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The mechanism of action of bupropion is unclear but believed to be related to the fact that bupropion is a [[norepinephrine-dopamine reuptake inhibitor]] and antagonist of several [[Nicotinic acetylcholine receptor|nicotinic receptors]].<ref name=pmid31124380/> It is uncertain if it is a [[norepinephrine-dopamine releasing agent]].<ref name=pmid31124380/> Pharmacological actions of bupropion, to a significant degree, are due to its active metabolites hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion that are present in the blood plasma at comparable or higher levels.<ref name=pmid31124380/> Overall action of these metabolites, and particularly one enantiomer [[radafaxine|''S,S''-hydroxybupropion]], is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic antagonism (see the Chart on the right).<ref name=pmid31124380/>
The mechanism of action of bupropion is unclear but believed to be related to the fact that bupropion is a [[norepinephrine-dopamine reuptake inhibitor]] and antagonist of several [[Nicotinic acetylcholine receptor|nicotinic receptors]].<ref name=pmid31124380/> It is uncertain if it is a [[norepinephrine-dopamine releasing agent]].<ref name=pmid31124380/> Pharmacological actions of bupropion, to a significant degree, are due to its active metabolites hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion that are present in the blood plasma at comparable or higher levels.<ref name=pmid31124380/> Overall action of these metabolites, and particularly one enantiomer [[radafaxine|''S,S''-hydroxybupropion]], is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic antagonism (see the Chart on the right).<ref name=pmid31124380/>


Bupropion also weakly inhibits the [[Alpha-1 adrenergic receptor|α{{sub|1}} adrenergic receptor]], with a 14% potency of its dopamine uptake inhibition, and the [[histamine H1 receptor|H{{sub|1}} receptor]], with a 9% potency.<ref name="Horst_Preskorn_1998">{{cite journal |vauthors=Horst WD, Preskorn SH | title = Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion | journal = J Affect Disord | volume = 51 | issue = 3 | pages = 237–54 | date = December 1998 | pmid = 10333980 | doi = 10.1016/S0165-0327(98)00222-5 }}</ref>

====Antinicotinic and other activities====
Bupropion is also known to act as a [[non-competitive antagonist]] of the [[alpha-3 beta-2 nicotinic receptor|α{{sub|3}}β{{sub|2}}]], [[alpha-3 beta-4 nicotinic receptor|α{{sub|3}}β{{sub|4}}]], [[alpha-4 beta-2 nicotinic receptor|α{{sub|4}}β{{sub|2}}]], and, very weakly, [[alpha-7 nicotinic receptor|α{{sub|7}}]] [[nicotinic acetylcholine receptor|nACh receptors]],<ref name="LemkeWilliams2012">{{cite book | vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry |url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA611 |date=24 January 2012 |publisher=Lippincott Williams & Wilkins |isbn=978-1-60913-345-0 |pages=611–613}}</ref><ref name="pmid24484978">{{Cite book |vauthors=Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI |title=Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse |chapter=Bupropion and bupropion analogs as treatments for CNS disorders |journal=Adv. Pharmacol. |volume=69 |pages=177–216 |year=2014 |pmid=24484978 |doi=10.1016/B978-0-12-420118-7.00005-6 |series=Advances in Pharmacology |isbn=9780124201187 }}</ref> and these actions appear to be importantly involved in its beneficial properties not only in smoking cessation, but in depression as well.<ref name="Dwoskin2014" /><ref name="LemkeWilliams2012" /><ref name="pmid16109583">{{cite journal |vauthors=Warner C, Shoaib M|title=How does bupropion work as a smoking cessation aid? |journal=Addict Biol |volume=10 |issue=3 |pages=219–31 |date=September 2005 |pmid=16109583 |doi=10.1080/13556210500222670 |s2cid=24002888 }}</ref><ref name="pmid19497387">{{cite journal |vauthors=Arias HR |title=Is the inhibition of nicotinic acetylcholine receptors by bupropion involved in its clinical actions? |journal=Int. J. Biochem. Cell Biol. |volume=41 |issue=11 |pages=2098–108 |year=2009 |pmid=19497387 |doi=10.1016/j.biocel.2009.05.015}}</ref> The metabolites of bupropion also act as non-competitive antagonists of these nACh receptors, and hydroxybupropion is even more potent in comparison.<ref name="Dwoskin2014"/><ref name="pmid15322260">{{cite journal |vauthors=Damaj MI, Carroll FI, Eaton JB, etal |s2cid=1577336 |title=Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors |journal=Mol. Pharmacol. |volume=66 |issue=3 |pages=675–82 |date=September 2004 |pmid=15322260 |doi=10.1124/mol.104.001313 }}</ref><ref name="pmid23149928">{{cite journal |vauthors=Zhu AZ, Cox LS, Nollen N, etal |title=CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion |journal=Clin. Pharmacol. Ther. |volume=92 |issue=6 |pages=771–7 |date=December 2012 |pmid=23149928 |pmc=3729209 |doi=10.1038/clpt.2012.186 }}</ref><ref name="FoxhallRodriguez2014">{{cite book | vauthors = Foxhall LE, Rodriguez MA |title=Advances in Cancer Survivorship Management |url=https://books.google.com/books?id=YIjLBAAAQBAJ&pg=PA265 |date=2014 |publisher=Springer |isbn=978-1-4939-0986-5 |pages=265–}}</ref><ref name="Johnson2010">{{cite book | vauthors = Johnson BA |title=Addiction Medicine: Science and Practice |url=https://books.google.com/books?id=zvbr4Zn9S9MC&pg=PA433 |date=10 October 2010 |publisher=Springer Science & Business Media |isbn=978-1-4419-0338-9 |pages=433–}}</ref> At therapeutically-relevant concentrations bupropion and hydroxybupropion act as [[negative allosteric modulator]]s of the [[serotonin]] [[5-HT3 receptor|5-HT{{sub|3A}} receptor]].<ref name="pmid27671323">{{cite journal |vauthors=Pandhare A, Pappu AS, Wilms H, Blanton MP, Jansen M |title=The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors |journal=Neuropharmacology |volume=113 |issue=Pt A |pages=89–99 |year=2016 |pmid=27671323 |pmc=5148637 |doi=10.1016/j.neuropharm.2016.09.021 }}</ref> Pharmacological data on bupropion and its metabolites are shown in the table. Bupropion is known to weakly inhibit the [[Alpha-1 adrenergic receptor|α{{sub|1}} adrenergic receptor]], with a 14% potency of its dopamine uptake inhibition, and the [[histamine H1 receptor|H{{sub|1}} receptor]], with a 9% potency.<ref name="Horst_Preskorn_1998">{{cite journal |vauthors=Horst WD, Preskorn SH | title = Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion | journal = J Affect Disord | volume = 51 | issue = 3 | pages = 237–54 | date = December 1998 | pmid = 10333980 | doi = 10.1016/S0165-0327(98)00222-5 }}</ref>

===Pharmacokinetics===
===Pharmacokinetics===
[[File:Bupropion metabolism.png|thumb|upright=1.7|[[Drug metabolism|Phase I Metabolism]] of racemic bupropion. The carbonyl reductase enzyme that is responsible for producing ''erythro''-bupropion is unknown as of March 2015.]]
[[File:Bupropion metabolism.png|thumb|upright=1.7|[[Drug metabolism|Phase I Metabolism]] of racemic bupropion. The carbonyl reductase enzyme that is responsible for producing ''erythro''-bupropion is unknown as of March 2015.]]

Revision as of 12:39, 18 April 2021

Not to be confused with Buprenorphine or Buspirone.

