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Atomoxetine for ADHD

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Atomoxetine for ADHD

Earlier names of atomoxetine were: Tomoxetine, LY139603

Brand name: Strattera; several generics 1

1. Impact path

Atomoxetine requires a flare-up of several weeks, as is known from common antidepressants. It can take up to 6 months until the maximum effect is reached.2

It is sometimes reported that depression may occur during the several-week acclimation period of atomoxetine. This likelihood is higher than with methylphenidate, imipramine, nortriptyline (Nortrilen), or bupropion (Elontril).

1.1. Effect of atomoxetine in the PFC

In the laboratory, atomoxetine appears to act primarily as a norepinephrine (transporter) reuptake inhibitor. The results in vivo differ from this.3

In addition, it should be noted that the noradrenaline transporter can also reuptake dopamine, just as the dopamine transporter can also transport noradrenaline.

Atomoxetine

  • Increases extracellular norepinephrine in the PFC 3-fold45
  • Increases extracellular dopamine in the PFC 3-fold456
  • May also act as a serotonin reuptake inhibitor
    • A study in live monkeys found that atomoxetine addressed the serotonin transporter at about the same strength as the norepinephrine transporter, so atomoxetine also acted as a serotonin reuptake inhibitor.7
  • Increases the expression of the neuronal activity marker Fos in the PFC by 3.7-fold45

The effect of atomoxetine in the PFC explains the improvement in working memory and executive functions.8 A single dose reduces the activity of the vmPFC in relation to reward evaluation9
The noradrenaline increase by atomoxetine in PFC is hardly dose-dependent and therefore very difficult to achieve in a graded manner. The noradrenaline increase by D-amphetamine in PFC, on the other hand, is much more dose-dependent and therefore seems to be much more controllable.6

1.2. No effect of atomoxetine in the striatum/nucleus accumbens

Atomoxetine causes

  • No dopamine increase in the striatum645
  • Therefore no increase in dopamine in the nucleus accumbens645
  • No increase in the expression of the neuronal activity marker Fos in the striatum or nucleus accumbens
  • (as a single dose) did not alter nucleus accumbens activity related to reward expectancy.9
  • Therefore, no improvements on hyperactivity/impulsivity and motivation (drive) are expected via this route of action. Atomoxetine appears to have other pathways with respect to hyperactivity and impulsivity.

1.3. Other areas of influence of atomoxetine

Atomoxetine

  • Has an extremely high affinity for norepinephrine transporters (NET) for reuptake inhibition (much higher than MPH and AMP) and a much lower affinity for dopamine transporters (DAT) than MPH or AMP. DAT are mainly responsible in the striatum for the degradation of dopamine.6 The smaller the inhibition constant Ki, the higher the affinity.
    As we understand it, the extreme NET affinity of atomoxetine makes it difficult to dose, which is difficult anyway due to the very slow onset.
  • Acts as NMDA glutamate receptor antagonist10
  • Does not change the extracellular serotonin level

Consequently, contrary to other assumptions, atomoxetine is not a pure norepinephrine reuptake inhibitor with no effect on dopamine balance.11

1.4. Effect of atomoxetine different from MPH

Methylphenidate

  • Increases extracellular norepinephrine in the PFC (like atomoxetine)4
  • Increases extracellular dopamine in the PFC (like atomoxetine)4
  • Unclear whether MPH increases extracellular dopamine also in the striatum and there in the nucleus accumbens (different from atomoxetine)
    • Increase of extracellular dopamine also in the striatum and there in the nucleus accumbens412
      • MPH responders exhibit increased DAT count in the striatum, whereas MPH nonresponders exhibit decreased DAT count in the striatum 13
    • No dopamine increase in the striatum by MPH14

The nucleus accumbens is part of the striatum, the brain’s reward/reinforcement system, which is involved in ADHD. Therefore, in sufferers with acute addiction problems, atomoxetine may have advantages. If the reward system is impaired, methylphenidate and possibly nicotine (patches) are likely to be more effective.

1.5. Specific mode of action on hyperactivity/impulsivity

Hyperactivity and impulsivity are also caused by overexpression of the Atxn7 gene in the PFC and striatum.15 Atomoxetine was able to resolve the hyperactivity and impulsivity in this case.

