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Not to be confused with Aporphine.
Prof. Squirrel/sandbox 2
Clinical data
Trade namesApokyn
AHFS/Drugs.comMonograph
MedlinePlusa604020
Pregnancy
category
  • AU: B3
Routes of
administration		SQ
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% following injection
Protein binding~50%
MetabolismHepatic, phase II
Onset of action10–20 min
Elimination half-life40 minutes
Duration of action60–90 min
ExcretionHepatic
Identifiers
  • (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H17NO2
Molar mass267.322 g/mol g·mol−1
3D model (JSmol)
  • OC1=C(O)C(C2=CC=CC3=C2[C@@H](C4)N(C)CC3)=C4C=C1
  • 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 checkY
  • Key:VMWNQDUVQKEIOC-CYBMUJFWSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Apomorphine (brand names Apokyn, Ixense, Spontane, Uprima) is a type of aporphine dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors.[1] It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity. The compound is historically a morphine decomposition product made by boiling morphine with concentrated acid, hence the -morphine suffix. Apomorphine does not actually contain morphine or its skeleton, nor does it bind to opioid receptors. The apo- prefix relates to it being a morphine derivative ("[comes] from morphine").

Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinson's disease. It is a potent emetic, which is exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.

Apomorpine was also used as a private treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. Burroughs and others claimed that it was a "metabolic regulator" with a restorative dimension to a damaged or dysfunctional dopaminergic system. There is more than enough anecdotal evidence to suggest that this offers a plausible route to an abstinence based model; however, no clinical trials have ever tested this hypothesis. 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.[3]

Uses

[edit]

Apomorphine is used in advanced Parkinson's disease intermittent hypermobility ("off" episodes), where a decreased response to an anti-Parkinson drug such as L-DOPA causes muscle stiffness and loss of muscle control.[4][5] 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 often has many of dyskinesias caused by L-DOPA and hypermobility periods.[6][7] When an episode sets in, the apomorphine is injected subcutaneously, and signs subside. It is used an average of three times a day.[6] Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the "on" state and using apomorphine as an effective monotherapy.[7][8]

Contraindications

[edit]

The main and absolute contraindication to using apomorphine is the concurrent use of serotonin receptor antagonists; combined, they cause a severe drop in blood pressure and fainting.[6][5] Alcohol causes an increased frequency of orthostatic hypotension (a sudden drop in blood pressure when getting up), and can also increase the chances of pneumonia and heart attacks.[6] Dopamine antagonists, by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine.[6][5]

IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot (thrombus) and block a pulmonary artery (pulmonary embolism).[6][5]

Side effects

[edit]

Nausea and vomiting are common side effects when first beginning therapy with apomorphine;[9] antiemetics such as trimethobenzamide or domperidone, dopamine antagonists,[10] are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine's emetic effects that they can discontinue the antiemetic.[5][6]

Other side effects include orthostatic hypotension and resultant fainting, sleepiness, dizziness, runny nose, sweating, paleness, and flushing. More serious side effects include dyskenesias (especially when taking L-DOPA), fluid accumulation in the limbs (edema), suddenly falling asleep, confusion and hallucinations, increased heart rate and heart palpitations, and persistent erections (priaprism).[5][6][11] The priaprism is caused by apomorphine increasing arterial blood supply to the penis. This side effect has been exploited in studies attempting to treat erectile dysfunction.[12]

Pharmacology

[edit]

Mechanism of action

[edit]

Apomorphine's R-enantiomer is an agonist of both D1 and D2 dopamine receptors, with higher activity at D2.[6][10] The members of the D2 subfamily, consisting of D2, D3, and D4 receptors, are inhibitory G protein–coupled receptors. The D4 receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders.[13] Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states.[14]

Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, the limbic system, the hypothalamus, and the pituitary gland.[15] It also increases blood flow to the supplementary motor area and to the dorsolateral prefrontal cortex (stimulation of which has been found to reduce the tardive dyskinesia effects of L-DOPA).[16] [17] Parkinson's has also been found to have excess iron at the sites of neurodegeneration; both the R- and S-enantiomers of apomorphine are potent iron chelators and radical scavengers.[10][18]

