Bupropion

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of the bupropion enantiomers
( S ) -form (top) and ( R ) -form (bottom), 1: 1 stereoisomeric mixture
General
Non-proprietary name Bupropion
other names
  • ( RS ) -1- (3-chlorophenyl) -2- tert -butylamino-propan-1-one ( IUPAC )
  • (±) -1- (3-Chlorophenyl) -2- tert -butylamino-propan-1-one
  • rac -1- (3-chlorophenyl) -2- tert- butylamino-propan-1-one
  • DL -1- (3-chlorophenyl) -2- tert- butylamino-propan-1-one
Molecular formula
  • C 13 H 18 ClNO (bupropion)
  • C 13 H 18 ClNO HCl (bupropion hydrochloride)
External identifiers / databases
CAS number
PubChem 444
DrugBank DB01156
Wikidata Q834280
Drug information
ATC code
Drug class
Mechanism of action

Selective norepinephrine and dopamine reuptake inhibitors

properties
Molar mass
  • 239.74 g · mol -1 (Bupropion)
  • 276,20 g · mol -1 (Bupropion Hydrochloride)
Physical state
  • Oil (bupropion)
  • Solid (bupropion hydrochloride)
Melting point

233–234 ° C (bupropion hydrochloride)

boiling point

52 ° C (0.67 Pa ) (bupropion)

pK s value

7.9 (bupropion hydrochloride)

solubility

Water: 312 mg ml −1 (bupropion hydrochloride)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302
P: no P-phrases
Toxicological data

544 mg kg −1 ( LD 50 ,  mouse ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Bupropion (until 2000 the INN was amfebutamone ) is a medicinal substance that is used to treat depression , to quit smoking and as an anorectic . The active ingredient belongs to the group of amphetamines and is chemically closely related to amfepramone and cathinone .

Bupropion is primarily classified as a selective inhibitor of the reuptake of dopamine and norepinephrine ( NDRI ). The clinical relevance of its dopaminergic effect is increasingly being questioned (see mode of action ).

application areas

depression

Bupropion has been approved in Germany for the treatment of depression under the trade name Elontril since 2007 . In the United States, bupropion has been used as an antidepressant since 1984. Several studies have shown that the effectiveness of bupropion is comparable to the effectiveness of antidepressants from the class of so-called selective serotonin reuptake inhibitors (SSRIs). While bupropion in anxious depression less effective than SSRIs, there are indications that it for increased physical and mental fatigue ( Fatigue ) associated with a depressive syndrome , is more effective can go hand in hand. In terms of response and remission, it works worse than venlafaxine in comparison . Sexual dysfunction, which is common with many SSRIs, is less common with bupropion.

In the second-line therapy after therapy failure of citalopram, bupropion works just as well as buspirone , venlafaxine and sertraline and leads to remission in about a quarter of patients.

In a publication in the New England Journal of Medicine was pointed out that the US approval of SR -Retardformulierung of bupropion (Wellbutrin SR) was based as an antidepressant in three efficacy studies, of which the US Medicines Agency (FDA) two as judged negatively.

Combination therapy

The combination of bupropion with other antidepressants (except citalopram and desipramine ), benzodiazepines (except diazepam ) and neuroleptics has not been systematically studied. Combinations of bupropion with different SSRIs were only carried out in the context of studies on the effect of bupropion on sexual dysfunction caused by SSRIs.

In combination with other antidepressants, bupropion is said to offset some of the side effects of these substances. Unwanted fatigue caused by sedating antidepressants (e.g. mianserin and mirtazapine ) can be counteracted by the stimulating effect of bupropion. To relieve symptoms of tiredness, bupropion is taken at the beginning, the tiring antidepressant at the end of the day. Sleep-promoting or sexually depressant antidepressants can counteract the sleep disorders or priapism triggered by bupropion . Correcting the side effects of other antidepressants is not an approved indication for bupropion.