Bupropion
Skeletal formula of bupropion
Ball-and-stick model of the (S) isomer of the bupropion molecule
1 : 1 mixture (racemate)
Clinical data
Pronunciation/bjuːˈproʊpiɒn/
bew-PROH-pee-on
Trade namesWellbutrin, Zyban, others
Other namesAmfebutamone; 3-Chloro-N-tert-butyl-β-keto-α-methylphenethylamine;
3- Chloro-N-tert-butyl-β-ketoamphetamine;
Bupropion hydrochloride[1]
AHFS/Drugs.comMonograph
MedlinePlusa695033
License data
Pregnancy
category
Routes of
administration		Medical: By mouth
Recreational: by mouth, insufflation, intravenous
Drug classAntidepressants
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: WARNING[3]Rx-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding84% (bupropion), 77% (hydroxybupropion metabolite), 42% (threohydrobupropion metabolite)[4]
MetabolismLiver (mostly CYP2B6-mediated hydroxylation, but with some contributions from CYP1A2, CYP2A6, CYP2C9, CYP3A4, CYP2E1 and CYP2C19)[4][7][5][8]
Elimination half-life12–30 hours[5][6]
ExcretionRenal (87%; 0.5% unchanged), faecal (10%)[4][7][5]
Identifiers
  • (RS)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO
Molar mass239.74 g·mol−1
3D model (JSmol)
  • O=C(C(C)NC(C)(C)C)C1=CC=CC(Cl)=C1
  • InChI=1S/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3 checkY
  • Key:SNPPWIUOZRMYNY-UHFFFAOYSA-N checkY
  (verify)

Bupropion, sold under the brand names Wellbutrin and Zyban among others, is a medication primarily used to treat major depressive disorder and to support smoking cessation.[9] It is an effective antidepressant on its own, but it is also used as an add-on medication in cases of incomplete response to first-line antidepressants.[9][10] Bupropion is taken in tablet form and is available only by prescription in industrialized countries.[9]

Common side effects of bupropion include a dry mouth, difficulty sleeping, agitation, and headaches.[9] Serious side effects include an increased risk for epileptic seizures and suicide.[9] In comparison to some other antidepressants, bupropion may have a lower rate of sexual dysfunction or sleepiness and may result in weight loss.[11] It is unclear if its use during pregnancy or breastfeeding is safe.[9][2]

Bupropion is an atypical antidepressant.[12] It acts as a norepinephrine–dopamine reuptake inhibitor (NDRI) and a nicotinic receptor antagonist.[11][13][14] Chemically, it is an aminoketone that belongs to the class of substituted cathinones and more generally that of substituted amphetamines and substituted phenethylamines.[1][15]

Bupropion was first made by chemist Nariman Mehta in 1969, and patented by Burroughs Wellcome in 1974.[16] It was first approved for medical use in the United States in 1985.[9] It was originally called by the generic name amfebutamone, before being renamed in 2000.[17] In 2018, it was the 27th most commonly prescribed medication in the United States, with more than 24 million prescriptions.[18][19]

Medical uses

Wellbutrin XL

Depression

A majority of controlled clinical trials support efficacy of bupropion for the treatment of depression.[20][21][22] However, the overall quality of the evidence is low,[22][21] with one meta-analysis, for example, finding small[22] effect size of bupropion in depression and another - large[21] effect size. Comparative head-to-head clinical trials indicate that bupropion is similar in efficacy against depression to fluoxetine, sertraline, paroxetine, and venlafaxine.[21]

Given over the fall and winter months, bupropion prevents development of depression in those who suffer from recurring seasonal affective disorder: 15% of participants on bupropion experienced a major depressive episode vs 27% of those on placebo.[23] Bupropion also improves depression in bipolar disorder, with the efficacy and risk of affective switch being similar to other antidepressants.[24]

Bupropion has several features that distinguish it from other antidepressants: for instance, unlike the majority of antidepressants, it does not usually cause sexual dysfunction, and the occurrence of sexual side effects is not different from placebo.[21][25] Bupropion treatment is not associated with weight gain; on the contrary, the majority of studies observed significant weight loss in bupropion-treated participants.[21] Bupropion treatment also is not associated with the sleepiness that may be produced by other antidepressants.[26] Bupropion is more effective than selective serotonin reuptake inhibitors (SSRIs) at improving symptoms of hypersomnia and fatigue in depressed patients.[27][28] There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of depression with high anxiety; they are equivalent for the depression with moderate or low anxiety.[29]

The addition of bupropion to a prescribed SSRI is a common strategy when people do not respond to the SSRI,[30] and it is supported by clinical trials;[21] however, it appears to be inferior to the addition of atypical antipsychotic aripiprazole.[31]

Smoking cessation

Prescribed as an aid for smoking cessation bupropion reduces the severity of craving for tobacco and withdrawal symptoms[32][33][34] such as depressed mood, irritability, difficulty concentrating, and increased appetite.[35] Initially, bupropion slows the weight gain that often occurs in the first weeks after quitting smoking. With time, however, this effect becomes negligible.[35]

The bupropion treatment course lasts for seven to twelve weeks, with the patient halting the use of tobacco about ten days into the course.[35][36] After the course, the effectiveness of bupropion for maintaining abstinence from smoking declines over time, from 37% of tobacco abstinence at 3 months to 20% at one year.[37] It is unclear whether extending bupropion treatment helps to prevent relapse of smoking.[38]

Overall, six months after the therapy, bupropion increases the likelihood of quitting smoking by approximately 1.6 fold as compared to placebo. In this respect, bupropion is as effective as nicotine replacement therapy but inferior to varenicline. Combining bupropion and nicotine replacement therapy does not improve the quitting rate.[39]

In children and adolescents, the use of bupropion for smoking cessation does not appear to offer any significant benefits.[40] The evidence for its use to aid smoking cessation in pregnant women is insufficient.[41]

Attention deficit hyperactivity disorder

The treatment of ADHD is not an approved indication of bupropion, and it is not mentioned in the current (2019) guideline on the ADHD treatment from the American Academy of Pediatrics.[42] Systematic reviews of bupropion for the treatment of ADHD in both adults and children note that bupropion may be effective for ADHD but warn that this conclusion has to be interpreted with caution, because clinical trials were of low quality due to small sizes and risk of bias.[43][44][45][46]

Sexual dysfunction

Bupropion is less likely than other antidepressants to cause sexual dysfunction.[47] A range of studies indicate that bupropion not only produces fewer sexual side effects than other antidepressants but can actually help to alleviate sexual dysfunction[48] including sexual dysfunction induced by SSRI antidepressants.[49] There have also been small studies suggesting that bupropion or a bupropion/trazodone combination may improve some measures of sexual function in women who have hypoactive sexual desire disorder (HSDD) and are not depressed.[50] According to an expert consensus recommendation from the International Society for the Study of Women's Sexual Health, bupropion can be considered as an off-label treatment for HSDD despite limited safety and efficacy data.[51]

Obesity

Bupropion, when used for treating obesity over a period of 6 to 12 months, results in an average weight loss of 2.7 kg (5.9 lbs) over placebo.[52] This is not much different from the weight loss produced by several other weight-loss medications such as sibutramine or orlistat.[52] The combination drug naltrexone/bupropion has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of obesity.[53][54]

Other uses

Bupropion is not effective in the treatment of cocaine dependence,[55] but it is showing promise in reducing drug use in light methamphetamine users.[56] Based on studies indicating that bupropion lowers the level of the inflammatory mediator TNF-alpha, there have been suggestions that it might be useful in treating inflammatory bowel disease, psoriasis, and other autoimmune conditions, but very little clinical evidence is available.[57][58][59] Bupropion is not effective in treating chronic low back pain.[60]

Contraindications

The drug label advises that bupropion should not be prescribed to individuals with epilepsy or other conditions that lower the seizure threshold, such as anorexia nervosa, bulimia nervosa, benzodiazepine or alcohol withdrawal. It should be avoided in individuals who are taking monoamine oxidase inhibitors (MAOIs). When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications.[5] The label recommends that caution should be exercised when treating people with liver damage, severe kidney disease, and severe hypertension, and in children, adolescents and young adults due to the increased risk of suicidal ideation.[5]

Side effects

See also: List of side effects of bupropion

The common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating.[61] Bupropion has highest incidence of insomnia of all second-generation antidepressants, bar desvenlafaxine.[62] It is also associated with about 20% increased risk of headache.[63]

Bupropion rises systolic blood pressure by 6 mm Hg and the heart rate by 7 beats per minute.[64] The prescribing information notes that hypertension, sometimes severe, is observed in some people taking bupropion, both with and without pre-existing hypertension.[61] Safety of bupropion in people with cardiovascular conditions and its general cardiovascular safety profile remain unclear due to the lack of data.[65][66]