Apomorphine also reduces the breakdown of dopamine in the brain (though it inhibits its synthesis as well).[19][20] It is a powerful upregulator of certain neural growth factors,[21] in particular NGF and BDNF, epigenetic downregulation of which has been associated with addictive behaviour in rats.[22][23]

Apomorphine causes vomiting by acting on dopamine receptors in the chemoreceptor trigger zone of the medulla; this activates the nearby vomiting center.[15][20][24]

Pharmacokinetics

[edit]

While apomorphine has lower bioavailability when taken orally, due to not being absorbed well in the GI tract and undergoing heavy first-pass metabolism,[18][8] it has a bioavailability of 100% when given subcutaneously.[6][15] It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the cerebrospinal fluid. Its lipophilic structure allows it to cross the blood–brain barrier.[6][15]

Apomorphine possesses affinity for the following receptors (note that a higher Ki indicates a lower affinity):[25][26][27]

Dopamine
Receptor Ki (nM) Action
D1 484 (partial) agonista
D2 52 partial agonist (IA = 79% at D2S; 53% at D2L)
D3 26 partial agonist (IA = 82%)
D4 4.37 partial agonist (IA = 45%)
D5 188.9 (partial) agonista
aThough its efficacies at D1 and D5 are unclear, it is known to act as an agonist at these sites.[28]
Serotonin
Receptor Ki (nM) Action
5-HT1A 2,523 partial agonist
5-HT1B 2,951 no action
5-HT1D 1,230 no action
5-HT2A 120 antagonist
5-HT2B 132 antagonist
5-HT2C 102 antagonist
Norepinephrine/Epinephrine
Receptor Ki (nM) Action
α1A-adrenergic 1,995 antagonist
α1B-adrenergic 676 antagonist
α1D-adrenergic 64.6 antagonist
α2A-adrenergic 141 antagonist
α2B-adrenergic 66.1 antagonist
α2C-adrenergic 36.3 antagonist


It has a Ki of over 10,000 nM (and thus negligible affinity) for β-adrenergic, H1, and mACh.[1]

Apomorphine has a high clearance rate (3–5 L/kg/hr) and is mainly metabolized and excreted by the liver.[15] It is likely that while the cytochrome P450 system plays a minor role, most of apomorphine's metabolism happens via auto-oxidation, O-glucuronidation, O-methylation, N-demethylation, and sulfation.[6][15][20] Only 3–4% of the apomorphine is excreted unchanged and into the urine. The half-life is 30–60 minutes, and the effects of the injection last for up to 90 minutes.[6][7][15]

Toxicity depends on the route of administraion; the LD50s in mice were 300 mg/kg for the oral route, 160 mg/kg for intraperitoneal, and 56 mg/kg intravenous.[29]

Chemistry

[edit]

Properties

[edit]

Apomorphine has a catechol structure similar to that of dopamine.[19]

Synthesis

[edit]

Several techniques exist for the creation of apomorphine from morphine. In the past, morphine had been combined with hydrochloric acid at high temperatures (around 150 °C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%.[30]

More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type alkaloids, such as phosphoric acid. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as phthalic anhydride or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%.[30]

Conversion of Morphine (I) to Apomorphine (II) in the presence of acid following the example of the morphine skeleton dehydration rearrangement, outlined by Bentley.[31]

History

[edit]

The pharmacological effects of the naturally-occurring analog aporphine in the blue lotus (N. caerulea)[32] were known to the ancient Egyptians and Mayans,[33] with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties.

The modern medical history of apomorphine begins with its synthesis by Arppe in 1845[34] from morphine and sulphuric acid, although it was named sulphomorphide at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulphuric acid in the process, naming the resulting compound apomorphine. Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor Samuel Gee,[35] and for the treatment of stereotypies in farmyard animals.[36] Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.

