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			{{Short description|Group of stereoisomers}}
			{{Redirect|Hydroxyamfetamine|other uses|Hydroxyamphetamine}}
	{{Use mdy dates|date=April 2014}}		{{Use mdy dates|date=April 2014}}
			{{cs1 config|name-list-style=vanc|display-authors=6}}
	{{redirect|Hydroxyamfetamine|other uses|Hydroxyamphetamine}}
	{{Drugbox		{{Drugbox
			| verifiedrevid = 606168923
			| drug_name = Hydroxyamphetamine
			| INN = Hydroxyamfetamine
			| USAN = Hydroxyamphetamine
	| IUPAC_name = 4-(2-aminopropyl)phenol		| IUPAC_name = 4-(2-aminopropyl)phenol
	| image = P-Hydroxyamphetamine.svg		| image = P-Hydroxyamphetamine.svg
	| width = 200		| width = 225px
	| drug_name = 4-Hydroxyamphetamine
	<!--Clinical data-->		<!-- Clinical data -->
	| tradename = Hydroxyamfetamine		| tradename = Paredrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others
	| legal_status = Rx-only		| legal_status = Rx-only
	| routes_of_administration = Topical (ocular)		| routes_of_administration = ]s
	<!--Identifiers-->		<!-- Identifiers -->
			| CAS_number_Ref = {{cascite|correct|CAS}}
	| CAS_number = 1518-86-1
			| CAS_number = 103-86-6
	| ATC_prefix = None		| ATC_prefix = None
	| ATC_suffix =		| ATC_suffix =
	| PubChem = 3651		| PubChem = 3651
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 3525		| ChemSpiderID = 3525
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = FQR280JW2N
			| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 1546		| ChEMBL = 1546
			| synonyms = 4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine; ''para''-Hydroxyamphetamine; PHA; α-Methyltyramine; Methyltyramine
	| smiles = Oc1ccc(cc1)CC(N)C
	| InChI = 1/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3
	| InChIKey = GIKNHHRFLCDOEU-UHFFFAOYAW
	| StdInChI = 1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3
	| StdInChIKey = GIKNHHRFLCDOEU-UHFFFAOYSA-N
	<!--Chemical data-->		<!-- Chemical data -->
	| C = 9 | H = 13 | N = 1 | O = 1		| C=9 | H=13 | N=1 | O=1
			| SMILES = NC(C)Cc1ccc(O)cc1
	| molecular_weight = 151.206 g/mol
			| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| synonyms =
			| StdInChI = 1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3
			| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
			| StdInChIKey = GIKNHHRFLCDOEU-UHFFFAOYSA-N
	}}		}}
			<!-- Definition and medical uses -->
			'''Hydroxyamphetamine''', also known as '''4-hydroxyamphetamine''' or '''norpholedrine''' and sold under the brand names '''Paredrine''' and '''Paremyd''' among others, is a ] ] used in ]s to ] for ]s.<ref name="Elks2014" /><ref name="MortonHall2012" /><ref name="IndexNominum2004" /><ref name="DrugBank" />
			<!-- Side effects and mechanism of action -->
	'''4-Hydroxyamphetamine''', also known as '''hydroxyamfetamine''' (]), '''hydroxyamphetamine''' (] and ]), '''oxamphetamine''', '''norpholedrine''', '''''para''-hydroxyamphetamine''', and '''α-methyltyramine''', is a ], that is, a drug that ] the ]. When used in ]s, it dilates the ]. 4-Hydroxyamphetamine is sold in combination with ] under the brand name ''']'''. It occurs as a metabolite of ].
