4-Hydroxyamphetamine

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Hydroxyamphetamine
INN: Hydroxyamfetamine
P-Hydroxyamphetamine.svg
Clinical data
Trade names Paredrine, Paremyd, Pedrolon, Mycadrine, Paredrinex, others
Other names4-Hydroxyamphetamine; 4-HA; Hydroxyamfetamine; Oxamphetamine; Norpholedrine; para-Hydroxyamphetamine; PHA; α-Methyltyramine; Methyltyramine, Hydroxyamphetamine (USAN US)
Routes of
administration 		Eye drops
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 4-(2-aminopropyl)phenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.002.866 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H13NO
Molar mass 151.209 g·mol−1
3D model (JSmol)
  • NC(C)Cc1ccc(O)cc1
  • InChI=1S/C9H13NO/c1-7(10)6-8-2-4-9(11)5-3-8/h2-5,7,11H,6,10H2,1H3 Yes check.svgY
  • Key:GIKNHHRFLCDOEU-UHFFFAOYSA-N Yes check.svgY
   (verify)

Hydroxyamphetamine, also known as 4-hydroxyamphetamine or norpholedrine and sold under the brand names Paredrine and Paremyd among others, is a sympathomimetic medication used in eye drops to dilate the pupil for eye examinations. [1] [2] [3] [4]

Contents

Hydroxyamfetamine acts as a norepinephrine releasing agent and hence is an indirectly acting sympathomimetic. [5] [6] It is a substituted phenethylamine and amphetamine. [4]

Hydroxyamphetamine appeared to remain marketed only in the Czech Republic as of 2004. [3]

Medical uses

Hydroxyamphetamine is used in eye drops to dilate the pupil (a process called mydriasis) so that the back of the eye can be examined. This is a diagnostic test for Horner's syndrome. Patients with Horner's syndrome exhibit anisocoria brought about by lesions on the nerves that connect to the nasociliary branch of the ophthalmic nerve. [7] Application of hydroxyamphetamine to the eye can indicate whether the lesion is preganglionic or postganglionic based on the pupil's response. If the pupil dilates, the lesion is preganglionic. If the pupil does not dilate, the lesion is postganglionic. [7]

Hydroxyamphetamine has some limitations to its use as a diagnostic tool. If it is intended as an immediate follow up to another mydriatic drug (cocaine or apraclonidine), then the patient must wait anywhere from a day to a week before hydroxyamphetamine can be administered. [8] [5] 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. [7] [8]

Available forms

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 [9] : 543  while Paremyd consists of a combination of 1% hydroxyamphetamine hydrobromide and 0.25% tropicamide. [10]

Pharmacology

Pharmacodynamics

Hydroxyamphetamine acts as an indirect sympathomimetic and induces the release of norepinephrine which leads to mydriasis (pupil dilation). [5] [6]

It has also been found to act as a serotonin releasing agent. [11] The drug produces the head-twitch response, a behavioral proxy of psychedelic effects, when it is given by intracerebroventricular injection in animals. [11] This effect is blocked by the serotonin receptor antagonists cyproheptadine and dimethothiazine, by the serotonin reuptake inhibitor fluoxetine, and by the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). [11] These findings suggest that hydroxyamphetamine-induced head twitches are due to activation of the serotonin 5-HT2A receptor and that they are mediated by induction of serotonin release as opposed to direct agonism of the serotonin 5-HT2A receptor. [11] Although hydroxyamphetamine produces the head-twitch response in animals, serotonin releasing agents are not necessarily hallucinogenic in humans, and hence their induction of head twitches in animals has been considered a false positive for psychedelic effects. [12] [13] [14]

It additionally decreases metabolism of serotonin and certain other monoamines by inhibiting the activity of monoamine oxidases (MAOs), particularly type A (MAO-A).[ citation needed ] The inhibition of MAO-A prevents metabolism of serotonin and catecholamines in the presynaptic terminal, and thus increases the amount of neurotransmitters available for release into the synaptic cleft. [11]

Like amphetamine, hydroxyamphetamine is an agonist of human TAAR1. [15]

