause agranulocytosis, a condition involving a dangerous decrease in the number of white blood cells, that led to death in some patients. In 1989 after studies demonstrated that it was effective in treating treatment-resistant schizophrenia^[2] the United States Food and Drug Administration (FDA) approved the use of clozapine solely for that use, requiring regular white blood cell and absolute neutrophil counts.^[3]^[4] The FDA also requires clozapine to carry five black box warnings for agranulocytosis, seizures, myocarditis, for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis."^[5] In 2002 the FDA approved clozapine for reducing the risk of suicidal behavior for patients with schizophrenia.

Clozapine is usually used only in patients that have not responded to other anti-psychotic treatments due to its danger of causing agranulocytosis as well as the costs of having to have blood tests continually during treatment. It is, however, one of the very effective anti-psychotic treatment choices.^[6] Patients are monitored weekly for the first six months. If there are no low counts the patient can be monitored every two weeks for an additional six months. Afterwards, the patient may qualify for every four-week monitoring.^[7] Clozapine has numerous severe side effects including agranulocytosis, bowel infarction,^[8] and seizures,^[9] and has been associated with myocarditis^[10] and diabetes^[11] though those relationships have not been confirmed. Additionally, it also often causes less serious side effects such as hypersalivation and weight gain. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.^[12]

1 Medical uses
2 Adverse effects
- 2.1 Agranulocytosis
- 2.2 Cardiac toxicity
- 2.3 Gastrointestinal hypomotility
- 2.4 Hypersalivation
- 2.5 Central nervous system
- 2.6 Urinary incontinence
- 2.7 Withdrawal effects
- 2.8 Weight gain and diabetes
- 2.9 Interactions
3 Chemistry
4 Mechanism of action
5 Pharmacokinetics
6 History
7 Marketing
8 See also
9 References
10 Additional reading
11 External links

Medical uses

Clozapine is an atypical antipsychotic drug primarily prescribed to patients who are unresponsive to or intolerant of conventional and other atypical neuroleptics.^[13] It is used principally in treating treatment-resistant schizophrenia,^[14] a term used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics.^[15] It has been shown to be more effective in reducing symptoms of schizophrenia than the older typical antipsychotics, with more pronounced effects in those who have responded poorly to other medication. Though the relapse rate is lower and patient acceptability better, this has not translated to significant observed benefits in global functioning.^[14] There is some evidence clozapine may reduce propensity for substance abuse in schizophrenic patients.^[16]

There has been one case report of successful use of clozapine in isolated increase in creatine kinase (in absence of neuroleptic malignant syndrome) in a patient with schizophrenia where other atypical antipsychotics were not successful.^[17]

A number of case reports indicate that clozapine can be an effective treatment for schizophrenia while at the same time diminishing some symptoms associated with Parkinson's, such as the tremor and dyskinesia. Unlike typical antipsychotics such as haloperidol and some atypical antipsychotics such as risperidone, clozapine does not produce Parkinsonian symptoms, even at high doses. This is in part because it binds relatively weakly to the D2 dopamine receptor, compared to most other antipsychotics.^[18] Clozapine is not approved by the Food and Drug Administration (FDA) for the treatment of behavior problems in older adults with dementia.

Adverse effects

Clozapine may cause side effects; most are minor, although some are serious and potentially fatal. Common side effects include extreme constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, hyperglycemia, and weight gain. The risk of developing extrapyramidal symptoms such as tardive dyskinesia is below that of typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.^[19]

Clozapine also carries five black box warnings, including warnings for agranulocytosis, CNS depression, leukopenia, neutropenia, seizure disorder, bone marrow suppression, dementia, hypotension, myocarditis, orthostatic hypotension (with or without syncope) and seizures.^[20] Lowering of the seizure threshold may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for orthostatic hypotension and other adverse cardiovascular side effects.^[21]

Many male patients have experienced cessation of ejaculation during orgasm as a side effect of clozapine, though this is not documented in official drug guides.^[22]

Agranulocytosis

Clozapine carries a black box warning for drug-induced agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment;^[23] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.^[24]

It has been suggested that coadministration of clozapine with an antioxidant such as vitamin C can reduce the risk of agranulocytosis.^[25]