			Hydroxyamfetamine acts as a ] and hence is an indirectly acting sympathomimetic.<ref name="Lepore1985" /><ref name="Cho1978" /> It is a ] and ].<ref name="DrugBank" />
			<!-- History, society, and culture -->
	Once thought to be a human invention, 4-hydroxyamphetamine is now known to occur as an ] in plants including '']''.<ref>{{cite web |author=Shulgin, Alexander |url=http://www.cognitiveliberty.org/shulgin/adsarchive/acacia.htm |title=Ask Dr. Shulgin Online: Acacias and Natural Amphetamine |publisher=Center for Cognitive Liberty & Ethics |date=September 26, 2001 |accessdate=February 18, 2010 |authorlink=Alexander Shulgin}}</ref>
			Hydroxyamphetamine appeared to remain marketed only in the ] as of 2004.<ref name="IndexNominum2004" />
			==Medical uses==
	In 1944, the US ] researched the use of Paredrine to improve ] to ] in submarine personnel. A significant improvement in adaptation was shown in the 17 subjects they tested.<ref>{{cite journal |author=Verplanck, WS |year=1944 |title=The effects of paregrine on night vision performance. |journal=US Naval Submarine Medical Research Laboratory Technical Report |volume=42 |url=http://archive.rubicon-foundation.org/8242 |accessdate=February 18, 2010}}</ref>
			Hydroxyamphetamine is used in ] to dilate the ] (a process called ]) so that the back of the eye can be examined. This is a ] for ]. Patients with Horner's syndrome exhibit ] brought about by lesions on the nerves that connect to the ] branch of the ].<ref name="Walton2003">{{cite journal | vauthors = Walton KA, Buono LM | title = Horner syndrome | journal = Current Opinion in Ophthalmology | volume = 14 | issue = 6 | pages = 357–363 | date = December 2003 | pmid = 14615640 | doi = 10.1097/00055735-200312000-00007 | s2cid = 11262166 }}</ref> Application of hydroxyamphetamine to the eye can indicate whether the lesion is ] or ] based on the pupil's response. If the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic.<ref name="Walton2003" />
			Hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug (] or ]), then the patient must wait anywhere from a day to a week before hydroxyamphetamine can be administered.<ref name="Davagnanam2013">{{cite journal | vauthors = Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, Plant GT | title = Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm | journal = Eye | volume = 27 | issue = 3 | pages = 291–298 | date = March 2013 | pmid = 23370415 | pmc = 3597883 | doi = 10.1038/eye.2012.281 }}</ref><ref name="Lepore1985">{{cite journal | vauthors = Lepore FE | title = Diagnostic pharmacology of the pupil | journal = Clinical Neuropharmacology | volume = 8 | issue = 1 | pages = 27–37 | pmid = 3884149 | doi = 10.1097/00002826-198503000-00003 | year = 1985 }}</ref> It also has the tendency to falsely localize lesions. False localization can arise in cases of acute onset; in cases where a postganglionic lesion is present, but the nerve still responds to residual norepinephrine; or in cases in which unrelated nerve damage masks the presence of a preganglionic lesion.<ref name="Walton2003" /><ref name="Davagnanam2013" />
	{{Amphetamine pharmacokinetics|caption=In humans, 4-hydroxyamphetamine is a metabolite of amphetamine. The aromatic hydroxylation of ] is mediated by ] and ].}}
	== See also ==
	* ]
	* ]
	* ]
			===Available forms===
	== References ==
			Hydroxyamphetamine is a component of two controlled (prescription only), name-brand ophthalmic mydriatics: Paredrine and Paremyd. Paredrine consists of a 1% solution of hydroxyamphetamine hydrobromide<ref name="SlamovitsGlaser1999">{{cite book | vauthors = Slamovits TL, Glaser JS | chapter = The Pupils and Accommodation. | title = Neuro-ophthalmology | veditors = Glaser JS | publisher = Lippincott, Williams, & Wilkins | location = Philadelphia, PA | date = 1999 | isbn = 978-0781717298}}</ref>{{rp|543}} while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% ].<ref name="OrangeBook" />
			==Pharmacology==
			===Pharmacodynamics===
			Hydroxyamphetamine acts as an ] and ] which leads to ] (pupil dilation).<ref name="Lepore1985" /><ref name="Cho1978" />
