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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/07/25 16:26:43」(JST)

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Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor developed by a team at Hoechst AG in the 1960s.^[1] The drug was test marketed in the United States by Hoechst AG (now Sanofi-Aventis), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters.^[2] This is a mechanism of action shared by some recreational drugs like cocaine (see DRI).

Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic. There were relatively few adverse effects (mainly dry mouth, headache, nausea), the drug was not sedating, did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse.^[3]^[4]

Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).^[5]

In a 1989 study it has been investigated for use in treating adult ADHD and proven successful.^[6] In a 1977 study it has not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.^[7]

Due to the risk of a risk of haemolytic anaemia, the U.S. Food and Drug Administration (FDA) withdrew approval for nomifensine on March 20, 1992. Nomifensine has subsequently been withdrawn from the Canadian and UK markets as well.^[8] Some deaths were linked to immunohaemolytic anemia caused by this compound although the mechanism remained unclear.^[9]

In 2012 structure–affinity relationship data (compare SAR) were published.^[10]

References

^ US patent 3577424, "4-Phenyl-8-Amino Tetrahydroisoquinolines", issued 1971-05-04, assigned to Farbwerke Hoechst
^ Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. (1979). "Nomifensine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Depressive Illness". Drugs 18 (1): 1–24. PMID 477572. edit
^ Habermann, W. (1977). "A Review of Controlled Studies with Nomifensine, Performed Outside the UK". British Journal of Clinical Pharmacology 4 (Suppl 2): 237S–241S. PMC 1429098. PMID 334230. edit
^ Yakabow, A. L.; Hardiman, S.; Nash, R. J. (1984). "An Overview of Side Effects and long-term Experience with Nomifensine from United States Clinical Trials". The Journal of Clinical Psychiatry 45 (4 Pt 2): 96–101. PMID 6370985. edit
^ Böning, J.; Fuchs, G. (2008). "Nomifensine and Psychological Dependence - a Case Report". Pharmacopsychiatry 19 (5): 386–388. doi:10.1055/s-2007-1017275. PMID 3774872. edit
^ Shekim, W. O.; Masterson, A.; Cantwell, D. P.; Hanna, G. L.; McCracken, J. T. (1989). "Nomifensine Maleate in Adult Attention Deficit Disorder". The Journal of Nervous and Mental Disease 177 (5): 296–299. PMID 2651559. edit
^ Bedard, P.; Parkes, J. D.; Marsden, C. D. (1977). "Nomifensine in Parkinson's Disease". British Journal of Clinical Pharmacology 4 (Suppl 2): 187S–190S. PMC 1429119. PMID 334223. edit
^ "Nomifensine DB04821". Drugbank.ca.
^ Galbaud du Fort, G. (1988). "Hematologic toxicity of antidepressive agents" [Hematologic Toxicity of Antidepressive Agents]. L'Encephale (in French) 14 (4): 307–318. PMID 3058454. edit
^ Pechulis AD et al (2012): "4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors", Bioorg. Med. Chem. Lett., 7219. PMID 23084899

English Journal

Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum.

Robinson JD1, Howard CD, Pastuzyn ED, Byers DL, Keefe KA, Garris PA.
Neurotoxicity research.Neurotox Res.2014 Aug;26(2):152-67. doi: 10.1007/s12640-014-9459-y. Epub 2014 Feb 22.
Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impa
PMID 24562969

Bacillus Calmette-Guérin vaccine induces a selective serotonin reuptake inhibitor (SSRI)-resistant depression like phenotype in mice.

Vijaya Kumar K1, Rudra A1, Sreedhara MV1, Siva Subramani T1, Prasad DS1, Das ML1, Murugesan S2, Yadav R2, Trivedi RK2, Louis JV1, Li YW3, Bristow LJ3, Naidu PS1, Vikramadithyan RK4.
Brain, behavior, and immunity.Brain Behav Immun.2014 Jul 9. pii: S0889-1591(14)00390-0. doi: 10.1016/j.bbi.2014.06.205. [Epub ahead of print]
Preclinical studies have shown that administration of Bacillus Calmette-Guérin (BCG) vaccine induces depression-like behaviors in mice; however, the effect of antidepressant drug treatment has not been reported earlier. In the present study, we induced depression-like behavior by administering BCG
PMID 25016199

Region- and domain-dependent action of nomifensine.