Cardiac toxicity

A more recently identified and sometimes fatal side effect is that of myocarditis, which usually develops within the first month of commencement.^[26] First manifestations of illness are fever which may be accompanied by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. Typically C-reactive protein (CRP) increases with the onset of fever and rises in the cardiac enzyme, troponin, occur up to 5 days later. Monitoring guidelines advise checking CRP and troponin at baseline and weekly for the first 4 weeks after clozapine initiation and observing the patient for signs and symptoms of illness.^[27] Signs of cardiac failure are less common and may develop with the rise in troponin. A recent case-control study found that the risk of clozapine-induced myocarditis is increased with increasing rate of clozapine dose titration, increasing age and concomitant sodium valproate.^[28]

Gastrointestinal hypomotility

Another underrecognized and potentially life-threatening side effect spectrum is gastrointestinal hypomotility, which may manifest as severe constipation, fecal impaction, paralytic ileus, bowel obstruction, acute megacolon, ischemia or necrosis. Monitoring of bowel function is recommended, as untreated cases are occasionally fatal.^[29]^[30]

Hypersalivation

While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for the hypersalivation.^[31]

Central nervous system

CNS side effects include drowsiness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, akinesia, agitation, seizures, rigidity, akathisia, confusion, fatigue, insomnia, hyperkinesia, weakness, lethargy, ataxia, slurred speech, depression, myoclonic jerks, and anxiety. Rarely seen are delusions, hallucinations, delirium, amnesia, libido increase or decrease, paranoia and irritability, abnormal EEG, worsening of psychosis, paresthesia, status epilepticus, and obsessive compulsive symptoms. Similar to other antipsychotics clozapine rarely has been known to cause neuroleptic malignant syndrome.^[32]

Urinary incontinence

Clozapine is linked to urinary incontinence^[33] though its appearance may be under-recognized.^[34]

Withdrawal effects

Abrupt withdrawal may lead to cholinergic rebound effects, severe movement disorders as well as severe psychotic decompensation. It has been recommended that patients, families, and caregivers are aware of the symptoms and risks of abrupt withdrawal of clozapine. When discontinuing clozapine, gradual dose reduction is recommended to reduce the intensity of withdrawal effects.^[35]^[36]

Weight gain and diabetes

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.^[37] Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggest that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.^[38] A study has established that olanzapine and clozapine disturb the metabolism by making the body take preferentially its energy from fat (instead of privileging carbohydrates). Levels of carbohydrates remaining high, the body develops insulin resistance (causing diabetes).^[39]

Research has indicated that clozapine may cause a deficiency of selenium.^[40]

Interactions

Fluvoxamine inhibits the metabolism of clozapine leading to significantly increased blood levels of clozapine.^[41]

Chemistry

Clozapine is a dibenzodiazepine that is structurally related to loxapine. It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 188.9 mg/L (25 °C).^[1] Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).^[42]

Dibenzo-1,4-diazepines such as clozapine may be synthesised by various methods, including the Bischler–Napieralski reaction and intramolecular condensation in the presence of a dehydrating agent as depicted below:^[43]

Several patents have been granted.^[44]^[45]^[46]

Mechanism of action

Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.^[47]

Clozapine is a partial antagonist ^[48] at the 5-HT_1A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.^[49]

A direct interaction of clozapine with the GABA_B receptor has also been shown.^[50] GABA_B receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models.^[51] GABA_B receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.^[52]

Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,^[53] and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons. Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.^[54]

Binding Affinity (K_i [nM]) towards cloned human receptors unless otherwise specified^[55]

Receptor/Transporter Protein	Clozapine	Norclozapine
SERT	1624	316.6
NET	3168	493.9
DAT	>10000	>10000
5-HT_1A	123.7	13.9
5-HT_1B	519	406.8
5-HT_1D	1356	476.2
5-HT_2A	5.35	10.9
5-HT_2B	8.37	2.8
5-HT_2C	9.44	11.9
5-HT₃	241	272.2
5-HT_5A	3857	350.6
5-HT₆	13.49	11.6
5-HT₇	17.95	60.1
D₁	266.25	14.3
D₂	157	101.4
D₃	269.08	193.5
D₄	26.36	63.94
D₅	255.33	283.6
α_1A	1.62	104.8
α_1B	7	85.2
α_2A	37	137.6
α_2B	26.5	95.1
α_2C	6	117.7
β₁	5000	6239
β₂	1650	4725
M₁	6.17	67.6
M₂	36.67	414.5
M₃	19.25	95.7
M₄	15.33	169.9
M₅	15.5	35.4
H₁	1.13	3.4
H₂	153	345.1
H₃	>10000	>10000
H₄	665	1028
δ-opioid	1000 (Mouse receptor)	127.9
μ-opioid	1000 (Rat receptor)	>10000
κ-opioid	1000 (Guinea pig receptor)	>10000
σ₁	5000 (Guinea pig receptor)	>10000
σ₂	-	>10000

Pharmacokinetics

Norclozapine (N-desmethylclozapine), clozapine's chief active metabolite

The absorption of clozapine is almost complete, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).

Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and feces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents that induce (e.g., cigarette smoke) or inhibit (e.g., theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine. For example, the induction of metabolism caused by smoking means that smokers require up to double the dose of clozapine compared with non-smokers to achieve an equivalent plasma concentration.^[56]

Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.^[57] Monitoring of plasma levels of clozapine and norclozapine has been shown to be useful in assessment of compliance, metabolic status, prevention of toxicity, and in dose optimization.^[56]

History

Clozapine was developed by Sandoz in 1961, and trials took place in 1972, when it was released in Switzerland and Austria as Leponex. Two years later it was released in West Germany, and Finland in 1975. Early testing was performed in the United States around the same time.^[58] In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer.^[59] Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December 2002, clozapine was approved in the US for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.^[60] In 2005 FDA approved criteria to allow reduced blood monitoring frequency.^[61]

Marketing

In 2005 three pharmaceutical companies marketed this drug: Novartis Pharmaceuticals (manufacturer), Mylan Laboratories and Ivax Pharmaceuticals (market generic clozapine).^[62] The drug is manufactured by Sun Pharmaceuticals in India.

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Additional reading

Benkert, Hippius: Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. ed., Springer Verlag
B. Bandelow, S. Bleich, and S. Kropp: Handbuch Psychopharmaka (German), 2nd. ed. Hogrefe
Crilly JF (2007). The history of clozapine and its emergence in the US Market: A review and Analysis. History of Psychiatry, 18(1): 39–60. doi:10.1177/0957154X07070335

External links

Clozaril—Novartis
Clozapine
US Clozaril Package Insert (PDF)

UpToDate Contents

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1. 統合失調症に対するクロザピン投与のガイドライン guidelines for prescribing clozapine in schizophrenia
2. 治療抵抗性統合失調症 treatment resistant schizophrenia
3. 統合失調症に対する薬物療法：急性期および維持期の治療 pharmacotherapy for schizophrenia acute and maintenance phase treatment
4. 薬剤誘発性の好中球減少および無顆粒球症 drug induced neutropenia and agranulocytosis
5. Second-generation antipsychotic medications: Pharmacology, administration, and side effects

English Journal

Cognitive performance and response inhibition in developmentally vitamin D (DVD)-deficient rats.

Turner KM, Young JW, McGrath JJ, Eyles DW, Burne TH.SourceQueensland Brain Institute, The University of Queensland, St. Lucia, Queensland, Australia.
Behavioural brain research.Behav Brain Res.2013 Apr 1;242:47-53. doi: 10.1016/j.bbr.2012.12.029. Epub 2012 Dec 27.
Evidence from epidemiological studies suggest that low levels of vitamin D during early life alter brain development and may increase the risk of various adverse health outcomes, including schizophrenia. The aim of this experiment was to examine the effect of developmental vitamin D (DVD) deficiency
PMID 23275047

Electrochemical determination of clozapine on MWCNTs/new coccine doped PPY modified GCE: an experimental design approach.

Shahrokhian S, Kamalzadeh Z, Hamzehloei A.SourceDepartment of Chemistry, Sharif University of Technology, Tehran 11155-3516, Iran. shahrokhian@sharif.edu
Bioelectrochemistry (Amsterdam, Netherlands).Bioelectrochemistry.2013 Apr;90:36-43. doi: 10.1016/j.bioelechem.2012.10.002. Epub 2012 Nov 7.
The electrooxidation of clozapine (CLZ) was studied on the surface of a glassy carbon electrode (GCE) modified with a thin film of multiwalled carbon nanotubes (MWCNTs)/new coccine (NC) doped polypyrrole (PPY) by using linear sweep voltammetry (LSV). The pH of the supporting electrolyte (D), drop si
PMID 23178559

Japanese Journal

クロザピンの有効性とその臨床的意義

木田直也,大鶴卓,福田貴博 [他]
精神医学 54(11), 1145-1150, 2012-11
NAID 40019487372

医療観察法の現状と今後の課題 (特集医療観察法の現状と今後の課題)