The idea of ​​improving sexual dysfunction due to the use of other antidepressants by adding bupropion is controversial. However, significant improvement in SSRI- induced sexual dysfunction has been observed in some clinical studies .

Smoking cessation

The substance is approved for smoking cessation and is available in Germany under the name Zyban . A meta-analysis of 31 studies showed that the proportion of patients receiving bupropion treatment who did not smoke for at least six months after treatment was 19%, almost twice as high as that of 10.3% receiving placebo -Treatment. In direct comparison, bupropion is just as effective as nicotine patches . Nicotine patches added to bupropion did not improve the abstinence rate. There is some evidence that bupropion is inferior to varenicline . The therapy is only promising for carriers of a certain gene variant in the cytochrome P450 system, which is widespread among people of European descent: Around 45% of all people of European descent have the genotype CYP2B6 * 6. 33% of the carriers of this gene variant were able to stop smoking with bupropion (in the test subjects who received a placebo, it was only 14%). However, carriers of another gene variant (genotype CYP2B6 * 1) did not benefit from bupropion.

Further indications

Bupropion can be used against ADHD , although the substance has not been approved for it and has not been tested for effectiveness and safety in patients under 18 years of age.

Bupropion can also lead to decreased appetite and weight loss, but was not initially approved for this purpose. In a 48-week, manufacturer-funded study, patients treated with bupropion lost slightly more weight (up to 5.1%) than those who took a dummy drug ( placebo ). That would roughly correspond to the effect of other slimming products . Whether the body weight after discontinuation - as of similar substances like sibutramine known - rises again (yo-yo effect) is not yet clarified. A combination of bupropion and naltrexone has been shown in clinical trials to be an effective weight loss method for obese patients. It has been available in Germany under the brand name Mysimba since 2018 . The benefit-risk ratio was rated as unfavorable in the Deutsche Apothekerzeitung .

history

Bupropion had been approved as an antidepressant in the US since 1984, but was withdrawn in 1986 due to repeated reports of seizures, some of which were fatal. After subsequent additional studies, it was found that seizures are a rare and dose-dependent side effect. As a result, approval in the USA was granted again in 1989 in a lower dose. 1996 was approved by the Food and Drug Administration a (FDA) Retard formulation ( SR, sustained release approved), the twice daily regimen allowed; Then in 2003 one ( XL or XR, extended release ), which allows once a day administration.

In Germany, approval as an antidepressant in a retarded preparation form under the name Elontril was granted on April 2, 2007. Bupropion was used off-label as an antidepressant even before it was officially approved .

In Switzerland, the active ingredient was initially only registered for smoking cessation ( Zyban ). Since December 2007, bupropion has been approved as an antidepressant under the trade name Wellbutrin XR at 150 mg and 300 mg. It was included in the list of specialties and is therefore covered by the basic health insurance. There is a limitation : treatment of depressive episodes; therapy must be initiated by a psychiatrist or neurologist.

pharmacology

Chemically, bupropion is a β-ketoamphetamine derivative and belongs to the group of cathinones . In general, it is assigned to the phenethylamines and there to the subgroup of amphetamines . It is therefore possible that a urinal drug test for amphetamine or methamphetamine will be positive during treatment .

Another subgroup of the phenylethylamines are the catecholamines , which include, for example, the neurotransmitters dopamine , noradrenaline and adrenaline ; bupropion is therefore also closely related to these. However, unlike them and many other amphetamines, it has a ketone group ( functional group ). Substances with a similar effect as Radafaxin were developed on the basis of bupropion . Bupropion is chiral (exists in two mirror-image variants) and is used as a racemate [1: 1 mixture of ( S ) form and ( R ) form].

Mode of action

Based on animal experiments, bupropion was initially characterized as a weak dopamine norepinephrine reuptake inhibitor (NDRI). The ratio of inhibition of reuptake of dopamine to norepinephrine is about 2: 1. However, it has now been established that the active ingredient also causes dopamine and noradrenaline to be released ("norepinephrine and dopamine releasing agent", NDRA).