Pharmacokinetics

Hydroxyamphetamine is a major metabolite of amphetamine and a minor metabolite of methamphetamine. In humans, amphetamine is metabolized to hydroxyamphetamine by CYP2D6, which is a member of the cytochrome P450 superfamily and is found in the liver. [16] [17] 4-Hydroxyamphetamine is then metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine or eliminated in the urine. [6]

Metabolic pathways of amphetamine in humans [sources 1]
Amph pathway.svg
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
DBH
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
Interactive icon.svg
In humans, 4-hydroxyamphetamine is formed from CYP2D6 metabolism of amphetamine; 4-hydroxyamphetamine may subsequently be metabolized by dopamine β-hydroxylase into 4-hydroxynorephedrine.

Chemistry

Hydroxyamphetamine, also known as 4-hydroxy-α-methylphenethylamine, 4-hydroxyamphetamine, or α-methyltyramine, is a substituted phenethylamine and amphetamine derivative. It is the 4-hydroxylated analogue of amphetamine, the N-demethylated analogue of pholedrine (4-hydroxy-N-methylamphetamine), and the α-methylated analogue of tyramine (4-hydroxyphenethylamine). Other analogues include α-methyldopamine, corbadrine (levonordefrin; α-methylnorepinephrine), and dioxifedrine (α-methylepinephrine).

It has a predicted log P of 0.58 to 1.4. [29] [4] [30]

Hydroxyamphetamine is used pharmaceutically as the hydrobromide salt. [1]

History

Hydroxyamphetamine was first synthesized by 1910. [1]

In the 1990s, the trade name rights, patents, and new drug applications (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. [31] Around 1997, Akorn, Inc., obtained the rights to both Paredrine and Paremyd, [32] and in 2002, the company reintroduced Paremyd to the market as a fast acting ophthalmic mydriatic agent. [10] [33] [34]

In 2004, hydroxyamphetamine appeared to remain marketed only in the Czech Republic. [3]

Society and culture

Names

Hydroxyamphetamine is the generic name of the drug and its BAN Tooltip British Approved Name and DCF Tooltip Dénomination Commune Française, while hydroxyamfetamine is its INN Tooltip International Nonproprietary Name. [1] [2] [3] In the case of the hydrobromide salt, its generic name is hydroxyamphetamine hydrobromide and this is its USAN Tooltip United States Adopted Name. [1] [2] [3] It is also known by synonyms including methyltyramine, norpholedrine, and oxamphetamine. [1] [2] [3] [29] The drug is sold under brand names including Paredrine, Paredrinex, Paremyd, Pedrolon, and Mycadrine. [1] [3]

Other drugs

4-Hydroxyamphetamine is also a metabolite of amphetamine and certain other amphetamines. [2]

Notes

  1. ↑ 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo . [19] [24] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine; [24] [26] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain. [27] [28]

Reference notes

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.

<span class="mw-page-title-main">Phenylpropanolamine</span> Sympathomimetic agent

Phenylpropanolamine (PPA), sold under many brand names, is a sympathomimetic agent which is used as a decongestant and appetite suppressant. It was previously commonly used in prescription and over-the-counter cough and cold preparations. The medication is taken by mouth.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

<span class="mw-page-title-main">3,4-Methylenedioxyamphetamine</span> Empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family

3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as “sass,” is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.

<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Phenylacetone</span> Chemical compound

Phenylacetone, also known as phenyl-2-propanone, is an organic compound with the chemical formula C6H5CH2COCH3. It is a colorless oil that is soluble in organic solvents. It is a mono-substituted benzene derivative, consisting of an acetone attached to a phenyl group. As such, its systematic IUPAC name is 1-phenyl-2-propanone.

<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant.