Methylphenidate and amphetamine drugs increase the power of alpha in the EEG (in rats), whereas atomoxetine and guanfacine do not.16

1.6. Overview of ATX and neurotransmitters

1.6.1. Binding affinity of ATX, AMP, MPH to DAT / NET / SERT

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes inhibition of the activity of the respective transporters.17

Binding affinity: stronger with smaller number (KD = Ki) DAT NET SERT
MPH 34 - 200 339 > 10,000
d-AMP (Elvanse, Attentin) 34 - 41 23.3 - 38.9 3,830 - 11,000
l-AMP 138 30.1 57,000
ATX 1451 - 1600 2.6 - 5 48 - 77

1.6.2. Effect of ATX, AMP, MPH on dopamine / norepinephrine per brain region

The drugs methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) alter extracellular dopamine (DA) and norepinephrine (NE) differently in different brain regions. Table based on Madras,17 modified.

PFC striatum nucleus accumbens
MPH DA +
NE (+)
DA +
NE +/- 0
DA + NE
+/-


0


AMP DA +
** NE +**
DA +
NE +/- 0
DA + NE
+/-


0


ATX DA +
** NE +**
DA +/- 0
NE +/- 0
DA +/-

0


NE








+/- 0

2. Impact quality

In MPH nonresponders, lisdexamfetamine and atomoxetine were compared in a randomized double-blind trial with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.18

Atomoxetine produces a 3.8-point reduction in ADHD RS-IV total score, compared with 8.9 by guanfacine.19

In affected person forums, quite a few (but not all) atomoxetine users report that atomoxetine only had excellent effects in the first few days, up to a maximum of about 14 days, which then had clearly diminished or disappeared completely. This could repeat itself after dosage increases, even several times.20 We believe that this is a pattern that occurs more often in ADHD with primarily tonic noradrenergic medications and suspect that this indicates that in ADHD in general and in the respective affected individuals in particular, the phasic noradrenaline level is impaired rather than the tonic one.
Phasic is the short-term (stress or exertion occasion-related) altered level of a neurotransmitter or hormone.
Tonic is the permanent level and its typical circadian level changes throughout the day.
Phasic behaves to tonic like waves to swell.

If the long-lasting norepinephrine level is in order, an increase regularly causes receptor downregulation, i.e., a compensatory adjustment of the receptors in the direction of reduced sensitivity.
As an unverified hypothesis, we consider whether intermittent administration (every 2 to 4 days or interruption of administration every 3 days) might prevent such receptor adaptations. Affected individuals in whom atomoxetine has led to such adaptation reactions could discuss this with their physician. Experiments not discussed with the physician are strongly discouraged!

For the efficacy of individual medications and forms of treatment, see Effect size of different forms of treatment for ADHD.

3. Indications for which atomoxetine is suitable / unsuitable

3.1. Nonresponding to stimulants

Atomoxetine is widely believed to be recommended when neither methylphenidate nor amphetamines work, which is reported to be the case in 17%21 to 33%22 of ADHD sufferers. We suggest testing guanfacine beforehand, especially in younger children and in sufferers with hypertension, as guanfacine has a better mean effect size with lower side effects than atomoxetine.
About 50% of sufferers who do not respond to MPH should respond to atomoxetine, and about 75% of sufferers who respond to MPH should also respond to atomoxetine.23

3.2. Comorbid anxiety disorder

Positive effects of atomoxetine on comorbid anxiety disorders have been reported,24 with one study finding slightly greater improvement in anxiety symptomatology with atomoxetine than with MPH.25

3.3. Comorbid social phobia

Positive effects of atomoxetine on comorbid social anxiety have been reported.24

3.4. SCT (sluggish cognitive tempo)

In one study, atomoxetine significantly improved 7 of 9 Kiddie-Sluggish Cognitive Tempo Interview (K-SCT) symptoms in SCT. Symptom improvement in SCT was completely independent of ADHD symptoms.26

SCT sufferers are also particularly frequent MPH nonresponders. In contrast, the ADHD-HI and ADHD-I subtypes do not differ in MPH response rates.27

3.5. Comorbid depression: ATX unsuitable

Atomoxetine does not appear to be suitable for the treatment of comorbid depression.28

When taking SSRIs concomitantly, the possible interaction via CYP2D6 should be noted (see below).