			It has also been found to act as a ].<ref name="NakagawasaiAraiSatoh2004">{{cite journal | vauthors = Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, Oka R, Hiraga H, Tadano T | title = Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives | journal = Neurotoxicology | volume = 25 | issue = 1-2 | pages = 223–232 | date = January 2004 | pmid = 14697897 | doi = 10.1016/S0161-813X(03)00101-3 | url = }}</ref> The drug produces the ], a behavioral proxy of ] effects, when it is given by ] in animals.<ref name="NakagawasaiAraiSatoh2004" /> This effect is blocked by the ]s ] and ], by the ] ], and by the ] ] (PCPA).<ref name="NakagawasaiAraiSatoh2004" /> These findings suggest that hydroxyamphetamine-induced head twitches are due to activation of the ] ] and that they are mediated by induction of serotonin release as opposed to direct ] of the serotonin 5-HT<sub>2A</sub> receptor.<ref name="NakagawasaiAraiSatoh2004" /> Although hydroxyamphetamine produces the head-twitch response in animals, serotonin releasing agents are not necessarily ]ic in humans, and hence their induction of head twitches in animals has been considered a false positive for psychedelic effects.<ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title=Behavioral Neurobiology of Psychedelic Drugs | chapter=Effect of Hallucinogens on Unconditioned Behavior | veditors = Halberstadt AL, Vollenweider FX, Nichols DE | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | series = Current Topics in Behavioral Neurosciences | volume=36 | date=2018 | isbn=978-3-662-55878-2 | pmid=28224459 | pmc=5787039 | doi=10.1007/7854_2016_466 | doi-access=free | pages=159–199 | quote = Amphetamine and methamphetamine, which act primarily by increasing carrier-mediated release of dopamine and norepinephrine, do not provoke head twitches (Corne and Pickering 1967; Silva and Calil 1975; Yamamoto and Ueki 1975; Jacobs et al. 1976; Bedard and Pycock 1977; Halberstadt and Geyer 2013). By contrast, the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.}}</ref><ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | pages = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = | quote = Indirect 5-HT2A agonists such as fenfluramine, p-chloroamphetamine (PCA), and 5-hydroxytryptophan (5-HTP) induce head twitches in rodents (Corne et al. 1963; Singleton and Marsden 1981; Darmani 1998) but do not act as hallucinogens in humans (van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), However, overdoses of compounds that increase serotonin (5-HT) release can result in 5-HT syndrome, which sometimes includes hallucinations (Birmes et al. 2003; Evans and Sebastian 2007).}}</ref><ref name="WojtasGołembiowska2023">{{cite journal | vauthors = Wojtas A, Gołembiowska K | title = Molecular and Medical Aspects of Psychedelics | journal = Int J Mol Sci | volume = 25 | issue = 1 | date = December 2023 | page = 241 | pmid = 38203411 | pmc = 10778977 | doi = 10.3390/ijms25010241 | doi-access = free | url = | quote = While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists .}}</ref>
			It additionally decreases metabolism of ] and certain other ]s by inhibiting the activity of ]s (MAOs), particularly type A (]).{{Citation needed|date=February 2017}} The inhibition of MAO-A prevents metabolism of serotonin and ] in the ], and thus increases the amount of neurotransmitters available for release into the ].<ref name="NakagawasaiAraiSatoh2004" />
			Like amphetamine, hydroxyamphetamine is an agonist of human ].<ref name="LewinMillerGilmour2011">{{cite journal | vauthors = Lewin AH, Miller GM, Gilmour B | title = Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 23 | pages = 7044–7048 | date = December 2011 | pmid = 22037049 | pmc = 3236098 | doi = 10.1016/j.bmc.2011.10.007 }}</ref>
			===Pharmacokinetics===
			Hydroxyamphetamine is a major ] of ] and a minor metabolite of ]. In humans, amphetamine is metabolized to hydroxyamphetamine by ], which is a member of the ] superfamily and is found in the ].<ref name="MarkowitzPatrick2001">{{cite journal | vauthors = Markowitz JS, Patrick KS | title = Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder | journal = Clinical Pharmacokinetics | volume = 40 | issue = 10 | pages = 753–772 | pmid = 11707061 | doi = 10.2165/00003088-200140100-00004 | year = 2001 | s2cid = 20884365 }}</ref><ref name="HaefelyBartholiniPletscher1976">{{cite journal | vauthors = Haefely W, Bartholini G, Pletscher A | title = Monoaminergic drugs: general pharmacology | journal = Pharmacology & Therapeutics B | volume = 2 | issue = 1 | pages = 185–218 | pmid = 817330 | year = 1976 | doi = 10.1016/0306-039x(76)90030-1 }}</ref> 4-Hydroxyamphetamine is then metabolized by ] into ] or ] in the ].<ref name="Cho1978">{{cite journal | vauthors = Cho AK, Wright J | title = Pathways of metabolism of amphetamine and related compounds | journal = Life Sciences | volume = 22 | issue = 5 | pages = 363–372 | date = February 1978 | pmid = 347211 | doi = 10.1016/0024-3205(78)90282-5 }}</ref>
			{{Amphetamine pharmacokinetics|caption=In humans, 4-hydroxyamphetamine is formed from ] metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized by ] into ].}}
			==Chemistry==
			Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is a ] and ] ]. It is the 4-]lated ] of ], the ''N''-]ated analogue of ] (4-hydroxy-''N''-methylamphetamine), and the α-methylated analogue of ] (4-hydroxyphenethylamine). Other analogues include ], ] (levonordefrin; α-methylnorepinephrine), and ] (α-methylepinephrine).
