塩酸ドスレピン

関: dosulepin

WordNet

a complex consisting of an organic base in association with hydrogen chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/26 14:40:19」(JST)

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Dosulepin (INN, BAN) formerly known as dothiepin (USAN), and marketed under the brand names Prothiaden, Dothep, Thaden, and Dopress, is a tricyclic antidepressant that is used in several European and South Asian countries, as well as Australia, South Africa, and New Zealand. It is not used in the United States.^[7]

Medical uses

Dosulepin is used for the treatment of major depressive disorder and neuropathic pain.^[1] Dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder.^[8]^[9] There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.^[10]

Adverse effects

Common adverse effects:^[2]

Drowsiness
Extrapyramidal symptoms
Tremor
Confusion
Disorientation
Dizziness
Paresthesias
Alterations to ECG patterns
Dry mouth
Sweating
Urinary retention
Hypotension
Postural hypotension
Tachycardia
Palpitations
Arrhythmias
Conduction defects
Increased or decreased libido
Nausea
Vomiting
Constipation
Blurred vision

Less common adverse effects:^[2]

Disturbed concentration
Delusions
Hallucinations
Anxiety
Fatigue
Headaches
Restlessness
Excitement
Insomnia
Hypomania
Nightmares
Peripheral neuropathy
Ataxia
Incoordination
Seizures
Paralytic ileus
Hypertension
Heart block
Myocardial infarction
Stroke
Gynecomastia (swelling of breast tissue in males)
Testicular swelling
Impotence
Epigastric distress
Abdominal cramps
Parotid swellings
Diarrhea
Stomatitis (swelling of the mouth)
Black tongue
Peculiar taste sensations
Cholestatic jaundice
Altered liver function
Hepatitis (swelling of the liver)
Skin rash
Urticaria (hives)
Photosensitisation
Skin blisters
Angioneurotic edema
Weight loss
Urinary frequency
Mydriasis
Weight gain
Hyponatremia (low blood sodium)
Movement disorders
Dyspepsia (indigestion)
Increased intraocular pressure
Changes in blood sugar levels

Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds)
Eosinophilia (an abnormally high amount of eosinophils in the blood)
Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections)
Galactorrhea (lactation that is unassociated with breastfeeding and lactation)

Contraindications

Contraindications include:^[2]

Epilepsy as it can lower the seizure threshold
TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome
Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias
Liver failure
Hypersensitivity to dothiepin

Drug interactions

Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination.^[2] TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants.^[2] Guanethidine and other adrenergic neurone blocking drugs can have their antihypertensive effects blocked by dosulepin.^[2] Sympathomimetics may potentiate the sympathomimetic effects of dosulepin.^[2] Due to the anticholinergic and antihistamine effects of dosulepin anticholinergic and antihistamine medications may have their effects potentiated by dosulepin and hence these combinations are advised against.^[2] Dosulepin may have its postural hypotensive effects potentiated by diuretics.^[2] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.^[2]

Overdose

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.^[8] Dosulepin may be particularly toxic in overdose compared to other TCAs.^[8] The onset of toxic effects is around 4–6 hours after dosulepin is ingested.^[2] In order to minimise the risk of overdose it is advised that patients only receive a limited number of tablets at a time so as to limit their risk of overdosing.^[2] It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses.^[2] The medication should also be kept out of reach of children.^[2]

Mechanism of action

Dosulepin is a serotonin-norepinephrine reuptake inhibitor (SNRI) with anticholinergic, antihistamine, and antiadrenergic effects.^[11]

Receptor/Transporter	K_i (nM)^[12]
SERT	8.6
NET	46
DAT	5,310
5-HT_1A	4,004
5-HT_2A	152
M₁	18
M₂	109
M₃	38
M₄	61
M₅	92
α₁	419
α₂	12
H₁	4

Pharmacokinetics

Dothiepin is readily absorbed from the small intestine and is extensively metabolised on first-pass through the liver into its chief active metabolite, northiaden (desmethyldosulepin).^[2] Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL occur within 2–3 hours of oral administration.^[2] It is distributed in breast milk and crosses the placenta and blood-brain barrier.^[2] It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.^[2]

Chemistry

Dosulepin is also the dibenzothiepine analogue of doxepin, from which it differs by the replacement of the oxygen position with that of sulfur.

