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a tranquilizer (trade name Loxitane) used to treat schizophrenia (同)Loxitane

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/07/23 18:22:09」(JST)

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Loxapine is a typical antipsychotic medication, used primarily in the treatment of schizophrenia. Trade names for loxapine taken by mouth include Loxapac and Loxitane; the inhalable form is approved as Adasuve. The drug is a member of the dibenzoxazepine class and structurally related to clozapine (which belongs to the chemically akin class of dibenzodiazepines). Several researchers have argued that loxapine may behave as an atypical antipsychotic.^[2]

Loxapine may be metabolized by N-demethylation to amoxapine, a tetracyclic antidepressant.^[3]

Therapeutic uses and dosages

The typical starting dosage is 10 mg twice daily; usual dose range 30–50 mg twice daily; maximum recommended dosage is 250 mg per day. The US Food and Drug Administration (FDA) has approved loxapine inhalation powder 10 mg (Adasuve, Alexza Pharmaceuticals) for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.^[4]

A brief review of loxapine^[5] found no conclusive evidence that it was particularly effective in patients with paranoid schizophrenia. A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics.^[6]

Loxapine was one of five antipsychotics used in a study on the structure of neurons in parts of the brain thought to be involved in schizophrenia. Only loxapine was linked to the development of new connections between neurons.^[7]

Precautions

This drug is unrelated to the habit-forming benzodiazepines, and loxapine abuse is rare.^[8] The risks and side effect profile are comparable to other antipsychotics.

Side effects

Note: Percentages given after possible adverse effects refer to the incidence of said adverse effects, according to DrugPoint.^[1]

Common side effects of loxapine (≥1% incidence) when inhaled include: ^[1]

Taste sense altered (14%)
Sedated (12%)
Pharyngitis (3%)

Intense Sleeping (Highest Procentage) In Pill Form Blurred Speech (In Pill Form)

Common side effects of orally-administered loxapine include: ^[1]

Constipation
Dry mouth
Akathisia
Dizziness
Intense Sleeping (Highest Procentage) (In Pill Form)
Blurred Speech (In Pill Form)
Extrapyramidal disease (dose-dependent. At lower dosages its propensity for causing extrapyramidal side effects appears to be similar to that of atypical antipsychotics^[9]
Blurred vision
Urinary retention
Somnolence (which appears to be moderate in severity compared to other antipsychotic drugs^[10])
Dyspnoea
Nasal congestion

Rare side effects include: ^[1]

Paralytic ileus
Agranulocytosis
Leukopenia
Thrombocytopenia
Hepatocellular liver damage
Neuroleptic malignant syndrome
Seizure
Tardive dyskinesia
Stroke
Transient ischaemic attack
Death

Pharmacology

The data in the following table was obtained from the PDSP Ki database and they are for binding towards human cloned proteins (receptor and transporter) unless otherwise specified.^[11]

Molecular target	Binding affinity (K_i [nM]) for loxapine	Binding affinity (K_i [nM]) for amoxapine
5-HT_1A	2456	-
5-HT_1B	388	-
5-HT_1D	3468	-
5-HT_1E	1399	-
5-HT_2A	6.63	0.5
5-HT_2C	13.3	2 (Cloned rat receptor protein)
5-HT₃	190	-
5-HT_5A	776	-
5-HT₆	31.0	50
5-HT₇	87.6	40.2 (Rat, Cloned)
α_1A	31	-
α_1B	53	-
α_2A	150.9	-
α_2B	107.8	-
α_2C	80.0	-
β₁	>10000	-
β₁	>10000	-
M₁	119.5	-
M₂	445	-
M₃	211.3	-
M₄	1266	-
M₅	166	-
D₁	54	-
D₂	11	20.8
D₃	19.33	21
D₄	8.4	21
D₅	75	-
H₁	4.9	-
H₂	208	-
H₄	5048	-
SERT	>10000	58
NET	5698	16
DAT	>10000	58

Chemistry

Synthesis

Schmutz, J.; Kunzle, F.; Hunziker, F.; Gauch, R.; Helv. Chim. Acta 1967, 50, 245.

