WordNet

a morphine derivative that is not as strong as morphine; used as an emetic and in small doses as a sedative

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/06/25 15:17:37」(JST)

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Apomorphine (Apokyn, Ixense, Spontane, Uprima) is a non-selective dopamine agonist which activates both D₁-like and D₂-like receptors, with some preference for the latter subtypes.^[1] It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix. Apomorphine does not actually contain morphine or its skeleton, or bind to opioid receptors. The apo- prefix relates to it being an aporphine derivative.

Historically, apomorphine has been tried for a variety of uses including psychiatric treatment of homosexuality in the early 20th century, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinson's disease. It is a potent emetic (i.e., it induces vomiting) and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.

It was also successfully used as an unofficial treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. A recent study indicates that apomorphine might be a suitable marker for assessing central dopamine system alterations associated with chronic heroin consumption.^[2] There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate addiction. Early studies involved aversion therapy in alcoholism and anxiety, and modern reports are rather anecdotal.^[3]

For treatment of erectile dysfunction, it is believed that dopamine receptors in the hypothalamic region of the brain are the main target, as although dopamine receptors in the penis do facilitate erection, they do so far more weakly than those in the brain.^[4]

Uses

Alcoholism

Apomorphine was used with some notable success as a treatment for alcohol and morphine addiction. Its chief practitioner in the 1950s was Dr John Yerbury Dent 1888-1961 who, early on in his research, mistakenly believed that it was the emetic properties of apomorphine which was efficacious.

Parkinson's disease

First mooted as a treatment for Parkinson's disease as early as 1951,^[5] its clinical use was first reported in 1970 by Cotzias et al.,^[6] although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the antiemetic domperidone improved results significantly.^[7]

Therapeutic use in Parkinson's disease is effective because of the drug's strong dopaminergic action. When administered subcutaneously, apomorphine is the most effective dopamine agonist. Within 3–20 minutes of injection apomorphine demonstrates a magnitude of effect (ability to convert the patient with Parkinson's disease to the "on" state) that is comparable to l-dopa. A single subcutaneous injection lasts for up to 90 minutes.^[8] While apomorphine can be used in combination with l-dopa, the intention is usually to reduce the l-dopa dosing, as by this stage the patient with Parkinson's disease will probably be experiencing a great deal of dopa-induced dyskinesias and "off" periods.^[8] Following a successful apomorphine challenge, training of patient and caregiver, and careful dose titration, the patient can be maintained in the "on" state by the use of an apomorphine pump as an effective monotherapy.^[8]

Erectile dysfunction

Apomorphine hydrochloride (trade name "Uprima", "Ixense") was a therapy used in the treatment of erectile dysfunction (male impotence). It is its mode of stimulating dopamine in the brain which is believed to enhance the sexual response. It was found to be of poor efficacy^[9] in a large-scale study by Researchers at the UK's Drug Safety Research Unit and University of Portsmouth and discontinued in the UK in January 2006.^[9] Around 65-70% of doctors felt it was ineffective, with 60% of over 11,000 patients (avg age 61) discontinuing in month 1 and a further 23% in month 2.^[9]^[10] UK studies concentrated on males with generalized erectile dysfunction. Uprima effects desire and is not meant to produce an overall effect as say Viagra which works on blood flow. In those males who have problems with desire as opposed to generalized erectile dysfunction it works as expected.

Alzheimer's disease

Apomorphine has been reported to be an inhibitor of Beta amyloid fibril formation, and may thus have potential as a therapeutic for Alzheimer's disease.^[11]

Opiate addiction

In his Deposition: Testimony Concerning a Sickness in the introduction to later editions of Naked Lunch, William S. Burroughs wrote that apomorphine treatment was the only effective cure to opiate addiction he has encountered. "The apomorphine cure is qualitatively different from other methods of cure. I have tried them all. Short reduction, slow reduction, cortisone, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine. None of these cures lasted beyond the first opportunity to relapse. I can say that I was never metabolically cured until I took the apomorphine cure... The doctor explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days. Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse. (No one would take apomorphine for kicks. Not one case of addiction to apomorphine has ever been recorded.)" He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting.