安藤久美子,永田貴子,平林直次
日本精神科病院協会雑誌 31(7), 702-708, 2012-07
NAID 40019384375

Effects of clozapine and N-desmethylclozapine on synaptic transmission at hippocampal inhibitory and excitatory synapses

Ohno-Shosaku Takako,Sugawara Yuto,Muranishi Chiho,Nagasawa Keisuke,Kubono Kozue,Aoki Nami,Taguchi Mitsuki,Echigo Ryousuke,Sugimoto Naotoshi,Kikuchi Yui,Watanabe Ryoko,Yoneda Mitsugu
Brain Research 1421, 66-77, 2011-11-03
… Clozapine is the first atypical antipsychotic, and improves positive and negative symptoms of many patients with schizophrenia resistant to treatment with other antipsychotic agents. … Clozapine induces minimal extrapyramidal side effects, but is more often associated with seizures. … A large number of studies have been conducted to elucidate pharmacological profiles of clozapine and its major active metabolite, N-desmethylclozapine (NDMC). …
NAID 120003497598

Related Pictures

★リンクテーブル★

リンク元	「クロザピン」「prohibitive」「other than」「無顆粒球症」

「クロザピン」

Clozapine
Systematic (IUPAC) name
	8-Chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
Clinical data
Trade names	Clozaril
AHFS/Drugs.com	monograph
MedlinePlus	a691001
Pregnancy cat.	C (AU) B (US)
Legal status	Prescription Only (S4) (AU) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	60 to 70%
Metabolism	Hepatic, by several CYP isozymes
Half-life	6 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion	80% in metabolized state: 30% biliary and 50% renal
Identifiers
CAS number	5786-21-0
ATC code	N05AH02
PubChem	CID 2818
IUPHAR ligand	38
DrugBank	DB00363
ChemSpider	10442628
UNII	J60AR2IKIC
KEGG	D00283
ChEBI	CHEBI:3766
ChEMBL	CHEMBL42
Chemical data
Formula	C18H19ClN4
Mol. mass	326.823 g/mol
	SMILES CN1CCN(CC1)C2=Nc3cc(ccc3Nc4c2cccc4)Cl;
	InChI InChI=1S/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3 ; Key:QZUDBNBUXVUHMW-UHFFFAOYSA-N ;
Physical data
Melt. point	183 °C (361 °F)
Solubility in water	0.1889 mg/mL (20 °C)
(what is this?) (verify)

　　[★]

英: clozapine
同: Clozaril CLOZARIL
商: クロザリル
関: 抗精神病薬。精神神経用剤

first aid step1 2006 p.207,370

抗精神病薬

非定型抗精神病薬

特徴

1990年にアメリカで最初に認可、発売された非定形型抗精神病薬。
錐体外路症状を惹起しない。プロラクチンの分泌を昂進させない。定型抗精神病薬に反応不良な症例にも有効
副作用のため、日本では臨床応用されていない。

薬理作用

block 5-HT2 receptor and dopamine receptor

抗dopamine作用：弱い
抗D4受容体の選択的アゴニスト

副作用

無顆粒球症、起立性低血圧、洞性頻脈、hypersalivation、temperrature elevation、lowerd seizure threshold、便秘

「prohibitive」

　　[★]

adj.

禁止する、謹製の。(値段が)ひどく高い、(税が)極端に重い。勝利(など)が間違いない

clozapine is generally prescribed only after several other alternative neuroeptic medication have failed, because of the possibility of agranulocytosis and the drug's prohibitive cost.

関: abstinent, ban, forbid, interdict, prohibit, prohibition, prohibitively

「other than」

　　[★]

～のほかに(besides)、～をのぞいて(except for)

patients with a penicillin allergy other than anaphylaxis may receive a cephalosporin.

This serious complication occurs in not more than 1 in 10,000 patients receiving chlorpromazine or other low-potency agents (other than clozapine).

「無顆粒球症」

　　[★]

英: agranulocytosis
ほぼ同: 好中球減少症
関

first aid step1 2006 p.

clozapine, carbamazepine, colchicine(first aid step1 2006 p.207)

[Hopfinger-1] Hopfinger A, Esposito EX, Llinas A, Glen RC, Goodman JM.. Findings of the Challenge To Predict Aqueous Solubility. Journal of Chemical Information and Modeling. 2009;49:1-5.

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匿名

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案内

clozapine