			It has a predicted ] of 0.58 to 1.4.<ref name="PubChem">{{cite web | title=4-(2-Aminopropyl)phenol | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3651 | access-date=30 August 2024}}</ref><ref name="DrugBank">{{cite web | title=Hydroxyamphetamine: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=30 January 1992 | url=https://go.drugbank.com/drugs/DB09352 | access-date=30 August 2024}}</ref><ref name="ChemSpider">{{cite web | title=C9H13NO | website=Hydroxyamphetamine | date=30 August 2024 | url=https://www.chemspider.com/Chemical-Structure.3525.html | access-date=30 August 2024}}</ref>
			Hydroxyamphetamine is used ] as the ] ].<ref name="Elks2014" />
			==History==
			Hydroxyamphetamine was first ] by 1910.<ref name="Elks2014" />
			In the 1990s, the trade name rights, patents, and ]s (NDAs) for Paredrine and Paremyd were exchanged among a few different manufacturers after a shortage of the raw material required for their production, which caused both drugs to be indefinitely removed from the market.<ref>{{cite web | work = Akorn press release | date = March 24, 1999 | url = http://www.thefreelibrary.com/Akorn+Acquires+Paredrine+-+Specialty+Ophthalmic+Diagnostic+Product...-a054197191 | title = Akorn Acquires Paredrine - Specialty Ophthalmic Diagnostic Product From Pharmics, Inc. | access-date = December 9, 2014 | archive-date = September 16, 2018 | archive-url = https://web.archive.org/web/20180916144249/https://www.thefreelibrary.com/Akorn+Acquires+Paredrine+-+Specialty+Ophthalmic+Diagnostic+Product...-a054197191 | url-status = dead }}</ref> Around 1997, ], obtained the rights to both Paredrine and Paremyd,<ref name="Akorn">{{cite web | url = http://investors.akorn.com/phoenix.zhtml?c=78132&p=irol-newsArticle&ID=247062 | title = Akorn press release }}{{Dead link|date=July 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent.<ref name="OrangeBook">{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019261&TABLE1=OB_Rx | title = Hydroxyamphetamine Hydrobromide; Tropicamide | work = Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations | archive-url = https://web.archive.org/web/20160304052043/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019261&TABLE1=OB_Rx | archive-date = 4 March 2016 }}</ref><ref name="Akorn-2">{{cite web | url = http://www.akorn.com/about_timeline.php | title = Akorn timeline | archive-url = https://web.archive.org/web/20190626065749/http://www.akorn.com/about_timeline.php | archive-date=June 26, 2019 | access-date = December 9, 2014 }}</ref><ref name="Lurcott2002">{{cite web | vauthors = Lurcott R | work = Ophthalmology Management | date = December 1, 2002 | url = http://www.ophthalmologymanagement.com/articleviewer.aspx?articleID=85623 | title = Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies }}</ref>
			In 2004, hydroxyamphetamine appeared to remain marketed only in the ].<ref name="IndexNominum2004" />
			==Society and culture==
			===Names===
			''Hydroxyamphetamine'' is the ] of the drug and its {{Abbrlink|BAN|British Approved Name}} and {{Abbrlink|DCF|Dénomination Commune Française}}, while ''hydroxyamfetamine'' is its {{Abbrlink|INN|International Nonproprietary Name}}.<ref name="Elks2014">{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA74 | access-date=30 August 2024 | page=74}}</ref><ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA90 | access-date=30 August 2024 | page=90}}</ref><ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | series=Index Nominum: International Drug Directory | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA609 | access-date=30 August 2024 | page=609}}</ref> In the case of the ] ], its generic name is ''hydroxyamphetamine hydrobromide'' and this is its {{Abbrlink|USAN|United States Adopted Name}}.<ref name="Elks2014" /><ref name="MortonHall2012" /><ref name="IndexNominum2004" /> It is also known by synonyms including ''methyltyramine'', ''norpholedrine'', and ''oxamphetamine''.<ref name="Elks2014" /><ref name="MortonHall2012" /><ref name="IndexNominum2004" /><ref name="PubChem" /> The drug is sold under brand names including ''Paredrine'', ''Paredrinex'', ''Paremyd'', ''Pedrolon'', and ''Mycadrine''.<ref name="Elks2014" /><ref name="IndexNominum2004" />
			==Other drugs==
			4-Hydroxyamphetamine is also a ] of ] and certain other amphetamines.<ref name="MortonHall2012" />
			==Notes==
			{{Reflist|group=note}}
			==Reference notes==
			{{Reflist|group=sources}}
			==References==
	{{Reflist}}		{{Reflist}}
	== External links ==		==External links==
	* {{MeshName|p-Hydroxyamphetamine}}		* {{MeshName|p-Hydroxyamphetamine}}
	{{Amphetamine|state=expanded}}		{{Amphetamine|state=expanded}}
			{{Mydriatics and cycloplegics}}
	{{Adrenergics}}
			{{Monoamine releasing agents}}
	{{Dopaminergics}}
			{{TAAR ligands}}
	{{Phenethylamines}}		{{Phenethylamines}}
	{{Stimulants}}
			{{DEFAULTSORT:Hydroxyamphetamine, 4-}}
	]
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	{{nervous-system-drug-stub}}
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