Treatment of alcoholism

[edit]

Apomorphine was one of the earliest used pharmacotherapies for alcoholism. The Keeley Cure (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins[37] and Charles Douglas.[38][39] Tompkins reported, after injection of 6.5 mg ("one tenth of a grain"):

In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.

Douglas saw two purposes for apomorphine:

[it can be used to treat] a paroxysm of dipsomania [an episode of intense alcoholic craving]... in minute doses it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… Four or even 3m [minim – roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.

This use of small, continuous doses (1/30th of a grain, or 2.16 mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before Pavlov's discovery and publication of the idea of the "conditioned reflex" in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onwards, also used low-dose apomorphine as a treatment, describing it as "the most useful drug single drug in the therapeutics of inebriety".[40] He wrote:

In (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania, in order to still the craving for alcohol; and (3) in essential insomnia of a special variety... [after giving apomorphine] the patient’s mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient. Doses of this size are rarely emetic. There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.

He also noted there appeared to be a significant prejudice against the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. In the US, the Harrison Narcotics Tax Act made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate.

In the 1950s the neurotransmitter dopamine was discovered in the brain by Kathleen Montagu, and characterised as a neurotransmitter a year later by Arvid Carlsson, for which he would be awarded the Nobel Prize.[41] A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors.[42] This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results.[43][44][45][46][47] However, there was little clinical consequence.

Parkinson's disease

[edit]

The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884,[48] although seemingly not pursued until 1951.[49] Its clinical use was first reported in 1970 by Cotzias et al.,[50] 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.[51] The commercialization of apomorphine for Parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions.[52]

Aversion therapy

[edit]

Aversion therapy in alcoholism had its roots in Russia in the early 1930s,[53] with early papers by Pavlov, Galant and Sluchevsky and Friken,[54] and would remain a strain in the Soviet treatment of alcoholism well into the 1980s. In the US a particularly notable devotee was Dr Voegtlin,[55] who attempted aversion therapy using apomorphine in the mid to late 1930s. However, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic emetine.

In the UK, however, the publication of J Y Dent's (who later went on to treat Burroughs) 1934 paper "Apomorphine in the treatment of Anxiety States"[56] laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:

He is given his favourite drink, and his favourite brand of that drink... He takes it stronger than is usual to him... The small dose of apomorphine, one-twentieth of a grain [3.24mg], is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. A glass of whisky and water and a bottle of whisky are left by his bedside. At six o'clock (four hours later) he is again visited and the same treatment is again administered... The nurse is told in confidence that if he does not drink, one-fortieth [1.62mg] of a grain of apomorphine should be injected during the night at nine o'clock, one o'clock, and five o'clock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. In the morning at about ten he is again given one or two glasses of whisky and water... and again one-twentieth of a grain [3.24mg] of apomorphine is injected... The next day he is allowed to eat what he likes, he may drink as much tea as he likes... He will be strong enough to get up and two days later he leaves the home.

However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – "though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect." – and by 1948 he wrote:[57]

It is now twenty-five years since I began treating cases of anxiety and alcoholism with apomorphine, and I read my first paper before this Society fourteen years ago. Up till then I had thought, and, unfortunately, I said in my paper, that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. This statement is not even a half truth… I have been forced to the conclusion that apomorphine has some further action than the production of a vomit.

This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann[58] and later scientific testing in the 1970s, some time after his death. However, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a British Army Captain Billy Clegg HIll in 1962,[59] helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies.

Opioid addiction

[edit]

In his Deposition: Testimony Concerning a Sickness in the introduction to later editions of Naked Lunch (first published in 1959), William S. Burroughs wrote that apomorphine treatment was the only effective cure to opioid 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, John Yerbury Dent, 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.

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.

Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure".[60] However, he insisted on apomorphine’s effectiveness in several works and interviews.

Society and culture

[edit]
  • Apomorphine has a vital part in Agatha Christie's detective story Sad Cypress.
  • The 1965 Tuli Kupferberg song "Hallucination Horrors" recommends apomorphine at the end of each verse as a cure for hallucinations brought on by a humorous variety of intoxicants; the song was recorded by The Fugs and appears on the album Virgin Fugs.