The synthesis of this agent is quite similar to that used for its oxygen analogue, doxepin (), though with a reversed functionality. The sequence in the present case starts with the alkylation of thiosalicylic acid () with benzyl chloride () to give the thioether (). The product is then cyclized by means of polyphosphoric acid to give the ketone (). Condensation with the familiar dimethylpropylamine Grignard reagent serves to introduce the side chain (). Dehydration of the tertiary alcohol then affords dothiepin () as a mixture of isomers.^[13]

References

^ ^a ^b Lancaster, SG; Gonzalez, JP (July 1989). "Dothiepin: a review of its pharmcodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs 38 (1): 123–147. doi:10.2165/00003495-198938010-00005. PMID 2670509.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v "Dothep Dothiepin hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 1 November 2013. Retrieved 3 December 2013.
^ Rees, JA (1981). "Clinical interpretation of pharmacokinetic data on dothiepin hydrochloride (Dosulepin, Prothiaden)". Journal of International Medical Research 9 (2): 98–102. PMID 7227628.
^ Maguire, KP; Burrows, GD; Norman, TR; Scoggins, BA (September 1981). "Metabolism and pharmacokinetics of dothiepin" (PDF). British Journal of Clinical Pharmacology 12 (3): 405–409. doi:10.1111/j.1365-2125.1981.tb01235.x. PMC 1401810. PMID 7295471.
^ ^a ^b Bareggi, SR; Cavallaro, R; Pirola, R; Altamura, AC (1990). "Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects". Progress in Neuro-Psychopharmacology and Biological Psychiatry 14 (2): 163–170. doi:10.1016/0278-5846(90)90098-2. PMID 2309034.
^ Ogura, C; Kishimoto, A; Mizukawa, R; Hazama, H; Honma, H; Kawahara, K (1983). "Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline". European Journal of Clinical Pharmacology 25 (6): 811–814. doi:10.1007/BF00542525. PMID 6662179.
^ Dosulepin Hydrochloride. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). 5 December 2011. Retrieved 3 December 2013.
^ ^a ^b ^c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
^ C Feinmann, M Harris, and R Cawley (11 February 1984). "Psychogenic facial pain: presentation and treatment.". http://www.ncbi.nlm.nih.gov/. The National Center for Biotechnology Information. Retrieved 6 April 2014.
^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
^ Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 3 December 2013.
^ Zirkle, C. L.; 1971, U.S. Patent 3,609,167.

UpToDate Contents

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1. 三環系抗うつ剤および四環系抗うつ剤：薬理学、投与、および副作用 tricyclic and tetracyclic drugs pharmacology administration and side effects

English Journal

Dose equivalents of antidepressants: Evidence-based recommendations from randomized controlled trials.

Hayasaka Y1, Purgato M2, Magni LR3, Ogawa Y1, Takeshima N1, Cipriani A4, Barbui C2, Leucht S5, Furukawa TA1.
Journal of affective disorders.J Affect Disord.2015 Jul 15;180:179-84. doi: 10.1016/j.jad.2015.03.021. Epub 2015 Mar 31.
BACKGROUND: Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the pres
PMID 25911132

Effect of cytochrome P450 2C19 and 2C9 amino acid residues 72 and 241 on metabolism of tricyclic antidepressant drugs.

Attia TZ1, Yamashita T, Hammad MA, Hayasaki A, Sato T, Miyamoto M, Yasuhara Y, Nakamura T, Kagawa Y, Tsujino H, Omar MA, Abdelmageed OH, Derayea SM, Uno T.
Chemical & pharmaceutical bulletin.Chem Pharm Bull (Tokyo).2014;62(2):176-81.
Although cytochromes P450 2C9 (CYP2C9) and 2C19 (CYP2C19) have 91% amino acid identity, they have different substrate specificities. Previous studies have suggested that several amino acid residues may be involved in substrate specificity. In this study, we focused on the roles of two amino acids, r
PMID 24492587

Drugs and other chemicals involved in fatal poisoning in England and Wales during 2000 – 2011.