However, due to its intensive metabolism, the mechanism of action of bupropion cannot be understood without its metabolites. Because these sometimes reach considerably higher concentrations than bupropion itself. Hydroxybupropion z. B. can reach up to 16-20 times the concentration of bupropion.

Several PET studies examined the occupation of the dopamine transporter (DAT) by bupropion in humans, with low values ​​between 14% and 26%. In a follow-up study, the extracellular concentration of dopamine was measured directly after ingestion of bupropion, and there was no increase in the dopamine level. However, an increase could be observed in rats. From this, the researchers concluded that the occupation of the DAT by bupropion in the human brain is probably too weak for a noticeable increase in dopamine concentrations.

Metabolism

Bupropion is in the liver mainly through CYP450 metabolized -2B6. ( R , R ) -hydroxybupropion ( 1 ), ( S , S ) -hydroxybupropion ( 2 ), threo -hydrobupropion ( 3 ) and erythro -hydrobupropion ( 4 ) have been identified as active metabolites . These are further metabolized into inactive metabolites, which are excreted in the urine.

Bupropion metabolites.png

The compound tends to hydrolyze in aqueous media . In a first step, 1- (3-chlorophenyl) -2-hydroxy-1-propanone is formed, which rapidly in three parallel reactions to the secondary products 3-chlorobenzoic acid , 1- (3-chlorophenyl) -1-hydroxy-2-propanone and 1- (3-chlorophenyl) -1,2-propanedione reacted further. The rate of hydrolysis depends on the pH. While practically no hydrolysis is observed at pH values ​​below 5, complete hydrolysis takes place in a few hours in a basic medium. The half-life in blood plasma at 37 ° C is 11.4 hours.

Bupropion hydrolysis.png

Substance properties

Bupropion occurs in two polymorphic crystal forms. Form 1 crystallizes in a monoclinic crystal lattice with the space group P 2 1 / c (space group no. 14) , form 2 in an orthorhombic lattice with the space group Pbca (no. 61) . When heated, form 2 shows an enantiotropic solid phase transition around 220 ° C and changes to form 1. Form 1 melts at 234 ° C. Form 2 is the thermodynamically more stable form at room temperature. Form 1 is metastable and rearranges to Form 2 only slowly when stored at room temperature for a period of one year. Template: room group / 14Template: room group / 61

Manufacturing

The synthesis of bupropion starts from 3-chloropropiophenone, which is brominated in a first step in the α-position to the keto group . This is followed by a nucleophilic substitution reaction with tert- butylamine to give the target compound. The synthesis results in the racemate .

Synthesis of bupropion.png

Interactions

MAO inhibitors must not be used at the same time , as these also act on catecholaminergic metabolic pathways. If alcohol is consumed during treatment, there is evidence of rare neuropsychiatric side effects. The risk of seizures increases with concomitant use of drugs that lower the seizure threshold, such as certain antipsychotics, antidepressants, antimalarials, tramadol , theophylline , systemic steroids , quinolone antibiotics, and sedating antihistamines.

Effect of bupropion on other drugs

Bupropion and its metabolic products inhibit the CYP450 -2D6 metabolic pathway and lead to an increase in the blood level of all tricyclics except doxepin (very strong: desipramine , nortriptyline , strong: clomipramine ) and many SSRIs , the pain reliever tramadol , antipsychotics such as risperidone and thioridazine , Beta blockers such as metoprolol , class 1C antiarrhythmics such as propafenone and flecainide . The citalopram level also rises despite a different metabolic path when taken at the same time. The sedative effect of diazepam is reduced. Simultaneous administration with nicotine patches can lead to an increase in blood pressure.