Shu Z1, Taylor IM, Walters SH, Michael AC.
The European journal of neuroscience.Eur J Neurosci.2014 Jul;40(2):2320-8. doi: 10.1111/ejn.12604. Epub 2014 Apr 26.
The dopamine (DA) terminal fields in the rat dorsal striatum (DS) and nucleus accumbens core (NAcc) are organized as patchworks of domains that exhibit distinct kinetics of DA release and clearance. The present study used fast-scan cyclic voltammetry recordings of electrically evoked DA overflow to
PMID 24766210

Japanese Journal

Motivational Effect of Nomifensine in the Intracranial Self-Stimulation Behavior Using a Runway Method(Pharmacology)

Sagara Hidenori,Kitamura Yoshihisa,Sendo Toshiaki [他],ARAKI Hiroaki,GOMITA Yutaka
Biological & pharmaceutical bulletin 31(5), 1036-1040, 2008-05-01
… In the present study, we investigated the effects of nomifensine on the experimental extinction process of non-reinforcing reward and pre-trial electric priming stimulations in lateral hypothalamic self-stimulation. … Nomifensine, an antidepressant drug, delayed the running speed of the extinction process at doses of 5 and 10 mg/kg (i.p.) compared with the vehicle alone. … Therefore, our findings suggest the possible application of nomifensine for improving motivation. …
NAID 110006663977

Caffeine の自発運動亢進効果に対する selective dopamine re-uptake inhibitor (nomifensine) 投与の影響

村上千夏,加藤龍二,鎌田邦栄,中村幹雄
杏林医学会雑誌 : JOURNAL OF THE KYORIN MEDICAL SOCIETY 34(1), 18-23, 2003-03-30
NAID 50000813705

Caffeineの自発運動亢進効果に対するselective dopamine re-uptake inhibitor (nomifensine)投与の影響

村上千夏,加藤龍二,鎌田邦栄,中村幹雄
杏林医学会雑誌 34(1), 18-23, 2003-03-30
NAID 110007374844

Related Pictures

★リンクテーブル★

リンク元

「ドパミン」

Nomifensine
Systematic (IUPAC) name
	(±)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine
Clinical data
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Half-life	1.5-4 hours
Identifiers
CAS number	24526-64-5
ATC code	N06AX04
PubChem	CID 4528
DrugBank	DB04821
ChemSpider	4371
UNII	1LGS5JRP31
ChEBI	CHEBI:116225
ChEMBL	CHEMBL273575
Chemical data
Formula	C16H18N2
Mol. mass	238.328 g/mol
	SMILES NC1=C(CN(C)CC2C3=CC=CC=C3)C2=CC=C1;
	InChI InChI=1S/C16H18N2/c1-18-10-14(12-6-3-2-4-7-12)13-8-5-9-16(17)15(13)11-18/h2-9,14H,10-11,17H2,1H3 ; Key:XXPANQJNYNUNES-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: dopamine DA DOA 3,4-dihydroxyphenethylamine
同: ドーパミン
化: 塩酸ドパミン, dopamine hydrochloride, ドパミン塩酸塩
商: イノバン、イブタント、カコージンD、カコージン、カタボン、ガバンス、クリトパン、ツルドパミ、ドパラルミン、ドミニン、トロンジン、プレドパ、マートバーン、ヤエリスタ
関: ドパミン受容体、カテコラミン。強心剤

概念

カテコラミンの一つ

生合成

チロシン→L-dopa→ドパミン→ノルアドレナリン→アドレナリン
脳、交感神経、交感神経節、副腎皮質のクロム親和性細胞で産生される

視床下部-下垂体系

視床下部弓状核や脳室周辺の隆起漏斗系ドパミンニューロンで産生される。
下垂体のD2受容体を介してホルモン分泌の調節を受けている。　→ e.g. プロラクチン放出抑制ホルモン(PIF)

ドパミン受容体

D₁受容体

低用量での血管拡張はこの受容体を介して起こる (GOO.249)

D₂受容体

中枢神経系に存在

神経伝達物質の薬理 (GOO.324)

神経伝達物質	トランスポーター阻害薬	受容体のサブタイプ	選択的作動薬	選択的阻害薬	受容体と共役する分子
ドパミン	cocaine mazindol nomifensine	D₁			G_s
		D₂	bromocriptine	sulpiride domperidone	G_i
		D₃	7-OH-DPAT
		D₄
		D₅			G_s