Handley SA, Flanagan RJ.
Clinical toxicology (Philadelphia, Pa.).Clin Toxicol (Phila).2014 Jan;52(1):1-12. doi: 10.3109/15563650.2013.872791.
CONTEXT: Fatal poisoning data can reveal trends in the poisons encountered, which can help guide prescribing practices and product safety and other legislation, and more recently has helped to monitor the use of emerging drugs of abuse ( ‘ legal highs ’ ).METHODS: We searched Mortality Statistic
PMID 24397714

Japanese Journal

症例報告自殺目的で塩酸セルトラリン,スルピリド,塩酸ドスレピン,フマル酸クエチアピン,塩酸トラゾドンを含む多剤大量服用後,悪性症候群もしくはセロトニン症候群を併発した1例

防衛衛生 55(4), 71-74, 2008-04
NAID 40015997038

フマル酸ケトチフェンによる接触皮膚炎の１例

皮膚 43(1), 19-23, 2001
NAID 130003844159

治療薬剤と咽喉頭異常感の消失率

耳鼻咽喉科臨床 85(6), 957-961, 1992
NAID 130001812351

「ドスレピン」

Dosulepin
Systematic (IUPAC) name
	(E,Z)-3-(dibenzo[b,e]thiepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade names	Dothep, Prothiaden
AHFS/Drugs.com	International Drug Names
Pregnancy; category	AU: C;
Legal status	AU: Prescription Only (S4); US: POM;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	30%
Protein binding	84%
Metabolism	Hepatic (via N-demethylation to active metabolite northiaden, S-oxidation and glucuronidation)
Half-life	51 hours, 14-45 hours, 54 hours (elderly)
Excretion	Urine (56%), faeces (15%)
Identifiers
CAS Registry Number	113-53-1
ATC code	N06AA16
PubChem	CID 13473
UNII	W13O82Z7HL
KEGG	D07872
ChEMBL	CHEMBL108947
Chemical data
Formula	C19H21NS
Molecular mass	295.45 g/mol
(what is this?) (verify)

　　[★]

英: dosulepin
化: 塩酸ドスレピン dosulepin hydrochloride
商: プロチアデン
関: ドチエピン

「dosulepin」

　　[★]

ドスレピン

関: dosulepin hydrochloride、dothiepin

「hydrochloride」

　　[★] 塩酸塩、ハイドロクロライド　

[Drugs-1] Lancaster, SG; Gonzalez, JP (July 1989). "Dothiepin: a review of its pharmcodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness". Drugs 38 (1): 123–147. doi:10.2165/00003495-198938010-00005. PMID 2670509.

[TGA-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v "Dothep Dothiepin hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 1 November 2013. Retrieved 3 December 2013.

[3] Rees, JA (1981). "Clinical interpretation of pharmacokinetic data on dothiepin hydrochloride (Dosulepin, Prothiaden)". Journal of International Medical Research 9 (2): 98–102. PMID 7227628.

[4] Maguire, KP; Burrows, GD; Norman, TR; Scoggins, BA (September 1981). "Metabolism and pharmacokinetics of dothiepin" (PDF). British Journal of Clinical Pharmacology 12 (3): 405–409. doi:10.1111/j.1365-2125.1981.tb01235.x. PMC 1401810. PMID 7295471.

[EldY-5] Bareggi, SR; Cavallaro, R; Pirola, R; Altamura, AC (1990). "Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects". Progress in Neuro-Psychopharmacology and Biological Psychiatry 14 (2): 163–170. doi:10.1016/0278-5846(90)90098-2. PMID 2309034.

[6] Ogura, C; Kishimoto, A; Mizukawa, R; Hazama, H; Honma, H; Kawahara, K (1983). "Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline". European Journal of Clinical Pharmacology 25 (6): 811–814. doi:10.1007/BF00542525. PMID 6662179.

[MD-7] Dosulepin Hydrochloride. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). 5 December 2011. Retrieved 3 December 2013.

[AMH-8] Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.

[BNF-9] Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.

[10] C Feinmann, M Harris, and R Cawley (11 February 1984). "Psychogenic facial pain: presentation and treatment.". http://www.ncbi.nlm.nih.gov/. The National Center for Biotechnology Information. Retrieved 6 April 2014.

[GG-11] Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.

[PDSP-12] Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 3 December 2013.

[13] Zirkle, C. L.; 1971, U.S. Patent 3,609,167.

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関連記事	「dosulepin」「hydrochloride」

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dosulepin hydrochloride