Effect of other drugs on bupropion

Bupropion itself is metabolized via the cytochrome P450-2B6 to its active metabolite hydroxybupropion. Drugs that affect this metabolic pathway (such as cyclophosphamide, isofosfamide, orphenadrine , ticlopidine, clopidogrel) shift the ratio of bupropion to hydroxybupropion, with an unexplained effect. Caution is advised when used concomitantly with other drugs such as carbamazepine , phenytoin and valproic acid , which are known to interfere with the metabolic pathways. Bupropion should be used with caution with levodopa and amantadine as side effects are increased.

Side effects

Bupropion is very different in its side effect profile from the commonly used antidepressants, because the side effects are mainly the typical side effects of psychostimulants . The most common side effects are dry mouth and insomnia, although the latter can be reduced by avoiding medication at bedtime. Other side effects may include a. be: headache, drowsiness, loss of appetite, joint and muscle pain, tremors, fear, difficulty concentrating, confusion. In addition, bupropion (the medical emergency) can trigger priapism or increase blood pressure and heart rate.

Bupropion can both induce seizures in people who have no history of it, and lower the seizure threshold in people with epilepsy. Overall, however, seizures are a rare and dose-dependent side effect even with this drug. The frequency is given as 0.1% in the dose range up to 450 mg. Only at doses above 600 mg / day does the statistical risk of seizures suddenly increase rapidly.

With prolonged or frequent use, addictive behavior cannot be ruled out. In a study by the Innsbruck University Clinic it was found that around six percent of all test subjects got a "high" feeling from bupropion. However, caffeine in an amount equivalent to two cups of strong coffee produced significantly stronger “pleasant effects” and “high feelings” than 150 mg of sustained-release bupropion in the group of smokers tested .

Particular caution is required in patients prone to psychosis, as bupropion can in rare cases trigger a psychotic phase. This also applies to manic-depressive people, because this active ingredient can trigger what is known as secondary mania. Caution should also be exercised in people with anorexia nervosa (anorexia), as bupropion can worsen anorexia due to the occasional side effect of weight loss.

In contrast to many other antidepressants - especially SSRIs  - bupropion has a much less or no limiting effect on sexual function. This was shown in comparative studies, especially in men, as women are far less prone to sexual dysfunction caused by antidepressants. In studies of venlafaxine , paroxetine , sertraline , escitalopram and fluoxetine , in particular , it was found that, unlike the comparator drugs, bupropion is largely free of side effects on sexual function.

pregnancy and breast feeding period

The safety of bupropion during pregnancy in humans has not been established. The potential risk to humans is unknown. Bupropion should therefore only be taken during pregnancy if absolutely necessary. Bupropion and its metabolites are excreted in breast milk. Mothers should not breast-feed while taking bupropion.

Trade names

Monopreparations

Elontril (D, A), Wellbutrin (A, CH, L), Zyban (D, A, CH), Forfivo XL (USA, 450 mg) and generics, e.g. E.g .: "Bupropion-neuraxpharm"

Combination preparations

Mysimba (D) (with naltrexone )

literature

  • J. Schöpf: Modern antidepressants - changing, combining and augmenting. Steinkopf Verlag, Darmstadt 2003, ISBN 3-7985-1426-7 .
  • Brigitte Woggon : Treatment with psychotropic drugs . 2nd, completely revised and expanded edition. Verlag Hans Huber, Hogrefe, Bern 2005, ISBN 3-456-83538-8 .