Pharmacology

Apomorphine possesses affinity for the following receptors:^[1]

D₁ (K_i = 372 nM)
D_2S (K_i = 35 nM)
D_2L (K_i = 83 nM)
D₃ (K_i = 26 nM)
D₄ (K_i = 4.4 nM)
D₅ (K_i = 15 nM)

5-HT_1A (K_i = 117 nM)
5-HT_2A (K_i = 120 nM)
5-HT_2B (K_i = 132 nM)
5-HT_2C (K_i = 102 nM)

α_1B-adrenergic (K_i = 676 nM)
α_1D-adrenergic (K_i = 65 nM)
α_2A-adrenergic (K_i = 141 nM)
α_2B-adrenergic (K_i = 66 nM)
α_2C-adrenergic (K_i = 36 nM)

It has > 1,000 nM affinity for 5-HT_1B, 5-HT_1D, and α_1A-adrenergic, and > 10,000 nM affinity for β-adrenergic, H₁, and mACh.^[1]

Apomorphine behaves as a partial agonist at D_2S ( IA = 79%), D_2L (IA= 53%), D₃ (IA = 82%), and D₄ (IA = 45%), and as an antagonist at 5-HT_1B, 5-HT_1D, 5-HT_2A, 5-HT_2B, 5-HT_2C, α₁-adrenergic, and α₂-adrenergic.^[12]^[13] Though its efficacies at D₁ and D₅ are unclear, it is known to act as an agonist at these sites.^[14]

Chemistry

Properties

Apomorphine is colourless as a liquid but stains green. Therefore care must be taken to avoid splashes. Apormophine does not remain stable for more than 24 hours in a plastic container, so syringes are discarded if not used within 24 hours.

Synthesis

Apomorphine hydrochloride is synthesized by heating stoichiometric amounts of morphine and concentrated hydrochloric acid at 140ºC.

References

^ ^a ^b ^c Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 791–804. DOI:10.1124/jpet.102.039867. PMID 12388666. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388666.
^ Guardia J, Casas M, Prat G, Trujols J, Segura L, Sánchez-Turet M (October 2002). "The apomorphine test: a biological marker for heroin dependence disorder?". Addict Biol 7 (4): 421–6. DOI:10.1080/1355621021000006206. PMID 14578019. http://www.ncbi.nlm.nih.gov/pubmed/14578019.
^ Dent JY (1949). “Apomorphine Treatment of Addiction.” British Journal of Addiction to Alcohol & Other Drugs 46 (1); 15-28. DOI: 10.1111/j.1360-0443.1949.tb04502.x
^ Matsumoto K, Yoshida M, Andersson K, Hedlund P (2005). "Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum". Br J Pharmacol 146 (2): 259–67. DOI:10.1038/sj.bjp.0706317. PMC 1576267. PMID 16025145. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1576267.
^ Schwab R, Amador L, Lettvin J (1951). "Apomorphine in Parkinson's disease". Trans Am Neurol Assoc 56: 251–3. PMID 14913646.
^ Cotzias G, Papavasiliou P, Fehling C, Kaufman B, Mena I (1970). "Similarities between neurologic effects of L-dopa and of apomorphine". N Engl J Med 282 (1): 31–3. DOI:10.1056/NEJM197001012820107. PMID 4901383.
^ Corsini G, Del Zompo M, Gessa G, Mangoni A (1979). "Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson's disease". Lancet 1 (8123): 954–6. DOI:10.1016/S0140-6736(79)91725-2. PMID 87620.
^ ^a ^b ^c Chaudhuri K, Clough C (1998). "Subcutaneous apomorphine in Parkinson's disease: Effective yet underused". BMJ 316 (7132): 641. PMC 1112674. PMID 9522772. http://bmj.bmjjournals.com/cgi/content/full/316/7132/641#B2.
^ ^a ^b ^c Pharmaceutical Business Review, "Study shows Abbott's Uprima ineffective for most UK patients"
^ MedicineNet study review
^ Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJE (2002). "New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". J Biol Chem 277 (45): 42881–42890. DOI:10.1074/jbc.M206593200. PMID 12167652. http://www.jbc.org/cgi/content/abstract/277/45/42881.
^ Newman-Tancredi A, Cussac D, Audinot V, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 805–14. DOI:10.1124/jpet.102.039875. PMID 12388667. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388667.
^ Newman-Tancredi A, Cussac D, Quentric Y, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 815–22. DOI:10.1124/jpet.102.039883. PMID 12388668. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388668.
^ Hsieh GC, Hollingsworth PR, Martino B, et al. (January 2004). "Central mechanisms regulating penile erection in conscious rats: the dopaminergic systems related to the proerectile effect of apomorphine". The Journal of Pharmacology and Experimental Therapeutics 308 (1): 330–8. DOI:10.1124/jpet.103.057455. PMID 14569075. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=14569075.

External links

PDSP K_i database
"Apomorphine - Frequently Asked Questions". Britannia Pharmaceuticals. http://www.apo-go.co.uk.
Andrew Lees and Kirsten Turner (2002). "Apomorphine for Parkinson's Disease" (PDF). Practical Neurology 2 (5): 280–287. DOI:10.1046/j.1474-7766.2002.00086.x. http://pn.bmjjournals.com/cgi/reprint/2/5/280.pdf. - Detailed usage guide for Apomorphine pumps for Parkinson's

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. パーキンソン病の薬理学的治療 pharmacologic treatment of parkinson disease
2. パーキンソン病における症状の変動およびジスキネジア motor fluctuations and dyskinesia in parkinson disease
3. パーキンソン病の診断 diagnosis of parkinson disease
4. 悪性症候群 neuroleptic malignant syndrome
5. 成長ホルモンの生理学 physiology of growth hormone

English Journal

In vivo effects of pardoprunox (SLV308), a partial D(2) /D(3) receptor and 5-HT(1A) receptor agonist, on rat dopamine and serotonin neuronal activity.