Seizure is a rare but serious adverse effect of bupropion. It is strongly dose-dependent: for the immediate release preparation, the seizure incidence is 0.4% at the dose 300-450 mg per day; the incidence climbs almost ten-fold for the higher than recommended dose of 600 mg.[61] For comparison, the incidence of unprovoked seizure in the general population is 0.07 to 0.09%, and the risk of seizure for a variety of other antidepressants is generally between 0 and 0.5% at the recommended doses.[67]

Cases of liver toxicity leading to death or liver transplantation have been reported for bupropion. It is considered to be one of several antidepressants with greater risk of hepatotoxicity.[68]

The prescribing information warns about bupropion triggering an angle-closure glaucoma attack.[5] On the other hand, bupropion may decrease the risk of development of open angle glaucoma.[69]

Bupropion use by mothers in the first trimester of pregnancy is associated with 23% increase of the odds in congenital heart defects in their children.[70]

Psychiatric

The FDA requires all antidepressants, including bupropion, to carry a boxed warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in suicidal thought and behavior in children and adolescents, and 1.5-fold increase in the 18–24 age group.[71] For this analysis the FDA combined the results of 295 trials of 11 antidepressants in order to obtain statistically significant results. Considered in isolation, bupropion was not statistically different from placebo.[71]

Bupropion prescribed for smoking cessation results in 25% increase of the risk of psychiatric side effects, in particular, anxiety (about 40% increase) and insomnia (about 80% increase). The evidence is insufficient to determine whether bupropion is associated with suicides or suicidal behavior. [72]

In rare cases, bupropion-induced psychosis may develop. It is associated with higher doses of bupropion; many cases described are at higher than recommended doses. Concurrent antipsychotic medication appears to be protective.[73] In most cases the psychotic symptoms are eliminated by reducing the dose, ceasing treatment or adding antipsychotic medication.[5][73]

Although studies are lacking, a handful of case reports suggest that abrupt discontinuation of bupropion may cause antidepressant discontinuation syndrome.[74]

Overdose

Bupropion is considered moderately dangerous in overdose.[75][76] According to an analysis of US National Poison Data System, adjusted for the number of prescriptions, bupropion and venlafaxine are the two new generation antidepressants (that is excluding tricyclic antidepressants) that result in the highest mortality and morbidity.[77] For significant overdoses, seizures have been reported in about a third of all cases; other serious effects include hallucinations, loss of consciousness, and abnormal heart rhythms. When bupropion was one of several kinds of pills taken in an overdose, fever, muscle rigidity, muscle damage, hypertension or hypotension, stupor, coma, and respiratory failure have been reported. While most people recover, some people have died, and before they died suffered multiple uncontrolled seizures and heart attacks.[5]

Interactions

Since bupropion is metabolized to hydroxybupropion by the enzyme CYP2B6, drug interactions with CYP2B6 inhibitors are possible: this includes such medications as paroxetine, sertraline, norfluoxetine (active metabolite of fluoxetine), diazepam, clopidogrel, and orphenadrine. The expected result is the increase of bupropion and decrease of hydroxybupropion blood concentration. The reverse effect (decrease of bupropion and increase of hydroxybupropion) can be expected with CYP2B6 inducers such as carbamazepine, clotrimazole, rifampicin, ritonavir, St John's wort, and phenobarbital.[78] Indeed, carbamazepine decreases exposure to bupropion by 90% and increases exposure to hydroxybupropion by 94%.[79] Ritonavir, lopinavir/ritonavir, and efavirenz have been shown to decrease levels of bupropion and/or its metabolites.[80] Ticlopidine and clopidogrel, both potent CYP2B6 inhibitors, have been found to considerably increase bupropion levels as well as decrease levels of its metabolite hydroxybupropion.[80]

Bupropion and its metabolites are inhibitors of CYP2D6, with hydroxybupropion responsible for most of the inhibition. Additionally, bupropion and its metabolites may decrease expression of CYP2D6 in the liver. The end effect is a significant slowing of the clearance of other drugs metabolized by this enzyme.[81] For instance, bupropion has been found to increase area-under-the-curve of desipramine, a CYP2D6 substrate, by 5-fold.[80] Bupropion has also been found to increase levels of atomoxetine by 5.1-fold, while decreasing the exposure to its main metabolite by 1.5-fold.[82] As another example, the ratio of dextromethorphan (a drug that is mainly metabolized by CYP2D6) to its major metabolite dextrorphan increased approximately 35-fold when it was administered to people being treated with 300 mg/day bupropion.[78] When people on bupropion are given MDMA, about 30% increase of exposure to both drugs is observed, with enhanced mood but decreased heart rate effects of MDMA.[83][84] Interactions with other CYP2D6 substrates, such as metoprolol, imipramine, nortriptyline,[84] venlafaxine,[78] and nebivolol[81] have also been reported. However, in a notable exception, bupropion does not affect the concentrations of CYP2D6 substrates fluoxetine and paroxetine.[78]

Bupropion lowers the seizure threshold, and therefore can potentially interact with other medications that also lower it, such as antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids.[5] The prescribing information recommends minimizing the use of alcohol, since in rare cases bupropion reduces alcohol tolerance.[5]

Caution should be observed when combining bupropion with a monoamine oxidase inhibitor (MAOI), as it may result in hypertensive crisis.[85]

Pharmacology

Pharmacology of bupropion and its metabolites.
  Bupropion R,R-
Hydroxy
bupropion 		S,S-
Hydroxy
bupropion 		Threo-
hydro
bupropion 		Erythro-
hydro
bupropion
Exposure and half-life
AUC relative
to bupropion[86][87] 		1 23.8 0.6 11.2 2.5
Half-life[88] 11 h 19 h 15 h 31 h 22 h
Inhibition IC50 (μM) in human cells, unless noted otherwise
DAT, uptake[89] 0.66 inactive 0.63 no data no data
NET, uptake[89] 1.85 9.9 0.24 no data no data
SERT, uptake[89] inactive inactive inactive no data no data
α3β4 nicotinic[89] 1.8 6.5 11 14 (rat)[90] no data
α4β2 nicotinic[91] 12 31 3.3 no data no data
α1β1γδ nicotinic[91] 7.9 7.6 28 no data no data

Pharmacodynamics and mechanism of action

The mechanism of action of bupropion is unclear but believed to be related to the fact that bupropion is a norepinephrine-dopamine reuptake inhibitor and antagonist of several nicotinic receptors.[81] It is uncertain if it is a norepinephrine-dopamine releasing agent.[81] Pharmacological actions of bupropion, to a significant degree, are due to its active metabolites hydroxybupropion, threo-hydrobupropion, and erythro-hydrobupropion that are present in the blood plasma at comparable or higher levels.[81] Overall action of these metabolites, and particularly one enantiomer S,S-hydroxybupropion, is also characterized by inhibition of norepinephrine and dopamine reuptake and nicotinic antagonism (see the Chart on the right).[81]

Bupropion also weakly inhibits the α1 adrenergic receptor, with a 14% potency of its dopamine uptake inhibition, and the H1 receptor, with a 9% potency.[92]

Pharmacokinetics

Phase I Metabolism of racemic bupropion. The carbonyl reductase enzyme that is responsible for producing erythro-bupropion is unknown as of March 2015.

Bupropion is metabolized in the liver by the cytochrome P450 isoenzyme CYP2B6.[93] It has several active metabolites: R,R-hydroxybupropion, S,S-hydroxybupropion, threo-hydrobupropion and erythro-hydrobupropion, which are further metabolized to inactive metabolites and eliminated through excretion into the urine. Both bupropion and its primary metabolite hydroxybupropion act in the liver as potent inhibitors of the enzyme CYP2D6, which metabolizes not only bupropion itself but also a variety of other drugs and biologically active substances.[94] This mechanism creates the potential for a variety of drug interactions.

The biological activity of bupropion can be attributed to a significant degree to its active metabolites, in particular to S,S-hydroxybupropion. GlaxoSmithKline developed this metabolite as a separate drug called radafaxine,[95] but discontinued development in 2006 due to "an unfavourable risk/benefit assessment".[96]

Bupropion is metabolized to hydroxybupropion by CYP2B6, an isozyme of the cytochrome P450 system. Alcohol causes an increase of CYP2B6 in the liver, and persons with a history of alcohol use metabolize bupropion faster. Bupropion is metabolized to threo-hydrobupropion via cortisone reductase.[97] The metabolic pathway responsible for the creation of erythro-hydrobupropion remains elusive.