Web links

Individual evidence

  1. ↑ a b c d The Merck Index : An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 246.
  2. ↑ a b Bupropion hydrochloride data sheet from Sigma-Aldrich , accessed on March 14, 2011 ( PDF ).
  3. ↑ Entry on bupropion in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  4. ^ WHO Drug Information, Vol. 14, No. 2, 2000; P. 132. (PDF) Retrieved January 15, 2020 .
  5. ↑ a b c Linda P. Dwoskin: Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse Elsevier Science ISBN 978-0-12-420177-4 pp. 177-216
  6. ↑ IQWiG preliminary report A05-20C Bupropion, mirtazapine and reboxetine in the treatment of depression. (PDF) Retrieved January 15, 2020 .
  7. ^ A b Edith Holsboer-Trachsler, Florian Holsboer: Antidepressants. In: Florian Holsboer, Gerhard founder, Otto Benkert (Hrsg.): Handbuch der Psychopharmakotherapie. Springer Verlag, Heidelberg 2008, ISBN 978-3-540-20475-6 , pp. 525-527.
  8. ↑ Maurizio Fava, George I. Papakostas: Antidepressants. In: Theodore A. Stern, Jerrold F. Rosenbaum, Maurizio Fava u. a. (Ed.): Comprehensive Clinical Psychiatry. Mosby Elsevier, Philadelphia, 2008, ISBN 978-0-323-04743-2 , p. 605.
  9. ↑ Papakostas et al. a .: 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. In: J Clin Psychiatry. 69 (8), Aug 2008, pp. 1287-1292. PMID 18605812 .
  10. ↑ M. Fava, AJ Rush, ME Thase, A. Clayton, SM Stahl, JF Pradko, JA Johnston: 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL . In: Prim Care Companion J Clin Psychiatry . tape 7 , no. 3 , 2005, p. 106-113 , PMID 16027765 , PMC 1163271 (free full text).
  11. ^ Website of the STAR * D study (English).
  12. ↑ EH Turner, AM Matthews et al. a .: Selective publication of antidepressant trials and its influence on apparent efficacy. In: N Engl J Med. 358 (3), Jan 17, 2008, pp. 252-260. PMID 18199864 .
  13. ↑ a b c d e f Specialist information Elontril ( Memento of December 6, 2013 in the Internet Archive ), GSK 02/2007.
  14. ↑ PS Masand, AK Ashton, S. Gupta, B. Frank: Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. In: Am J Psychiatry. 158 (5), May 2001, pp. 805-807. PMID 11329407 .
  15. ↑ AH Clayton, JK Warnock, SG Kornstein, R. Pinkerton, A. Sheldon-Keller, EL McGarvey: A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. In: J Clin Psychiatry. 65 (1), Jan 2004, pp. 62-67. PMID 14744170 .
  16. ↑ J. Schöpf: Modern antidepressants - changing, combining and augmenting. Steinkopf Verlag, Darmstadt 2003, ISBN 3-7985-1426-7 .
  17. ↑ Brigitte Woggon : treatment with psychotropic drugs. 2nd, completely revised and expanded edition. Verlag Hans Huber, Hogrefe, Bern 2005, ISBN 3-456-83538-8 .
  18. ↑ PS Masand, AK Ashton, S. Gupta, B. Frank: Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. In: The American Journal of Psychiatry. Volume 158, Number 5, May 2001, pp. 805-807, doi: 10.1176 / appi.ajp.158.5.805 , PMID 11329407 .
  19. ↑ AH Clayton, JK Warnock, SG Kornstein, R. Pinkerton, A. Sheldon-Keller, EL McGarvey: A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. In: The Journal of Clinical Psychiatry. Volume 65, Number 1, January 2004, pp. 62-67, PMID 14744170 .
  20. ↑ Hughes, JR, Stead LF, Lancaster T.: Antidepressants for smoking cessation. In: Cochrane Database of Systematic Reviews. No. 1, 2007, Art. No .: CD000031.