Betry C, Etievant A, Lambas-Senas L, McCreary AC, Haddjeri N.SourceLaboratory of Neuropharmacology, Universite de Lyon, F-69008, Lyon, France; Faculte de Pharmacie, Laboratoire de Neuropharmacologie, Universite Lyon 1, Lyon, F-69008, France.
Synapse (New York, N.Y.).Synapse.2011 Oct;65(10):1042-51. doi: 10.1002/syn.20936. Epub 2011 May 3.
The nonergot ligand pardoprunox (SLV308) is a dopamine (DA) D(2) /D(3) and serotonin (5-HT)(1A) receptor agonist and a new candidate for the treatment of Parkinson's disease. We used in vivo electrophysiological paradigm in the rat to assess the effects of pardoprunox on DA neuronal activity in vent
PMID 21446003

Significant effects of 4-aminopyridine and tetraethylammonium in the treatment of 6-hydroxydopamine-induced Parkinson's disease.

Haghdoost-Yazdi H, Faraji A, Fraidouni N, Movahedi M, Hadibeygi E, Vaezi F.SourceCellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin 3419759811, Iran. hhaghdoost@yahoo.com
Behavioural brain research.Behav Brain Res.2011 Sep 30;223(1):70-4. Epub 2011 Apr 21.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterizing by degeneration of dopaminergic neurons in the nigrostriatal pathway. The discovery of levodopa revolutionized the treatment of PD however, after several years of treatment most patients develop involuntary movements
PMID 21540059

Japanese Journal

Solid gastric emptying mediated by the serotonin (5-HT)3 receptor in mice is a simple marker to predict emesis

Ando Kentaro,Takagi Kan
The Journal of Toxicological Sciences 36(1), 23-29, 2011
… apomorphine, 0.01-0.3 mg/kg s.c.) and chemotherapeutics (cisplatin, 0.3-10 mg/kg i.v.; …
NAID 130000438635

Parkinson病モデルラットの便秘における腸管内ドパミン受容体の関与

谷川博人,砂川正隆,坂上聡志,齋藤悠,郭試瑜,久光正
昭和医学会雑誌 70(6), 472-479, 2010
… り片側中枢のドパミン神経を破壊したPDモデルラットを作製し，コントロール群より排便量が減ることを確認した．次に大腸を摘出し，Krebs液の中で腸管運動を記録しながらドパミンレセプター作動薬であるapomorphineを投与したところ，PDモデルラットでは腸管運動が有意に抑制され，ドパミンに対する感受性が高まっていることが示唆された．更にPDモデルラットの腸管壁におけるD2Rを免疫染色したところ，その数が有 …
NAID 130000852785

Related Pictures

★リンクテーブル★

リンク元	「化学受容器引金帯」「アポモルヒネ」

「化学受容器引金帯」

Apomorphine
Systematic (IUPAC) name
	(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol
Clinical data
Trade names	Apokyn
AHFS/Drugs.com	monograph
MedlinePlus	a604020
Pregnancy cat.	C
Legal status	℞ Prescription only
Routes	Oral, SC
Pharmacokinetic data
Bioavailability	100% following sc injection
Protein binding	~50%
Metabolism	Hepatic
Half-life	40 minutes (range 30-60 minutes)
Identifiers
CAS number	41372-20-7
ATC code	G04BE07 N04BC07
PubChem	CID 6005
IUPHAR ligand	33
DrugBank	DB00714
ChemSpider	5783
UNII	F39049Y068
KEGG	D07460
ChEBI	CHEBI:48538
ChEMBL	CHEMBL53
Chemical data
Formula	C17H17NO2
Mol. mass	267.322 g/mol
	SMILES Oc4ccc3c(c1c2c(ccc1)CCN([C@@H]2C3)C)c4O;
	InChI InChI=1S/C17H17NO2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20H,7-9H2,1H3/t13-/m1/s1 ; Key:VMWNQDUVQKEIOC-CYBMUJFWSA-N ;
(what is this?) (verify);

　　[★]

英: chemoreceptor trigger zone, CTZ
関: 嘔吐、嘔吐中枢、催吐薬、鎮吐薬

[show details]