Research

[edit]

There is renewed interest in the use of apomorphine to treat addiction, in both smoking cessation[61] and alcoholism.[62] As the drug is old, out of patent, and safe for use in humans, it is a viable target for repurposing.

Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though the arousal effects were found not to be reliable enough. One large study found that only 39.4% got erections (compared to baseline 13.1); another found that apomorphine was successful 45–51% of the time, but the placebo also worked 36% of the time.[12][63] Nonetheless, it was under development as a treatment for erectile dysfunction by TAP Pharmaceuticals under the brand name Uprima. In 2000, TAP withdrew its new drug application after an FDA review panel raised questions about the drug's safety, due to many clinical trial subjects fainting after taking the drug.[64]

Alzheimer's disease

[edit]

Apomorphine is reported to be an inhibitor of amyloid beta protein (Aβ) fiber formation, whose presence is a hallmark of Alzheimer's disease (AD), and a potential therapeutic under the amyloid hypothesis.[65] While it promotes oligomerization of the Aβ40 group of molecules, it inhibits more advanced fibril formation; this is thought to be due to the autoxidation that occurs at the hydroxyl groups. Once this functional group was altered, the inhibitory effect could be seen to decrease, reducing either the indirect or direct interference of the fibril formation.[65]

The protective effects of apomorphine were tested in mouse models with mutations in genes related to AD, such as the amyloid precursor protein gene. Apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze. The levels of the aberrant proteins that lead to neuronal disruption were also tested in the brains of mice. Treatment was seen to decrease the intraneuronal levels of the more aggressive Aβ42 molecule when compared to the control mice. This result is consistent with the finding that another protein linked to AD, tau protein, was seen to decrease with apomorphine treatment.[66]

Veterinary use

[edit]

Apomorphine is the drug of choice for inducing vomiting in dogs the after ingestion of various toxins or foreign bodies. It can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the conjunctival sac.[67][68] The oral route is ineffective, as apomorphine cannot cross the blood–brain barrier fast enough, and blood levels don't reach a high enough concentration to stimulate the chemoreceptive trigger zone.[67]

One of the reasons apomorphine is a preferred drug is its reversibility:[69] in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the phenothiazines (for example, acepromazine). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorhine's target receptors are already occupied.[67] An animal who undergoes severe respiratory depression under apomoprhine can be saved with naloxone.[67][68]

Apomorphine does not work in cats, who have too few dopamine receptors.[67]

See also

[edit]