<span class="mw-page-title-main">Chlorphentermine</span> Weight loss medication

Chlorphentermine, sold under the brand names Apsedon, Desopimon, and Lucofen, is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the para-chloro derivative of the better-known appetite suppressant phentermine, which is still in current use.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Methamphetamine</span> Central nervous system stimulant

Methamphetamine is a potent central nervous system (CNS) stimulant that is mainly used as a recreational or performance-enhancing drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder (ADHD). It has also been researched as a potential treatment for traumatic brain injury. Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine. Methamphetamine properly refers to a specific chemical substance, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the hydrochloride salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving its potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy such as Adderall and Vyvanse. While pharmaceutical formulations of methamphetamine in the United States are labeled as methamphetamine hydrochloride, they contain dextromethamphetamine as the active ingredient. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.

<span class="mw-page-title-main">Dopamine beta-hydroxylase</span> Mammalian protein found in Homo sapiens

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.

<i>para</i>-Chloroamphetamine Chemical compound

para-Chloroamphetamine (PCA), also known as 4-chloroamphetamine (4-CA), is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and serotonergic neurotoxin of the amphetamine family. It is used in scientific research in the study of the serotonin system, as a serotonin releasing agent (SRA) at lower doses to produce serotonergic effects, and as a serotonergic neurotoxin at higher doses to produce long-lasting depletions of serotonin.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; monoamine releasing agents can induce the release of one or more of these neurotransmitters.

<span class="mw-page-title-main">Serotonin releasing agent</span> Class of compounds

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

α-Methyldopamine Chemical compound

α-Methyldopamine (α-Me-DA), also known as 3,4-dihydroxyamphetamine or as catecholamphetamine, is a research chemical of the catecholamine and amphetamine families. It is a monoamine releasing agent and a metabolite of MDMA and MDA. The bis-glutathionyl metabolite of α-methyldopamine is slightly neurotoxic when directly injected into the brain's ventricles.

<span class="mw-page-title-main">6-APB</span> Psychoactive drug

6-APB is an empathogenic psychoactive drug of the substituted benzofuran and substituted phenethylamine classes. 6-APB and other compounds are sometimes informally called "Benzofury" in newspaper reports. It is similar in structure to MDA, but differs in that the 3,4-methylenedioxyphenyl ring system has been replaced with a benzofuran ring. 6-APB is also the unsaturated benzofuran derivative of 6-APDB. It may appear as a tan grainy powder.

<i>p</i>-Hydroxynorephedrine Chemical compound

p-Hydroxynorephedrine is the para-hydroxy analog of norephedrine and an active sympathomimetic metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced from both p-hydroxyamphetamine and norephedrine.

<span class="mw-page-title-main">4-Hydroxyphenylacetone</span> Chemical compound

4-Hydroxyphenylacetone is the para-hydroxy analog of phenylacetone, an inactive metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced directly from the inactive metabolite phenylacetone.