薬理学

低濃度

D₁受容体に作用して血管拡張→腎血流量↑→GFP↑→Na排出↑→利尿

やや高濃度

β₁受容体に作用→心拍出量↑・心収縮力↑(頻脈はない)・収縮期圧↑・拡張期圧不変

アドレナリン低用量投与と同じ？

高濃度

α₁受容体に作用→血管平滑筋収縮(→収縮期圧↑、拡張期圧↑？？？)

アドレナリン高用量投与と同じ？

ran]]

(PT.218)

中脳に細胞体を持つものが多く、黒質から線条体に至る黒質線条体系と黒質や腹側被蓋野から報酬系の神経核、辺縁系、前頭葉に至る中脳皮質系がある。視床下部やその周辺にもドーパミン作動性線維の細胞体とその終末があり、隆起漏斗系、隆起下垂体系、不確帯視床下部系、脳室周囲系を形成する。黒質線条体系の変性はパーキンソン病をもたらす。ドーパミン誘導体には幻覚剤となるものがある。ドーパミンの分泌増大や脳のD2受容体の増加は精神分裂病（統合失調症）の発病に関与している可能性がある。モルヒネはドーパミンの分泌を促進する。コカインは輸送体によるドーパミンの取り込みを阻害し作用の持続時間を延長する。一部の覚醒剤中毒はドーパミン輸送体の抑制による。

ホルモンの調節

プロラクチンは視床下部でドパミンの産生を促進　←　プロラクチン抑制因子として作用
ドパミンは視床下部でGnRHの分泌を抑制　→　卵巣機能の抑制
ドパミンは下垂体前葉？でD受容体に作用してプロラクチンを抑制　←　抗精神病薬(D2受容体をブロックする)を使うと高プロラクチン血症となる。

循環不全治療薬として

イノバン

下記のような急性循環不全(心原性ショック、出血性ショック)

(1) 無尿、乏尿や利尿剤で利尿が得られない状態　　←　　低濃度で用いれば、腎血流を増加させ尿量の増加が期待できる　→　ドパミン#薬理学
(2) 脈拍数の増加した状態　　←　　高濃度でなければ、頻脈を起こさず心拍出量を増やす。　→　ドパミン#薬理学
(3) 他の強心・昇圧剤により副作用が認められたり、好ましい反応が得られない状態

[1] US patent 3577424, "4-Phenyl-8-Amino Tetrahydroisoquinolines", issued 1971-05-04, assigned to Farbwerke Hoechst

[2] Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. (1979). "Nomifensine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Depressive Illness". Drugs 18 (1): 1–24. PMID 477572. edit

[3] Habermann, W. (1977). "A Review of Controlled Studies with Nomifensine, Performed Outside the UK". British Journal of Clinical Pharmacology 4 (Suppl 2): 237S–241S. PMC 1429098. PMID 334230. edit

[4] Yakabow, A. L.; Hardiman, S.; Nash, R. J. (1984). "An Overview of Side Effects and long-term Experience with Nomifensine from United States Clinical Trials". The Journal of Clinical Psychiatry 45 (4 Pt 2): 96–101. PMID 6370985. edit

[5] Böning, J.; Fuchs, G. (2008). "Nomifensine and Psychological Dependence - a Case Report". Pharmacopsychiatry 19 (5): 386–388. doi:10.1055/s-2007-1017275. PMID 3774872. edit

[6] Shekim, W. O.; Masterson, A.; Cantwell, D. P.; Hanna, G. L.; McCracken, J. T. (1989). "Nomifensine Maleate in Adult Attention Deficit Disorder". The Journal of Nervous and Mental Disease 177 (5): 296–299. PMID 2651559. edit

[7] Bedard, P.; Parkes, J. D.; Marsden, C. D. (1977). "Nomifensine in Parkinson's Disease". British Journal of Clinical Pharmacology 4 (Suppl 2): 187S–190S. PMC 1429119. PMID 334223. edit

[8] "Nomifensine DB04821". Drugbank.ca.

[9] Galbaud du Fort, G. (1988). "Hematologic toxicity of antidepressive agents" [Hematologic Toxicity of Antidepressive Agents]. L'Encephale (in French) 14 (4): 307–318. PMID 3058454. edit

[10] Pechulis AD et al (2012): "4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors", Bioorg. Med. Chem. Lett., 7219. PMID 23084899

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案内

案内

nomifensine