  21. ↑ K. Cahill, LF Stead, T. Lancaster: Nicotine receptor partial agonists for smoking cessation. In: Cochrane Database of Systematic Reviews. No. 1, 2007, Art. No .: CD006103. doi: 10.1002 / 14651858.CD006103.pub2 .
  22. ↑ AM Lee, C. Jepson, E. Hoffmann, L. Epstein, LW Hawk, C. Lerman, RF Tyndale: CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. In: Biological psychiatry. Volume 62, No. 6, September 2007, pp. 635-641, doi: 10.1016 / j.biopsych.2006.10.005 . PMID 17223085 .
  23. ↑ aerzteblatt-studieren.de: Stop smoking: Gene improves the effect of bupropion ( Memento from August 21, 2009 in the Internet Archive ) from September 11, 2007.
  24. ↑ Friedrich Linderkamp, ​​Gerhard Lauth: On the effectiveness of pharmacological and psychotherapeutic therapies in attention deficit / hyperactivity disorder (ADHD) in adulthood . In: behavior therapy . tape 21 , no. 4 , 2011, p. 229-238 , doi : 10.1159 / 000332429 ( karger.com [PDF]).
  25. ↑ Bloodhound Scientist - Sniffing out the latest research at Nutrition Week 2002 ( Memento of the original from September 27, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. at T-Nation ™ . @1@ 2Template: Webachiv / IABot / www.t-nation.com
  26. ↑ JW Anderson, FL Greenway, K. Fujioka, KM Gadde, J. McKenney, PM O'Neil: Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. In: Obesity research. Volume 10, No. 7, July 2002, pp. 633-641, doi: 10.1038 / oby.2002.86 . PMID 12105285 .
  27. ↑ Kishore M Gadde, Glen L Xiong: Bupropion for weight reduction. In: Expert Review of Neurotherapeutics. 7, 2007, p. 17, doi: 10.1586 / 14737175.7.1.17 .
  28. ↑ Orexigen: Bupropion and Naltrexone for the Treatment of Obesity ( Memento of the original from May 4, 2009 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 95 kB). @1@ 2Template: Webachiv / IABot / professional.diabetes.org
  29. ↑ Dangerous diet pill: Pharmacology expert advises against Mysimba in: Deutsche Apothekerzeitung online, February 27, 2018, accessed on August 7, 2020.
  30. ↑ Thomas L. Lemke, David A. Williams: Foye's Principles of Medicinal Chemistry . Lippincott Williams & Wilkins, 2012, ISBN 978-1-60913-345-0 , pp. 611-613 ( google.com ).
  31. ^ Hugo R. Arias, Abel Santamaría, Syed Ali: Pharmacological and Neurotoxicological Actions Mediated By Bupropion and Diethylpropion . Academic Press, Jan 1, 2009, Chapter 9, pp. 223-255 , doi : 10.1016 / s0074-7742 (09) 88009-4 .
  32. ↑ Susan M Learned-Coughlin et al .: In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography . In: Elsevier (Ed.): Biological Psychiatry . tape 54 , no. 8 , October 15, 2003, p. 800-805 , doi : 10.1016 / s0006-3223 (02) 01834-6 .
  33. ↑ Jeffrey H. Meyer et al .: Bupropion occupancy of the dopamine transporter is low during clinical treatment . In: Psychopharmacology . tape 163 , no. 1 , July 13, 2002, p. 102-105 , doi : 10.1007 / s00213-002-1166-3 .
  34. ↑ Allan Tasman et al. a .: Psychiatry , John Wiley & Sons, ISBN 978-1-119-96540-4 .
  35. ↑ WD Horst, SH Preskorn: Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion. In: J. Affect. Disord. 51, 1998, pp. 237-254, doi: 10.1016 / S0165-0327 (98) 00222-5 .
  36. ↑ Benkert, O., 1940-, Hippius, Hanns ,: Compendium of Psychiatric Pharmacotherapy . 12th, completely revised and updated edition. Berlin, Germany 2019, ISBN 978-3-662-57334-1 .