References

  1. 1 2 3 4 5 6 7 Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 74. ISBN   978-1-4757-2085-3 . Retrieved August 30, 2024.
  2. 1 2 3 4 5 Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 90. ISBN   978-94-011-4439-1 . Retrieved August 30, 2024.
  3. 1 2 3 4 5 6 7 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 609. ISBN   978-3-88763-101-7 . Retrieved August 30, 2024.
  4. 1 2 3 "Hydroxyamphetamine: Uses, Interactions, Mechanism of Action". DrugBank Online. January 30, 1992. Retrieved August 30, 2024.
  5. 1 2 3 Lepore FE (1985). "Diagnostic pharmacology of the pupil". Clinical Neuropharmacology. 8 (1): 27–37. doi:10.1097/00002826-198503000-00003. PMID   3884149.
  6. 1 2 3 Cho AK, Wright J (February 1978). "Pathways of metabolism of amphetamine and related compounds". Life Sciences. 22 (5): 363–372. doi:10.1016/0024-3205(78)90282-5. PMID   347211.
  7. 1 2 3 Walton KA, Buono LM (December 2003). "Horner syndrome". Current Opinion in Ophthalmology. 14 (6): 357–363. doi:10.1097/00055735-200312000-00007. PMID   14615640. S2CID   11262166.
  8. 1 2 Davagnanam I, Fraser CL, Miszkiel K, Daniel CS, Plant GT (March 2013). "Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm". Eye. 27 (3): 291–298. doi:10.1038/eye.2012.281. PMC   3597883 . PMID   23370415.
  9. ↑ Slamovits TL, Glaser JS (1999). "The Pupils and Accommodation.". In Glaser JS (ed.). Neuro-ophthalmology. Philadelphia, PA: Lippincott, Williams, & Wilkins. ISBN   978-0781717298.
  10. 1 2 "Hydroxyamphetamine Hydrobromide; Tropicamide". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Archived from the original on March 4, 2016.
  11. 1 2 3 4 5 Nakagawasai O, Arai Y, Satoh SE, Satoh N, Neda M, Hozumi M, et al. (January 2004). "Monoamine oxidase and head-twitch response in mice. Mechanisms of alpha-methylated substrate derivatives". Neurotoxicology. 25 (1–2): 223–232. doi:10.1016/S0161-813X(03)00101-3. PMID   14697897.
  12. ↑ Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". In Halberstadt AL, Vollenweider FX, Nichols DE (eds.). Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 159–199. doi: 10.1007/7854_2016_466 . ISBN   978-3-662-55878-2. PMC   5787039 . PMID   28224459. 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.
  13. ↑ Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology. 167: 107933. doi:10.1016/j.neuropharm.2019.107933. PMC   9191653 . PMID   31917152. 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).
  14. ↑ Wojtas A, Gołembiowska K (December 2023). "Molecular and Medical Aspects of Psychedelics". Int J Mol Sci. 25 (1): 241. doi: 10.3390/ijms25010241 . PMC   10778977 . PMID   38203411. 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 [15].
  15. ↑ Lewin AH, Miller GM, Gilmour B (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry. 19 (23): 7044–7048. doi:10.1016/j.bmc.2011.10.007. PMC   3236098 . PMID   22037049.
  16. ↑ Markowitz JS, Patrick KS (2001). "Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder". Clinical Pharmacokinetics. 40 (10): 753–772. doi:10.2165/00003088-200140100-00004. PMID   11707061. S2CID   20884365.
  17. ↑ Haefely W, Bartholini G, Pletscher A (1976). "Monoaminergic drugs: general pharmacology". Pharmacology & Therapeutics B. 2 (1): 185–218. doi:10.1016/0306-039x(76)90030-1. PMID   817330.
  18. ↑ "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved December 30, 2013.
  19. 1 2 Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN   9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  20. ↑ Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). Journal of Biological Chemistry. 249 (2): 454–458. doi: 10.1016/S0021-9258(19)43051-2 . PMID   4809526 . Retrieved November 6, 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
  21. ↑ Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacology & Therapeutics. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC   1828602 . PMID   15922018.
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  22. ↑ Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1251–1260. PMID   10027866.
  23. ↑ Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". Journal of Pharmaceutical and Biomedical Analysis. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID   12191709.
  24. 1 2 3 Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". British Journal of Pharmacology and Chemotherapy. 20 (2): 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC   1703637 . PMID   13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
  25. ↑ Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID   23650932. S2CID   23738007. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
  26. ↑ Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circulation Research. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID   4713201. S2CID   28641000. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
  27. ↑ Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID   4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
  28. ↑ Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems". Journal of Pharmacology and Experimental Therapeutics. 251 (3): 901–908. PMID   2600821. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
  29. 1 2 "4-(2-Aminopropyl)phenol". PubChem. Retrieved August 30, 2024.
  30. ↑ "C9H13NO". Hydroxyamphetamine. August 30, 2024. Retrieved August 30, 2024.
  31. ↑ "Akorn Acquires Paredrine - Specialty Ophthalmic Diagnostic Product From Pharmics, Inc". Akorn press release. March 24, 1999. Archived from the original on September 16, 2018. Retrieved December 9, 2014.
  32. ↑ "Akorn press release".[ permanent dead link ]
  33. ↑ "Akorn timeline". Archived from the original on June 26, 2019. Retrieved December 9, 2014.
  34. ↑ Lurcott R (December 1, 2002). "Unique Mydriatic Returns: The combination formula fosters patient flow efficiencies". Ophthalmology Management.
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