References

[edit]
  1. ^ a b 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. S2CID 6200455.
  2. ^ 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. S2CID 32386793.
  3. ^ Dent JY (1949). "Apomorphine Treatment of Addiction." British Journal of Addiction to Alcohol & Other Drugs 46 (1); 15-28. [1] doi:10.1111/j.1360-0443.1949.tb04502.x
  4. ^ "Apomorphine Uses, Side Effects & Warnings". Drugs.com. Retrieved 27 February 2018.
  5. ^ a b c d e f Clayton, Bruce D.; Willihnganz, Michelle (2016). Basic Pharmacology for Nurses – E-Book. Elsevier Health Sciences. pp. 210–211. ISBN 978-0-323-37697-6.
  6. ^ a b c d e f g h i j k l m "Apomorphine Hydrochloride Monograph for Professionals". Drugs.com. Retrieved 26 February 2018.
  7. ^ a b c Chaudhuri K, Clough C (1998). "Subcutaneous apomorphine in Parkinson's disease: Effective yet underused". BMJ. 316 (7132): 641. doi:10.1136/bmj.316.7132.641. PMC 1112674. PMID 9522772.
  8. ^ a b Schapira, Anthony Henry Vernon; Olanow, Charles Warren (2005). Principles of Treatment in Parkinson's Disease (illustrated ed.). Elsevier Health Sciences. p. 35. ISBN 978-0-7506-5428-9.
  9. ^ Dressler, D. (June 2005). "[Apomorphine in the treatment of Parkinson's Disease]". Der Nervenarzt (in ger). 76 (6): 681–689. doi:10.1007/s00115-004-1830-4. ISSN 0028-2804. PMID 15592807. S2CID 19617827.{{cite journal}}: CS1 maint: unrecognized language (link)
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  12. ^ a b Porst, Hartmut; Buvat, Jacques (2008). Standard Practice in Sexual Medicine. John Wiley & Sons. p. 77. ISBN 978-1-4051-7872-3.
  13. ^ Ptácek R, Kuzelová H, Stefano GB (Sep 2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor. 17 (9): RA215–RA220. doi:10.12659/MSM.881925. PMC 3560519. PMID 21873960.
  14. ^ Stacy, Mark; Silver, Dee (2008). "Apomorphine for the acute treatment of "off" episodes in Parkinson's disease". Parkinsonism & Related Disorders. 14 (2): 85–92. doi:10.1016/j.parkreldis.2007.07.016. PMID 18083605.
  15. ^ a b c d e f g U.S. National Library of Medicine. "Apomorphine". PubChem. Retrieved 26 February 2018.
  16. ^ Lewitt, Peter; Oertel, Wolfgang H. (1999). Parkinsons's Disease: The Treatment Options. CRC Press. p. 22. ISBN 978-1-85317-379-0.
  17. ^ Rektorova, I.; Sedlackova, S.; Telecka, S.; Hlubocky, A.; Rektor, I. (2008). "Dorsolateral prefrontal cortex: a possible target for modulating dyskinesias in Parkinson's disease by repetitive transcranial magnetic stimulation". International Journal of Biomedical Imaging. 2008: 372125. doi:10.1155/2008/372125. ISSN 1687-4188. PMC 2233877. PMID 18274665.
  18. ^ a b Galvez-Jimenez, Nestor (2013). Scientific Basis for the Treatment of Parkinson's Disease, Second Edition. CRC Press. p. 195. ISBN 978-0-203-33776-9.
  19. ^ a b Iversen, Leslie (2012). Biogenic Amine Receptors. Springer Science & Business Media. p. 238. ISBN 978-1-4684-8514-1.
  20. ^ a b c Advances in Pharmacology and Chemotherapy, Volume 15. Silvio Garattini, A. Goldin, F. Hawking, Irwin J. Kopin. Academic Press. 1978. p. 27, 93, 96. ISBN 978-0-08-058106-4.{{cite book}}: CS1 maint: others (link)
  21. ^ Ohta, M.; Mizuta, I.; Ohta, K.; Nishimura, M.; Mizuta, E.; Hayashi, K.; Kuno, S. (2000-05-27). "Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes". Biochemical and Biophysical Research Communications. 272 (1): 18–22. doi:10.1006/bbrc.2000.2732. ISSN 0006-291X. PMID 10872797.
  22. ^ McGeary, John E.; Gurel, Volkan; Knopik, Valerie S.; Spaulding, James; McMichael, John (October 2011). "Effects of nerve growth factor (NGF), fluoxetine, and amitriptyline on gene expression profiles in rat brain". Neuropeptides. 45 (5): 317–322. doi:10.1016/j.npep.2011.06.002. ISSN 1532-2785. PMID 21820738. S2CID 38444849.
  23. ^ Heberlein, Annemarie; Muschler, Marc; Frieling, Helge; Behr, Michael; Eberlein, Christian; Wilhelm, Julia; Gröschl, Michael; Kornhuber, Johannes; Bleich, Stefan (May 2013). "Epigenetic down regulation of nerve growth factor during alcohol withdrawal". Addiction Biology. 18 (3): 508–510. doi:10.1111/j.1369-1600.2010.00307.x. ISSN 1369-1600. PMID 21392176. S2CID 20317993.
  24. ^ Riviere, Jim E.; Papich, Mark G. (2009). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. p. 318. ISBN 978-0-8138-2061-3.
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