References

^ ^a ^b ^c ^d ^e ^f ^g Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
^ Glazer WM (1999). "Does loxapine have "atypical" properties? Clinical evidence". The Journal of Clinical Psychiatry 60 (Suppl 10): 42–6. PMID 10340686.
^ Cheung SW, Tang SW, Remington G (March 1991). "Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography". Journal of Chromatography 564 (1): 213–21. doi:10.1016/0378-4347(91)80083-O. PMID 1860915.
^ Harrison, Pam: Inhalant Approved for Agitation in Bipolar I, Schizophrenia. Medscape. Dec 24, 2012.
^ "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin 29 (11): 41–2. May 1991. PMID 1747161.
^ Chakrabarti A, Bagnall A, Chue P, et al. (2007). "Loxapine for schizophrenia". In Chakrabarti, Abhijit. Cochrane Database of Systematic Reviews (Online) (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMID 17943763.
^ Brennand, Kristen; Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yangling Mu, Gong Chen, Diana Yu, Shane McCarthy, Jonathan Sebat & Fred H. Gage (13 April 2011). "Modelling schizophrenia using human induced pluripotent stem cells". Nature 473 (7346): 221–5. doi:10.1038/nature09915. PMID 21490598. Cite uses deprecated parameters (help)
^ Sperry L, Hudson B, Chan CH (March 1984). "Loxapine abuse". The New England Journal of Medicine 310 (9): 598. doi:10.1056/NEJM198403013100920. PMID 6694719.
^ Nordstrom K. Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: an update. Neuropsychiatry [Internet]. 2012 Jun [cited 2013 Sep 21];2(3):253–60. Available from: http://www.futuremedicine.com/doi/abs/10.2217/npy.12.23
^ Taylor D, Paton C, Kapur S, Taylor D, South London and Maudsley NHS Trust. The Maudsley prescribing guidelines in psychiatry [Internet]. Chichester, West Sussex: John Wiley & Sons; 2012 [cited 2013 Sep 21]. Available from: http://site.ebrary.com/lib/uqat/Doc?id=10531429
^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Aug 3]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php

External links

Product monograph from Medscape (free registration required).

UpToDate Contents

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1. 第1世代抗精神病剤：薬理学、投与、および副作用の比較 first generation antipsychotic medications pharmacology administration and comparative side effects
2. 統合失調症に対する薬物療法：副作用マネージメント pharmacotherapy for schizophrenia side effect management
3. 成人における双極性障害：急性躁病および軽躁に対する薬物療法 bipolar disorder in adults pharmacotherapy for acute mania and hypomania

English Journal

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation.

Descoeur J1, Philibert L2, Chalard K3, Attal J4, Petit P5, Klouche K6, Olivier M7.
Therapie.Therapie.2017 Dec;72(6):643-647. doi: 10.1016/j.therap.2017.03.003. Epub 2017 May 29.
PMID 28647110

Response to inhaled loxapine in patients with schizophrenia or bipolar I disorder: PANSS-EC responder analyses.

Zeller S1, Zun L2, Cassella JV3, Spyker DA4, Yeung PP5.
BJPsych open.BJPsych Open.2017 Nov 10;3(6):285-290. doi: 10.1192/bjpo.bp.117.005363. eCollection 2017 Nov.
PMID 29163985

The in vitro actions of loxapine on dopaminergic and serotonergic receptors. Time to consider atypical classification of this antipsychotic drug?