The metabolism of bupropion is highly variable: the effective doses of bupropion received by persons who ingest the same amount of the drug may differ by as much as 5.5 times (with a half-life of 12–30 hours), while the effective doses of hydroxybupropion may differ by as much as 7.5 times (with a half-life of 15–25 hours).[5][6][98] Based on this, some researchers have advocated monitoring of the blood level of bupropion and hydroxybupropion.[99] The half-lives of erythrohydrobupropion and threohydrobupropion are roughly 23–43 hours and 24–50 hours respectively.[4][5]

There have been reported cases of false-positive urine amphetamine tests in persons taking bupropion.[100][101][102]

In 2016, three new major metabolites of bupropion, all formed exclusively by CYP2C19, were identified.[103] These include 4'-OH-bupropion, erythro-4'-OH-hydrobupropion and threo-4'-OH-hydrobupropion, and represent 24% of a dose of bupropion excreted in urine.[103] For comparison, bupropion and its three previously known primary metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion represent 23% of a dose of bupropion excreted in urine.[103]

Chemistry

Bupropion is a unicyclic aminoketone that belongs to the class of substituted cathinones and the more general class of substituted phenethylamines.[1][15] Although two optical isomers on bupropion can be separated at 20 oC,[104] they spontaneously racemize even during storage of solid samples. FDA-approved and commercially available bupropion is racemic.

Synthesis

It is synthesized in two chemical steps starting from 3'-chloro-propiophenone. The alpha position adjacent to the ketone is first brominated followed by nucleophilic displacement of the resulting alpha-bromoketone with t-butylamine and treated with hydrochloric acid to give bupropion as the hydrochloride salt in 75–85% overall yield.[16][105]

Bupropion synthesis diagram
3'-Chloro-propiophenone
3'-Chloro-2-bromopropiophenone
Bupropion hydrochloride
This diagram shows the synthesis of bupropion via 3'-chloro-propiophenone.

History

A bioequivalency profile comparison of 150 mg extended-release bupropion as produced by Impax Laboratories for Teva and Biovail for GlaxoSmithKline.

Bupropion was invented by Nariman Mehta of Burroughs Wellcome (now GlaxoSmithKline) in 1969, and the US patent for it was granted in 1974.[16] It was approved by the U.S. Food and Drug Administration (FDA) as an antidepressant on 30 December 1985, and marketed under the name Wellbutrin.[106][107] However, a significant incidence of epileptic seizures at the originally recommended dosage caused the withdrawal of the drug in 1986. Subsequently, the risk of seizures was found to be highly dose-dependent, and bupropion was re-introduced to the market in 1989 with a lower maximum recommended daily dose.[108]

In 1996, the FDA approved a sustained-release formulation of alcohol-resistant bupropion called Wellbutrin SR, intended to be taken twice a day (as compared with three times a day for immediate-release Wellbutrin).[109] In 2003, the FDA approved another sustained-release formulation called Wellbutrin XL, intended for once-daily dosing.[110] Wellbutrin SR and XL are available in generic form in the United States and Canada. In Canada, generic XR bupropion is distributed by Mylan. In 1997, bupropion was approved by the FDA for use as a smoking cessation aid under the name Zyban.[111][109] In 2006, Wellbutrin XL was similarly approved as a treatment for seasonal affective disorder.[112][113]

In France, marketing authorization was granted for Zyban on 3 August 2001, with a maximum daily dose of 300 mg;[114] only sustained-release bupropion is available, and only as a smoking cessation aid. Bupropion was granted a licence for use in adults with major depression in the Netherlands in early 2007, with GlaxoSmithKline expecting subsequent approval in other European countries.[115] Bupropion was approved by the U.S. Food and Drug Administration (FDA), in 2006, for the prevention of seasonal affective disorder (SAD).[116] In some countries (including Australia, New Zealand and the UK) depression treatment and SAD prevention are off-label uses.[117][118]

On 11 October 2007, two providers of consumer information on nutritional products and supplements, ConsumerLab.com and The People's Pharmacy, released the results of comparative tests of different brands of bupropion.[119] The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that "one of a few generic versions of Wellbutrin XL 300 mg, sold as Budeprion XL 300 mg, didn't perform the same as the brand-name pill in the lab."[120] The FDA investigated these complaints and concluded that Budeprion XL is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL.[121] On 3 October 2012, however, the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg."[122] The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013.[122] As of October 2013 the FDA has made determinations on the formulations from some manufacturers not being bioequivalent.[122]

In April 2008, the FDA approved a formulation of bupropion as a hydrobromide salt instead of a hydrochloride salt, to be sold under the name Aplenzin by Sanofi-Aventis.[123][124][125]


In 2009, the FDA issued a health advisory warning that the prescription of bupropion for smoking cessation has been associated with reports about unusual behavior changes, agitation and hostility. Some people, according to the advisory, have become depressed or have had their depression worsen, have had thoughts about suicide or dying, or have attempted suicide.[126] This advisory was based on a review of anti-smoking products that identified 75 reports of "suicidal adverse events" for bupropion over ten years.[127] Based on the results of follow-up trials this warning was removed in 2016.[128]

In 2012, the U.S. Justice Department announced that GlaxoSmithKline had agreed to plead guilty and pay a $3-billion fine, in part for promoting the unapproved use of Wellbutrin for weight loss and sexual dysfunction.[129]

In 2017, the European Medicines Agency recommended suspending a number of nationally approved medicines due to misrepresentation of bioequivalence study data by Micro Therapeutic Research Labs in India.[130] The products recommended for suspension included several 300 mg modified-release Bupropion tablets.[131]

Society and culture

Recreational use

While bupropion demonstrates some potential for misuse, this potential is less than of other commonly used stimulants, being limited by features of bupropion's pharmacology.[132] Bupropion misuse is uncommon.[132] There have been a number of anecdotal and case-study reports of bupropion abuse, but the bulk of evidence indicates that the subjective effects of bupropion via the oral route are markedly different from those of addictive stimulants such as cocaine or amphetamine.[133] That said, bupropion, via non-conventional routes of administration (e.g., injection, insufflation), is reported to be abused in the United States and Canada, notably in prisons.[134][135][136][137]

Brands

It is sold under many trade names worldwide and in combinations with naltrexone.[138]

It is sold under many trade names worldwide including Aplenzin, Budeprion SR, Bup, Bupredol, Buproban, Bupropion GSK, BuPROPion HCL SR Watson, Bupropion Hydrochloride Anchen, Bupropion Hydrochloride Apotex, BuPROPion Hydrochloride Cadista, Bupropion Hydrochloride Mylan, Bupropion Hydrochloride Sandoz, buPROPion Hydrochloride SR actavis, Bupropion Hydrochloride Sun Pharma, buPROPion Hydrochloride Torrent Pharma, Bupropion Hydrochloride Wockhardt, buPROPion Hydrochloride XL actavis, BuPROPion Hydrochloride XL Watson, Bupropion SR Sanis Health, Bupropionhydrochlorid HEXAL, Bupropionhydrochloride GSK, Buprotrin, Butrin, Buxon, Carmubine, Depnox-SR, Elontril, Elontril XL, Forfivo XL, Funnix, Global buPROPion HCL, Le Fu Ting, Odranal, PMS-Bupropion SR, Prewell, Quomem, ratio-Bupropion SR, Sandoz Bupropion SR, Voxra, Wellbutrin, Wellbutrin Retard, Wellbutrin SR, Wellbutrin XL, Wellbutrin XR, Yue Ting, Zetron, Zyban, Zyban LP, Zybex SR, ZyGenerics Bupropion Hydrochloride XL, and Zyntabac.[138]

It is sold as a combination drug with naltrexone as Contrave.[138]

Legal status

In Russia bupropion is banned as a narcotic drug, yet not per se but rather as a derivative of methcathinone.[139] In Australia and the UK, smoking cessation is the only licensed use of bupropion.[117][118] In the US, the FDA granted approval for marketing of bupropion for depression and smoking cessation.[140]