  37. ^ A b P. M. O'Byrne, R. Williams, JJ Walsh, JF Gilmer: The aqueous stability of bupropion. In: J. Pharm. Biomed. Anal. 53, 2010, pp. 376-381. doi: 10.1016 / j.jpba.2010.04.024 .
  38. ↑ SC Laizure, CL DeVane: Stability of bupropion and its major metabolites in human plasma. In: Ther Drug Monit . 7, 1985, pp. 447-450.
  39. ↑ a b c d E. Maccaroni, L. Malpezzi, A. Famulari, N. Masciocchi: Structural and energetic aspects of a new bupropion hydrochloride polymorph. In: J. Pharm. Biomed. Anal. 60, 2012, pp. 65-70. doi: 10.1016 / j.jpba.2011.10.031 .
  40. ↑ NB Mehta: United States Patent 3,819,706: Meta-chloro substituted α-butylamino-propiophenones. USPTO, June 25, 1974, accessed June 2, 2008 .
  41. ↑ DM Perrine, JT Ross, SJ Nervi, RH Zimmerman: A Short, One-Pot Synthesis of Bupropion. In: J. Chem. Ed. 77, 2000, p. 1479. doi: 10.1021 / ed077p1479 .
  42. ↑ Wellbutrin (bupropion) ( Memento from November 8, 2014 in the Internet Archive ) (English) at NAMI .
  43. ↑ Zyban - Side Effects (English) at RxList .
  44. ↑ Yellow list: Elontril ® product information , April 2007.
  45. ↑ Gerald Zernig, Harriet De Wit u. a .: Subjective Effects of Slow-Release Bupropion versus Caffeine as Determined in a Quasi-Naturalistic Setting. In: Pharmacology. 70, 2004, p. 206, doi: 10.1159 / 000075550 .
  46. ↑ Smoking: Addicted to smoking cessation drugs? In: diepresse.com. Retrieved May 28, 2015 .
  47. ↑ ME Thase, AH Clayton, BR Haight, AH Thompson, JG Modell, JA Johnston: A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability. In: J Clin Psychopharmacol . 26 (5), Oct 2006, pp. 482-488. PMID 16974189 .
  48. ↑ SH Kennedy, KA Fulton, RM Bagby, AL Greene, NL Cohen, S. Rafi-Tari: Sexual function during bupropion or paroxetine treatment of major depressive disorder. In: Can J Psychiatry. 51 (4), Mar 2006, pp. 234-242. PMID 16629348 .
  49. ↑ H. Croft, E. Settle Jr, T. Houser, SR Batey, RM Donahue, JA Ascher: A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. In: Clin Ther . 21 (4), Apr 1999, pp. 643-658. PMID 10363731 .
  50. ↑ CC Coleman, LA Cunningham, VJ Foster, SR Batey, RM Donahue, TL Houser, JA Ascher: Sexual dysfunction associated with the treatment of depression: a placebo-controlled comparison of bupropion sustained release and sertraline treatment. In: Ann Clin Psychiatry. 11 (4), Dec 1999, pp. 205-215. PMID 10596735 .
  51. ^ RT Segraves, R. Kavoussi, AR Hughes, SR Batey, JA Johnston, R. Donahue, JA Ascher: Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. In: J Clin Psychopharmacol. 20 (2), Apr 2000, pp. 122-128. PMID 10770448 .
  52. ↑ AH Clayton, HA Croft, JP Horrigan, DS Wightman, A. Krishen, NE Richard, JG Model: Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies. In: J Clin Psychiatry. 67 (5), May 2006, pp. 736-746. PMID 16841623 .
  53. ↑ CC Coleman, BR King, C. Bolden-Watson, MJ Book, RT Segraves, N. Richard, J. Ascher, S. Batey, B. Jamerson, A. Metz: A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine. In: Clin Ther. 23 (7), Jul 2001, pp. 1040-1058. PMID 11519769 .
  54. ↑ Information for professionals of the Swiss Medicines Compendium: Wellbutrin® XR; Status: April 2007.
  55. ↑ Red List, 08/2009.
  56. ↑ AM comp. d. Switzerland, 08/2009.
  57. ↑ AGES-PharmMed, 08/2009.
  58. ↑ IntelGenX.