Ferreri F1, Drapier D2, Baloche E3, Ouzid M3, Zimmer L4, Llorca PM5.
The international journal of neuropsychopharmacology.Int J Neuropsychopharmacol.2017 Nov 2. doi: 10.1093/ijnp/pyx102. [Epub ahead of print]
PMID 29106549

「ロキサピン」

Loxapine
Systematic (IUPAC) name
	2-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine
Clinical data
Trade names	Loxapac, Loxitane, Adasuve
AHFS/Drugs.com	monograph
MedlinePlus	a682311
Licence data	EMA:Link, US Daily Med:link
Pregnancy cat.	C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (US)
Routes	Inhalation, oral
Pharmacokinetic data
Protein binding	96.8%
Metabolism	Liver, extensive; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-glycoprotein and is a substrate of CYP1A2, CYP3A4 and CYP2D6
Half-life	Oral, 4 hours; Inhalation, 7.61 hours
Excretion	Majority are excreted within 24 hours. Main route through urine(conjugated metabolites); Small amounts through the faeces(unconjugated metabolites)
Identifiers
CAS number	1977-10-2
ATC code	N05AH01
PubChem	CID 3964
IUPHAR ligand	205
DrugBank	DB00408
ChemSpider	3827
UNII	LER583670J
KEGG	D02340
ChEBI	CHEBI:50841
ChEMBL	CHEMBL831
Chemical data
Formula	C18H18ClN3O
Mol. mass	327.808 g/mol
	SMILES Clc2ccc1Oc4c(/N=C(\c1c2)N3CCN(C)CC3)cccc4;
	InChI InChI=1S/C18H18ClN3O/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18/h2-7,12H,8-11H2,1H3 ; Key:XJGVXQDUIWGIRW-UHFFFAOYSA-N ;
Physical data
Melt. point	109–110 °C (228–230 °F)
(what is this?) (verify)

　　[★]

英: loxapine
化: コハク酸ロキサピン loxapine succinate
関: 抗精神病薬

「succinate」

　　[★] コハク酸、コハク酸塩、コハク酸エステル, succinic acid

[DrugPoint-1] ^ ^a ^b ^c ^d ^e ^f ^g Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.

[pmid10340686-2] Glazer WM (1999). "Does loxapine have "atypical" properties? Clinical evidence". The Journal of Clinical Psychiatry 60 (Suppl 10): 42–6. PMID 10340686.

[pmid1860915-3] Cheung SW, Tang SW, Remington G (March 1991). "Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography". Journal of Chromatography 564 (1): 213–21. doi:10.1016/0378-4347(91)80083-O. PMID 1860915.

[4] Harrison, Pam: Inhalant Approved for Agitation in Bipolar I, Schizophrenia. Medscape. Dec 24, 2012.

[pmid1747161-5] "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin 29 (11): 41–2. May 1991. PMID 1747161.

[pmid17943763-6] Chakrabarti A, Bagnall A, Chue P, et al. (2007). "Loxapine for schizophrenia". In Chakrabarti, Abhijit. Cochrane Database of Systematic Reviews (Online) (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMID 17943763.

[7] Brennand, Kristen; Anthony Simone, Jessica Jou, Chelsea Gelboin-Burkhart, Ngoc Tran, Sarah Sangar, Yan Li, Yangling Mu, Gong Chen, Diana Yu, Shane McCarthy, Jonathan Sebat & Fred H. Gage (13 April 2011). "Modelling schizophrenia using human induced pluripotent stem cells". Nature 473 (7346): 221–5. doi:10.1038/nature09915. PMID 21490598. Cite uses deprecated parameters (help)

[pmid6694719-8] Sperry L, Hudson B, Chan CH (March 1984). "Loxapine abuse". The New England Journal of Medicine 310 (9): 598. doi:10.1056/NEJM198403013100920. PMID 6694719.

[Nordstrom-9] Nordstrom K. Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: an update. Neuropsychiatry [Internet]. 2012 Jun [cited 2013 Sep 21];2(3):253–60. Available from: http://www.futuremedicine.com/doi/abs/10.2217/npy.12.23

[Maudlsey-10] Taylor D, Paton C, Kapur S, Taylor D, South London and Maudsley NHS Trust. The Maudsley prescribing guidelines in psychiatry [Internet]. Chichester, West Sussex: John Wiley & Sons; 2012 [cited 2013 Sep 21]. Available from: http://site.ebrary.com/lib/uqat/Doc?id=10531429

[11] National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Aug 3]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php

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案内

案内

loxapine succinate