References

  1. ^ a b c "Compound Summary". Bupropion. United States National Library of Medicine – National Center for Biotechnology Information. 28 July 2018. Retrieved 29 July 2018. {{cite encyclopedia}}: |work= ignored (help)
  2. ^ a b c "Bupropion Use During Pregnancy". Drugs.com. Retrieved 24 December 2018.
  3. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  4. ^ a b c d "Zyban 150 mg prolonged release film-coated tablets – Summary of Product Characteristics (SPC)". electronic Medicines Compendium. GlaxoSmithKline UK. 1 August 2013. Retrieved 22 October 2013.
  5. ^ a b c d e f g h i j k l "Wellbutrin SR- bupropion hydrochloride tablet, film coated". DailyMed. 5 November 2019. Retrieved 6 May 2020.
  6. ^ a b Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.[page needed]
  7. ^ a b "Prexaton Bupropion hydrochloride Product Information". TGA eBusiness Services. Ascent Pharma Pty Ltd. 2 October 2012. Retrieved 22 October 2013.
  8. ^ Zhu AZ, Zhou Q, Cox LS, Ahluwalia JS, Benowitz NL, Tyndale RF (September 2014). "Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes". Drug Metabolism and Disposition. 42 (11): 1971–7. doi:10.1124/dmd.114.060285. PMC 4201132. PMID 25187485.
  9. ^ a b c d e f g "Bupropion Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. 5 February 2018. Retrieved 15 July 2018.
  10. ^ Schwasinger-Schmidt TE, Macaluso M (8 September 2018). "Other Antidepressants". Handbook of Experimental Pharmacology. 250: 325–355. doi:10.1007/164_2018_167. ISBN 978-3-030-10948-6. PMID 30194544.
  11. ^ a b Fava M, Rush AJ, Thase ME, et al. (2005). "15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL". Prim Care Companion J Clin Psychiatry. 7 (3): 106–13. doi:10.4088/pcc.v07n0305. PMC 1163271. PMID 16027765.
  12. ^ Sweetman S (2011). Martindale: The Complete Drug Reference (37th ed.). p. 402. ISBN 9780853699828.
  13. ^ Dwoskin LP (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 177–216. ISBN 978-0-12-420177-4.
  14. ^ Tasman A, Kay J, Lieberman JA, First MB, Maj M (11 October 2011). Psychiatry. John Wiley & Sons. ISBN 978-1-119-96540-4.
  15. ^ a b Dye LR, Murphy C, Calello DP, Levine MD, Skolnik A (2017). Case Studies in Medical Toxicology: From the American College of Medical Toxicology. Springer. p. 85. ISBN 9783319564494.
  16. ^ a b c Mehta NB (25 June 1974). "United States Patent 3,819,706: Meta-chloro substituted α-butylamino-propiophenones". USPTO. Retrieved 2 June 2008.
  17. ^ World Health Organization (2000). "International nonproprietary names for pharmaceutical substances (INN) : proposed international nonproprietary names : list 83". WHO Drug Information. 14 (2). hdl:10665/58135.
  18. ^ "The Top 300 of 2021". ClinCalc. Retrieved 18 February 2021.
  19. ^ "Bupropion - Drug Usage Statistics". ClinCalc. Retrieved 18 February 2021.
  20. ^ Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C (February 2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis". Lancet. 373 (9665): 746–58. doi:10.1016/S0140-6736(09)60046-5. PMID 19185342.
  21. ^ a b c d e f g Patel K, Allen S, Haque MN, Angelescu I, Baumeister D, Tracy DK (April 2016). "Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant". Therapeutic Advances in Psychopharmacology. 6 (2): 99–144. doi:10.1177/2045125316629071. PMC 4837968. PMID 27141292.
  22. ^ a b c Monden R, Roest AM, van Ravenzwaaij D, Wagenmakers EJ, Morey R, Wardenaar KJ, de Jonge P (August 2018). "The comparative evidence basis for the efficacy of second-generation antidepressants in the treatment of depression in the US: A Bayesian meta-analysis of Food and Drug Administration reviews". J Affect Disord. 235: 393–398. doi:10.1016/j.jad.2018.04.040. PMID 29677603.
  23. ^ Gartlehner G, Nussbaumer-Streit B, Gaynes BN, Forneris CA, Morgan LC, Greenblatt A, Wipplinger J, Lux LJ, Van Noord MG, Winkler D (March 2019). "Second-generation antidepressants for preventing seasonal affective disorder in adults". Cochrane Database Syst Rev. 3: CD011268. doi:10.1002/14651858.CD011268.pub3. PMC 6422318. PMID 30883669.
  24. ^ Li DJ, Tseng PT, Chen YW, Wu CK, Lin PY (March 2016). "Significant Treatment Effect of Bupropion in Patients With Bipolar Disorder but Similar Phase-Shifting Rate as Other Antidepressants: A Meta-Analysis Following the PRISMA Guidelines". Medicine (Baltimore). 95 (13): e3165. doi:10.1097/MD.0000000000003165. PMC 4998539. PMID 27043678.
  25. ^ Clayton AH (2003). "Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge". Primary Psychiatry. 10 (1): 55–61.
  26. ^ Dhillon S, Yang LP, Curran MP (2008). "Bupropion: a review of its use in the management of major depressive disorder". Drugs. 68 (5): 653–89. doi:10.2165/00003495-200868050-00011. PMID 18370448.
  27. ^ Baldwin DS, Papakostas GI (2006). "Symptoms of Fatigue and Sleepiness in Major Depressive Disorder". J Clin Psychiatry. 67 (suppl 6): 9–15. PMID 16848671.
  28. ^ Baldwin DS, Papakostas GI (2006). "Symptoms of fatigue and sleepiness in major depressive disorder". J Clin Psychiatry. 67 Suppl 6 (Suppl 6): 9–15. PMID 16848671.
  29. ^ Papakostas GI, Stahl SM, Krishen A, Seifert CA, Tucker VL, Goodale EP, Fava M (August 2008). "Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies". J Clin Psychiatry. 69 (8): 1287–92. doi:10.4088/JCP.v69n0812. PMID 18605812. S2CID 25267685.
  30. ^ Arandjelovic K, Eyre HA, Lavretsky H (October 2016). "Clinicians' Views on Treatment-Resistant Depression: 2016 Survey Reports". Am J Geriatr Psychiatry. 24 (10): 913–7. doi:10.1016/j.jagp.2016.05.010. PMC 5540329. PMID 27591914.
  31. ^ Ruberto VL, Jha MK, Murrough JW (June 2020). "Pharmacological Treatments for Patients with Treatment-Resistant Depression". Pharmaceuticals (Basel). 13 (6). doi:10.3390/ph13060116. PMC 7345023. PMID 32512768.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  32. ^ Wilkes S (2008). "The use of bupropion SR in cigarette smoking cessation". International Journal of Chronic Obstructive Pulmonary Disease. 3 (1): 45–53. doi:10.2147/copd.s1121. PMC 2528204. PMID 18488428.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  33. ^ Howes S, Hartmann-Boyce J, Livingstone-Banks J, Hong B, Lindson N (April 2020). "Antidepressants for smoking cessation". The Cochrane Database of Systematic Reviews. 4: CD000031. doi:10.1002/14651858.CD000031.pub5. PMC 7175455. PMID 32319681.{{cite journal}}: CS1 maint: PMC embargo expired (link)
  34. ^ Wu P, Wilson K, Dimoulas P, Mills EJ (2006). "Effectiveness of smoking cessation therapies: a systematic review and meta-analysis". BMC Public Health. 6: 300. doi:10.1186/1471-2458-6-300. PMC 1764891. PMID 17156479.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  35. ^ a b c Mooney ME, Sofuoglu M (July 2006). "Bupropion for the treatment of nicotine withdrawal and craving". Expert Rev Neurother. 6 (7): 965–81. doi:10.1586/14737175.6.7.965. PMID 16831112.
  36. ^ "DailyMed - BUPROPION HYDROCHLORIDE SR- bupropion hydrochloride tablet, film coated, extended release".
  37. ^ Rosen LJ, Galili T, Kott J, Goodman M, Freedman LS (2018). "Diminishing benefit of smoking cessation medications during the first year: a meta-analysis of randomized controlled trials". Addiction. 113 (5): 805–816. doi:10.1111/add.14134. PMC 5947828. PMID 29377409.
  38. ^ Livingstone-Banks J, Norris E, Hartmann-Boyce J, West R, Jarvis M, Hajek P (February 2019). "Relapse prevention interventions for smoking cessation". Cochrane Database Syst Rev. 2: CD003999. doi:10.1002/14651858.CD003999.pub5. PMC 6372978. PMID 30758045.