化学受容器引き金帯 : 約 11,900 件
化学受容器引金帯 : 約 11,100 件
化学受容器誘発帯 : 1 件
化学受容器引き金領域 : 0 件
化学受容器引金領域 : 2 件
化学受容器誘発領域 : 0 件
化学受容体引き金帯 : 約 11,900 件
化学受容体引金帯 : 約 42 件
化学受容体誘発帯 : 約 21 件
化学受容体引き金領域 : 
化学受容体引金領域 : 2 件
化学受容体誘発領域 : 2 件

化学受容器引き金帯 CTZ : 91 件
化学受容器引金帯 CTZ : 99 件
化学受容器誘発帯 CTZ : 1 件
化学受容器引き金領域 CTZ : 0 件
化学受容器引金領域 CTZ : 2 件
化学受容器誘発領域 CTZ : 0 件
化学受容体引き金帯 CTZ : 28 件
化学受容体引金帯 CTZ : 41 件
化学受容体誘発帯 CTZ : 約 15 件
化学受容体引き金領域 CTZ : 
化学受容体引金領域 CTZ : 2 件
化学受容体誘発領域 CTZ : 1 件

概念

化学物質による刺激の入力を受け、延髄の外側網様体に存在する嘔吐中枢を興奮させる
血液脳関門が存在しないので、血液中の化学物質(薬物、重金属、代謝産物)をモニターして化学受容器引金帯が興奮する。
ドパミン受容体を持ち、受容体刺激により嘔吐が引き起こされる。

apomorphine, ergotalkaloide, morphine

中枢性鎮吐薬はドパミン受容体を遮断する。

解剖

第四脳室底、菱形窩下部の最後野

「アポモルヒネ」

　　[★]

英: apomorphine
化: 塩酸アポモルヒネ apomorphine hydrochloride
商: アポカイン
関: 抗パーキンソン剤

[pmid12388666-0] Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 791–804. DOI:10.1124/jpet.102.039867. PMID 12388666. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388666.

[1] Guardia J, Casas M, Prat G, Trujols J, Segura L, Sánchez-Turet M (October 2002). "The apomorphine test: a biological marker for heroin dependence disorder?". Addict Biol 7 (4): 421–6. DOI:10.1080/1355621021000006206. PMID 14578019. http://www.ncbi.nlm.nih.gov/pubmed/14578019.

[2] Dent JY (1949). “Apomorphine Treatment of Addiction.” British Journal of Addiction to Alcohol & Other Drugs 46 (1); 15-28. DOI: 10.1111/j.1360-0443.1949.tb04502.x

[3] Matsumoto K, Yoshida M, Andersson K, Hedlund P (2005). "Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum". Br J Pharmacol 146 (2): 259–67. DOI:10.1038/sj.bjp.0706317. PMC 1576267. PMID 16025145. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1576267.

[4] Schwab R, Amador L, Lettvin J (1951). "Apomorphine in Parkinson's disease". Trans Am Neurol Assoc 56: 251–3. PMID 14913646.

[5] Cotzias G, Papavasiliou P, Fehling C, Kaufman B, Mena I (1970). "Similarities between neurologic effects of L-dopa and of apomorphine". N Engl J Med 282 (1): 31–3. DOI:10.1056/NEJM197001012820107. PMID 4901383.

[6] Corsini G, Del Zompo M, Gessa G, Mangoni A (1979). "Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson's disease". Lancet 1 (8123): 954–6. DOI:10.1016/S0140-6736(79)91725-2. PMID 87620.

[subcutaneous-7] Chaudhuri K, Clough C (1998). "Subcutaneous apomorphine in Parkinson's disease: Effective yet underused". BMJ 316 (7132): 641. PMC 1112674. PMID 9522772. http://bmj.bmjjournals.com/cgi/content/full/316/7132/641#B2.

[pbr-8] Pharmaceutical Business Review, "Study shows Abbott's Uprima ineffective for most UK patients"

[9] MedicineNet study review

[10] Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJE (2002). "New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". J Biol Chem 277 (45): 42881–42890. DOI:10.1074/jbc.M206593200. PMID 12167652. http://www.jbc.org/cgi/content/abstract/277/45/42881.

[pmid12388667-11] Newman-Tancredi A, Cussac D, Audinot V, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 805–14. DOI:10.1124/jpet.102.039875. PMID 12388667. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388667.

[pmid12388668-12] Newman-Tancredi A, Cussac D, Quentric Y, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 815–22. DOI:10.1124/jpet.102.039883. PMID 12388668. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12388668.

[pmid14569075-13] Hsieh GC, Hollingsworth PR, Martino B, et al. (January 2004). "Central mechanisms regulating penile erection in conscious rats: the dopaminergic systems related to the proerectile effect of apomorphine". The Journal of Pharmacology and Experimental Therapeutics 308 (1): 330–8. DOI:10.1124/jpet.103.057455. PMID 14569075. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=14569075.

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案内

apomorphine