  39. ^ Patnode CD, Henderson JT, Coppola EL, Melnikow J, Durbin S, Thomas RG (January 2021). "Interventions for Tobacco Cessation in Adults, Including Pregnant Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force". JAMA. 325 (3): 280–298. doi:10.1001/jama.2020.23541. PMID 33464342.
  40. ^ Selph S, Patnode C, Bailey SR, Pappas M, Stoner R, Chou R (April 2020). "Primary Care-Relevant Interventions for Tobacco and Nicotine Use Prevention and Cessation in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force". JAMA. 323 (16): 1599–1608. doi:10.1001/jama.2020.3332. PMID 32343335.
  41. ^ Claire R, Chamberlain C, Davey MA, Cooper SE, Berlin I, Leonardi-Bee J, Coleman T (March 2020). "Pharmacological interventions for promoting smoking cessation during pregnancy". Cochrane Database Syst Rev. 3: CD010078. doi:10.1002/14651858.CD010078.pub3. PMC 7059898. PMID 32129504.
  42. ^ Wolraich ML, Hagan JF, Allan C, Chan E, Davison D, Earls M, Evans SW, Flinn SK, Froehlich T, Frost J, Holbrook JR, Lehmann CU, Lessin HR, Okechukwu K, Pierce KL, Winner JD, Zurhellen W (October 2019). "Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents". Pediatrics. 144 (4). doi:10.1542/peds.2019-2528. PMC 7067282. PMID 31570648.
  43. ^ Verbeeck W, Bekkering GE, Van den Noortgate W, Kramers C (October 2017). "Bupropion for attention deficit hyperactivity disorder (ADHD) in adults". Cochrane Database Syst Rev. 10: CD009504. doi:10.1002/14651858.CD009504.pub2. PMC 6485546. PMID 28965364.
  44. ^ Elliott J, Johnston A, Husereau D, Kelly SE, Eagles C, Charach A, Hsieh SC, Bai Z, Hossain A, Skidmore B, Tsakonas E, Chojecki D, Mamdani M, Wells GA (2020). "Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis". PLoS One. 15 (10): e0240584. doi:10.1371/journal.pone.0240584. PMC 7577505. PMID 33085721.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  45. ^ Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, Atkinson LZ, Tessari L, Banaschewski T, Coghill D, Hollis C, Simonoff E, Zuddas A, Barbui C, Purgato M, Steinhausen HC, Shokraneh F, Xia J, Cipriani A (September 2018). "Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis". Lancet Psychiatry. 5 (9): 727–738. doi:10.1016/S2215-0366(18)30269-4. PMC 6109107. PMID 30097390.
  46. ^ Ng QX (March 2017). "A Systematic Review of the Use of Bupropion for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents". J Child Adolesc Psychopharmacol. 27 (2): 112–116. doi:10.1089/cap.2016.0124. PMID 27813651.
  47. ^ Serretti A, Chiesa A (June 2009). "Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis". J Clin Psychopharmacol. 29 (3): 259–66. doi:10.1097/JCP.0b013e3181a5233f. PMID 19440080. S2CID 1663570.
  48. ^ Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S (2004). "A review of the neuropharmacology of bupropion, a dual norepinephrine and dopamine reuptake inhibitor". Prim Care Companion J Clin Psychiatry. 6 (4): 159–166. doi:10.4088/PCC.v06n0403. PMC 514842. PMID 15361919.
  49. ^ Basson R, Gilks T (2018). "Women's sexual dysfunction associated with psychiatric disorders and their treatment". Womens Health (Lond). 14: 1745506518762664. doi:10.1177/1745506518762664. PMC 5900810. PMID 29649948.
  50. ^ Clayton AH, Kingsberg SA, Goldstein I (June 2018). "Evaluation and Management of Hypoactive Sexual Desire Disorder". Sex Med. 6 (2): 59–74. doi:10.1016/j.esxm.2018.01.004. PMC 5960024. PMID 29523488.
  51. ^ Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R (January 2017). "Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review". Mayo Clin Proc. 92 (1): 114–128. doi:10.1016/j.mayocp.2016.09.018. PMID 27916394.
  52. ^ a b Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC (April 2005). "Meta-analysis: pharmacologic treatment of obesity". Ann. Intern. Med. 142 (7): 532–46. doi:10.7326/0003-4819-142-7-200504050-00012. PMID 15809465.
  53. ^ "Drug Approval Package: Contrave (naltrexone hydrochloride/bupropion hydrochloride) Extended-Release Tablets NDA #200063". U.S. Food and Drug Administration (FDA). Retrieved 5 May 2020.
  54. ^ "Contrave Extended-Release- naltrexone hydrochloride and bupropion hydrochloride tablet, extended release". DailyMed. 26 April 2019. Retrieved 5 May 2020.
  55. ^ Kampman KM (June 2008). "The search for medications to treat stimulant dependence". Addict Sci Clin Pract. 4 (2): 28–35. doi:10.1151/ascp084228. PMC 2797110. PMID 18497715.
  56. ^ Cao DN, Shi JJ, Hao W, Wu N, Li J (June 2016). "Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction". Eur J Pharmacol. 780: 129–35. doi:10.1016/j.ejphar.2016.03.040. PMID 27018393.
  57. ^ Mikocka-Walus AA, Turnbull DA, Moulding NT, Wilson IG, Andrews JM, Holtmann GJ (2006). "Antidepressants and inflammatory bowel disease: a systematic review". Clin Pract Epidemiol Ment Health. 2: 24. doi:10.1186/1745-0179-2-24. PMC 1599716. PMID 16984660.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  58. ^ Thorkelson G, Bielefeldt K, Szigethy E (June 2016). "Empirically Supported Use of Psychiatric Medications in Adolescents and Adults with IBD". Inflamm Bowel Dis. 22 (6): 1509–22. doi:10.1097/MIB.0000000000000734. PMID 27167571.
  59. ^ Eskeland S, Halvorsen JA, Tanum L (August 2017). "Antidepressants have Anti-inflammatory Effects that may be Relevant to Dermatology: A Systematic Review". Acta Derm Venereol. 97 (8): 897–905. doi:10.2340/00015555-2702. PMID 28512664.
  60. ^ Urquhart DM, Hoving JL, Assendelft WW, Roland M, van Tulder MW (2008). Urquhart DM (ed.). "Antidepressants for non-specific low back pain". Cochrane Database Syst Rev (1): CD001703. doi:10.1002/14651858.CD001703.pub3. PMC 7025781. PMID 18253994.
  61. ^ a b c "Wellbutrin XL® Prescribing Information" (PDF). GlaxoSmithKline. June 2006.
  62. ^ Alberti S, Chiesa A, Andrisano C, Serretti A (June 2015). "Insomnia and somnolence associated with second-generation antidepressants during the treatment of major depression: a meta-analysis". J Clin Psychopharmacol. 35 (3): 296–303. doi:10.1097/JCP.0000000000000329. PMID 25874915.
  63. ^ Telang S, Walton C, Olten B, Bloch MH (August 2018). "Meta-analysis: Second generation antidepressants and headache". J Affect Disord. 236: 60–68. doi:10.1016/j.jad.2018.04.047. PMID 29715610.
  64. ^ Wilens TE, Hammerness PG, Biederman J, Kwon A, Spencer TJ, Clark S, Scott M, Podolski A, Ditterline JW, Morris MC, Moore H (2005). "Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder". J Clin Psychiatry. 66 (2): 253–9. PMID 15705013.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  65. ^ Kittle J, Lopes RD, Huang M, Marquess ML, Wilson MD, Ascher J, Krishen A, Hasselblad V, Kolls BJ, Roe MT, McGuire DK, Russell SD, Mahaffey KW (October 2017). "Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort". Clin Cardiol. 40 (10): 899–906. doi:10.1002/clc.22744. PMC 6490529. PMID 28605035.
  66. ^ Grandi SM, Shimony A, Eisenberg MJ (December 2013). "Bupropion for smoking cessation in patients hospitalized with cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials". Can J Cardiol. 29 (12): 1704–11. doi:10.1016/j.cjca.2013.09.014. PMID 24267809.
  67. ^ Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R (2002). "Effects of psychotropic drugs on seizure threshold". Drug Saf. 25 (2): 91–110. doi:10.2165/00002018-200225020-00004. PMID 11888352. S2CID 25290793.
  68. ^ Voican CS, Corruble E, Naveau S, Perlemuter G (April 2014). "Antidepressant-induced liver injury: a review for clinicians". Am J Psychiatry. 171 (4): 404–15. doi:10.1176/appi.ajp.2013.13050709. PMID 24362450.
  69. ^ Wu A, Khawaja AP, Pasquale LR, Stein JD (January 2020). "A review of systemic medications that may modulate the risk of glaucoma". Eye (Lond). 34 (1): 12–28. doi:10.1038/s41433-019-0603-z. PMC 7002596. PMID 31595027.
  70. ^ De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E (March 2021). "A Systematic Review and Meta-Analysis Considering the Risk for Congenital Heart Defects of Antidepressant Classes and Individual Antidepressants". Drug Saf. 44 (3): 291–312. doi:10.1007/s40264-020-01027-x. PMID 33354752.
  71. ^ a b Levenson M, Holland C. "Antidepressants and suicidality in adults: statistical evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)". U.S. Food and Drug Administration (FDA). Archived from the original on 27 September 2007. Retrieved 13 May 2007.
  72. ^ Howes S, Hartmann-Boyce J, Livingstone-Banks J, Hong B, Lindson N (April 2020). "Antidepressants for smoking cessation". Cochrane Database Syst Rev. 4: CD000031. doi:10.1002/14651858.CD000031.pub5. PMID 32319681.
  73. ^ a b Kumar S, Kodela S, Detweiler JG, Kim KY, Detweiler MB (November–December 2011). "Bupropion-induced psychosis: folklore or fact? A Systematic Review of the Literature". Gen Hosp Psychiatry. 33 (12): 612–7. doi:10.1016/j.genhosppsych.2011.07.001. PMID 21872337.
  74. ^ Henssler J, Heinz A, Brandt L, Bschor T (May 2019). "Antidepressant Withdrawal and Rebound Phenomena". Dtsch Arztebl Int. 116 (20): 355–361. doi:10.3238/arztebl.2019.0355. PMC 6637660. PMID 31288917.
  75. ^ Taylor D, Carol P, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97969-3.
  76. ^ White N, Litovitz T, Clancy C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology. 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.
  77. ^ Nelson JC, Spyker DA (May 2017). "Morbidity and Mortality Associated With Medications Used in the Treatment of Depression: An Analysis of Cases Reported to U.S. Poison Control Centers, 2000-2014". Am J Psychiatry. 174 (5): 438–450. doi:10.1176/appi.ajp.2016.16050523. PMID 28135844.
  78. ^ a b c d Jefferson JW, Pradko JF, Muir KT (November 2005). "Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations". Clin Ther. 27 (11): 1685–95. doi:10.1016/j.clinthera.2005.11.011. PMID 16368442.
  79. ^ Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS, Callahan AM, Hinton ML, Chao J, Post RM (October 1995). "Carbamazepine but not valproate induces bupropion metabolism". J Clin Psychopharmacol. 15 (5): 327–33. doi:10.1097/00004714-199510000-00004. PMID 8830063.
  80. ^ a b c https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/200063s015lbl.pdf
  81. ^ a b c d e f Costa R, Oliveira NG, Dinis-Oliveira RJ (August 2019). "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metab Rev. 51 (3): 293–313. doi:10.1080/03602532.2019.1620763. PMID 31124380.
  82. ^ Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina (2016). "Evaluation of a Potential Metabolism-Mediated Drug-Drug Interaction Between Atomoxetine and Bupropion in Healthy Volunteers". Journal of Pharmacy & Pharmaceutical Sciences. 19 (2): 198–207. doi:10.18433/J3H03R. ISSN 1482-1826. PMID 27518170.
  83. ^ Schmid Y, Rickli A, Schaffner A, Duthaler U, Grouzmann E, Hysek CM, Liechti ME (April 2015). "Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects". J Pharmacol Exp Ther. 353 (1): 102–11. doi:10.1124/jpet.114.222356. PMID 25655950.
  84. ^ a b Protti M, Mandrioli R, Marasca C, Cavalli A, Serretti A, Mercolini L (September 2020). "New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others". Med Res Rev. 40 (5): 1794–1832. doi:10.1002/med.21671. PMID 32285503.
  85. ^ Feinberg SS (2004). "Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication". J Clin Psychiatry. 65 (11): 1520–4. doi:10.4088/jcp.v65n1113. PMID 15554766.
  86. ^ Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Schweiger J, Miller JP, Lenze EJ (May 2019). "Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial". Clin Pharmacol Ther. 105 (5): 1164–1174. doi:10.1002/cpt.1309. PMC 6465131. PMID 30460996.
  87. ^ Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ (November 2020). "Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults". Clin Pharmacol Ther. 108 (5): 1036–1048. doi:10.1002/cpt.1888. PMID 32386065.
  88. ^ Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z (August 2016). "Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers". J Pharmacol Exp Ther. 358 (2): 230–8. doi:10.1124/jpet.116.232876. PMC 4959100. PMID 27255113.
  89. ^ a b c d Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI (June 2010). "Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation". J Med Chem. 53 (12): 4731–48. doi:10.1021/jm1003232. PMC 2895766. PMID 20509659.
  90. ^ Bondarev ML, Bondareva TS, Young R, Glennon RA (August 2003). "Behavioral and biochemical investigations of bupropion metabolites". Eur. J. Pharmacol. 474 (1): 85–93. doi:10.1016/S0014-2999(03)02010-7. PMID 12909199.
  91. ^ a b Cite error: The named reference pmid15322260 was invoked but never defined (see the help page).
  92. ^ Horst WD, Preskorn SH (December 1998). "Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion". J Affect Disord. 51 (3): 237–54. doi:10.1016/S0165-0327(98)00222-5. PMID 10333980.
  93. ^ Hales E; Yudofsky JA, eds. (2003). The American Psychiatric Press Textbook of Psychiatry. Washington, DC: American Psychiatric Publishing, Inc.
  94. ^ Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT (2006). "Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent". CNS Drug Rev. 12 (3–4): 178–207. doi:10.1111/j.1527-3458.2006.00178.x. PMC 6506196. PMID 17227286.
  95. ^ "GlaxoSmithKline (GSK) Reviews Novel Therapeutics For CNS Disorders And Confirms Strong Pipeline Momentum" (Press release). PRNewswire. 23 November 2004. Archived from the original on 28 September 2007. Retrieved 18 August 2007.
  96. ^ GlaxoSmithKline (26 July 2006) "Pipeline Update" (PDF). Archived from the original (PDF) on 27 September 2007.  (136 KB). Press release. Retrieved on 18 August 2007.
  97. ^ Meyer A, Vuorinen A, Zielinska AE, Strajhar P, Lavery GG, Schuster D, Odermatt A (September 2013). "Formation of threohydrobupropion from bupropion is dependent on 11β-hydroxysteroid dehydrogenase 1". Drug Metabolism and Disposition. 41 (9): 1671–8. doi:10.1124/dmd.113.052936. PMC 3876805. PMID 23804523.
  98. ^ Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, Greenblatt DJ, Court MH (April 2004). "Pharmacogenetic determinants of inter-individual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes". Pharmacogenetics. 14 (4): 225–38. doi:10.1097/00008571-200404000-00002. PMID 15083067.
  99. ^ Preskorn SH (1991). "Should bupropion dosage be adjusted based upon therapeutic drug monitoring?". Psychopharmacol Bull. 27 (4): 637–43. PMID 1813908.
  100. ^ Weintraub D, Linder MW (2000). "Amphetamine positive toxicology screen secondary to bupropion". Depress Anxiety. 12 (1): 53–4. doi:10.1002/1520-6394(2000)12:1<53::AID-DA8>3.0.CO;2-4. PMID 10999247.
  101. ^ Nixon AL, Long WH, Puopolo PR, Flood JG (June 1995). "Bupropion metabolites produce false-positive urine amphetamine results". Clin. Chem. 41 (6 Pt 1): 955–6. doi:10.1093/clinchem/41.6.955. PMID 7768026.
  102. ^ Casey ER, Scott MG, Tang S, Mullins ME (June 2011). "Frequency of false positive amphetamine screens due to bupropion using the Syva EMIT II immunoassay". Journal of Medical Toxicology. 7 (2): 105–8. doi:10.1007/s13181-010-0131-5. PMC 3724447. PMID 21191682.
  103. ^ a b c Sager JE, Choiniere JR, Chang J, Stephenson-Famy A, Nelson WL, Isoherranen N (2016). "Identification and Structural Characterization of Three New Metabolites of Bupropion in Humans". ACS Med Chem Lett. 7 (8): 791–6. doi:10.1021/acsmedchemlett.6b00189. PMC 5026406. PMID 27660681.
  104. ^ Musso, David L.; Mehta, Nariman B.; Soroko, Francis E.; Ferris, Robert M.; Hollingsworth, Elizabeth B.; Kenney, Bernard T. (1993). "Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion". Chirality. 5 (7): 495–500. doi:10.1002/chir.530050704. PMID 8240925.
  105. ^ Perrine DM, Ross JT, Nervi SJ, Zimmerman RH (2000). "A Short, One-Pot Synthesis of Bupropion (Zyban, Wellbutrin)". Journal of Chemical Education. 77 (11): 1479. Bibcode:2000JChEd..77.1479P. doi:10.1021/ed077p1479.
  106. ^ "Wellbutrin approval package" (PDF). U.S. Food and Drug Administration (FDA). 30 December 1985. Retrieved 5 May 2020.
  107. ^ "Wellbutrin entry in the Orange Book". U.S. Food and Drug Administration Center for Drug Evaluation and Research. Archived from the original on 25 February 2011. Retrieved 18 August 2007.
  108. ^ "Bupropion (Wellbutrin)". eMedExpert.com. 31 March 2008. Retrieved 20 August 2013.
  109. ^ a b Whitten L (April 2006). "Bupropion helps people with schizophrenia quit smoking". National Institute on Drug Abuse Research Findings. 20 (5). Archived from the original on 5 August 2007. Retrieved 27 May 2013.
  110. ^ "Drug Approval Package: Wellbutrin XL (Bupropion HCI) NDA #021515". U.S. Food and Drug Administration (FDA). 22 April 2005. Archived from the original on 5 December 2019. Retrieved 4 December 2019.
  111. ^ "Drug Approval Package: Zyban NDA# 020711". U.S. Food and Drug Administration (FDA). 8 August 2003. Archived from the original on 5 December 2019. Retrieved 4 December 2019.
  112. ^ "FDA approval letter" (PDF). U.S. Food and Drug Administration (FDA). 6 December 2006.
  113. ^ "Seasonal affective disorder drug Wellbutrin XL wins approval". CNN. 14 June 2006. Archived from the original on 30 June 2007. Retrieved 19 August 2007.
  114. ^ "Zyban : sevrage tabagique et sécurité d'emploi" [Zyban: smoking cessation and job security] (Press release) (in French). Agence française de sécurité sanitaire des produits de santé. 18 January 2002. Archived from the original on 23 July 2011. Retrieved 25 January 2011.
  115. ^ GlaxoSmithKline (16 January 2007). "GlaxoSmithKline receives first European approval for Wellbutrin XR" (Press release). GlaxoSmithKline. Archived from the original on 27 December 2010. Retrieved 25 January 2011.
  116. ^ "First drug for seasonal depression". FDA Consum. 40 (5): 7. 2006. PMID 17328102.
  117. ^ a b Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  118. ^ a b Joint Formulary Committee (2015). British National Formulary (BNF) (69 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-156-2.
  119. ^ "Generic drug equality questioned". 12 October 2007. Retrieved 13 October 2007.
  120. ^ Stenson J (12 October 2007). "Report questions generic antidepressant". NBC News. Retrieved 13 October 2007.
  121. ^ "Review of therapeutic equivalence: generic bupropion XL 300 mg and Wellbutrin XL 300 mg". Archived from the original on 6 June 2011. Retrieved 19 April 2008.
  122. ^ a b c "Budeprion XL 300 mg not therapeutically equivalent to Wellbutrin XL 300 mg". U.S. Food and Drug Administration (FDA). 3 October 2012. Retrieved 23 March 2013. Public Domain This article incorporates text from this source, which is in the public domain.
  123. ^ Waknine Y (8 May 2008). "FDA Approvals: Advair, Relistor, Aplenzin". Medscape. Retrieved 9 May 2008.
  124. ^ "Drug Approval Package: Aplenzin (Bupropion Hydrobromide) NDA 22108". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 5 May 2020.
  125. ^ "Aplenzin- bupropion hydrobromide tablet, extended release". DailyMed. 2 June 2020. Retrieved 21 October 2020.
  126. ^ "Public Health Advisory: FDA requires new boxed warnings for the smoking cessation drugs Chantix and Zyban". U.S. Food and Drug Administration (FDA). 1 July 2009. Archived from the original on 19 October 2010. Retrieved 3 July 2009.
  127. ^ "The smoking cessation aids varenicline (marketed as Chantix) and bupropion (marketed as Zyban and generics) suicidal ideation and behavior" (PDF). Drug Safety Newsletter. 2 (1): 1–4. 2009. Archived from the original (PDF) on 11 February 2017. Retrieved 16 December 2019.
  128. ^ "Safety Alerts for Human Medical Products - Chantix (varenicline) and Zyban (bupropion): Drug Safety Communication – Mental Health Side Effects Revised". U.S. Food and Drug Administration (FDA). Archived from the original on 20 December 2016. Retrieved 20 December 2016.
  129. ^ Thomas K, Schmidt MS (2 July 2012). "Glaxo agrees to pay $3 billion in fraud settlement". The New York Times.
  130. ^ "EMA recommends suspension of medicines due to unreliable studies from Micro Therapeutic Research Labs | European Medicines Agency".
  131. ^ "Products for which the marketing authorisations are recommended for suspension and marketing authorisation applications which do not satisfy the criteria for authorisation as adopted by the CHMP on 23 March 2017" (PDF).
  132. ^ a b Naglich AC, Brown ES, Adinoff B (2019). "Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential". Am J Drug Alcohol Abuse. 45 (4): 341–354. doi:10.1080/00952990.2018.1545023. PMID 30601027.
  133. ^ Lile JA, Nader MA (2003). "The abuse liability and therapeutic potential of drugs evaluated for cocaine addiction as predicted by animal models". Current Neuropharmacology. 1: 21–46. CiteSeerX 10.1.1.325.9635. doi:10.2174/1570159033360566.
  134. ^ Antidepressant Wellbutrin becomes 'poor man's cocaine' on Toronto streets Global News 18 September 2013.
  135. ^ Phillips D (February 2012). "Wellbutrin®: misuse and abuse by incarcerated individuals". Journal of Addictions Nursing. 23 (1): 65–9. doi:10.3109/10884602.2011.647838. PMID 22468662. S2CID 1310940.
  136. ^ Baribeau D, Araki KF (May–June 2013). "Intravenous bupropion: a previously undocumented method of abuse of a commonly prescribed antidepressant agent". Journal of Addiction Medicine. 7 (3): 216–7. doi:10.1097/ADM.0b013e3182824863. PMID 23519045.
  137. ^ Stassinos GL, Klein-Schwartz W (2016). "Bupropion "Abuse" Reported to US Poison Centers". J Addict Med. 10 (5): 357–62. doi:10.1097/ADM.0000000000000249. PMID 27504927.
  138. ^ a b c "Bupropion International Brands". Drugs.com. Retrieved 1 June 2017.
  139. ^ "Постановление Правительства РФ от 30 июня 1998 г. N 681 "Об утверждении перечня наркотических средств, психотропных веществ и их прекурсоров, подлежащих контролю в Российской Федерации" (с изменениями и дополнениями)" (in Russian). Гарант. Retrieved 28 April 2019. Эфедрон (меткатинон) и его производные, за исключением производных, включенных в качестве самостоятельных позиций в перечень
  140. ^ "Bupropion hydrochloride (marketed as Wellbutrin, Zyban, and generics) Information". U.S. Food and Drug Administration (FDA). Retrieved 14 March 2019. Public Domain This article incorporates text from this source, which is in the public domain.

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