3.6. Comorbid addiction: Preference of ATX disputed

While one opinion favors atomoxetine in comorbid addiction due to the lower risk of abuse, another opinion sees advantages in stimulants due to the faster effect and greater effect size. That stimulants do not increase the risk of addiction in ADHD, but significantly reduce it during use, is now well established according to the updated 2018 European consensus on the diagnosis and treatment of ADHD in adults.28

4. Responding

Atomoxetine produced significant improvements in approximately 45% of sufferers in a placebo study, compared with 58% responders to Concerta (MPH) and 28% to placebo.29

One study examined the EEG structure of atomoxetine responders and nonresponders. According to this study, atomoxetine works better in those who have increased alpha and delta power in the frontal and temporal areas and who, at the same time, have no deviations in the beta and theta bands. In contrast, atomoxetine nonresponders showed decreased absolute power in all EEG frequencies or increased alpha and simultaneously increased beta power. Atomoxetine caused long-term normalization of the elevated alpha and delta values, whereas these remained unchanged in nonresponders. In the case of simultaneously elevated alpha, beta, and theta values, atomoxetine appeared unsuitable.30

About 50% of sufferers who do not respond to MPH should respond to atomoxetine, and about 75% of sufferers who respond to MPH should also respond to atomoxetine.23

5. Side effects

5.1. ATX and blood pressure

Atomoxetine caused an average increase in pulse of 6.4 beats, Concerta (MPH) 3 beats, placebo 0.3 beats.29

Systolic blood pressure increases by an average of 3.7 with atomoxetine, 2.4 with Concerta (MPH), and 1.3 with placebo.29

Diastolic blood pressure increases by an average of 3.8 with atomoxetine, 3.1 with Concerta (MPH), and 0.4 with placebo.29

One large study found no increased risks of serious cardiovascular events such as stroke, heart attack, or arrhythmia for atomoxetine among 2,566,995 children.31

5.2. ATX increases histamine

ATX increases histamine,3233 as do all other known ADHD medications

  • Amphetamine drugs
  • Methylphenidate
  • Modafinil
  • Nicotine
  • Caffeine

Therefore, people with histamine intolerance often have problems by taking ADHD medications.
One ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but could tolerate sustained-release MPH in small doses

5.3. Other side effects of ATX

Atomoxetine produced a weight loss of 0.6, Concerta (MPH) of 0.9, placebo of 1.1 (i.e., a greater loss than ATX and MPH).29
Atomoxetine has been associated with a low rate of serum aminotransferase elevations and with rare cases of acute, clinically apparent liver injury.34

6. Interactions

6.1. Atomoxetine and CYP2D6

Metabolism of atomoxetine by CYP2D6 depends on basic genetic parameters and complicates dosing. A study describes the prediction of atomoxetine plasma levels using simple physiologically based pharmacokinetic models.35

6.1.1. In affected individuals with genetically weak CYP2D6 metabolism

6.1.1.1. Atomoxetine without CYP2D6 inhibitors

Weak CYP2D6 metabolization was found to result in an average of 10-fold atomoxetine blood levels compared with strong CYP2D6 metabolization.
High response to atomoxetine (of 80% according to the manufacturer) with concomitant increased side effects, which, however, usually do not lead to discontinuation of use. Dosing with weak doses (40 mg/day) recommended.36 We recommend even much slower dosing (increments of 8 mg / day, increasing every 4 days).

6.1.1.2. Atomoxetine with concomitant use of CYP2D6 inhibitors

In the case of weak CYP2D6 metabolism, additional intake of CYP2D6 inhibitors did not further increase the already 10-fold increased atomoxetine blood level, since those affected by genetically weak CYP2D6 metabolism do not have CYP2D6 metabolism.36

6.1.2. In sufferers with genetically elevated CYP2D6 metabolism

6.1.2.1. Atomoxetine without CYP2D6 inhibitors

Strong CYP2D6 metabolism without concomitant use of CYP2D6 inhibitors was found to result in reduced atomoxetine blood levels on average compared to weak CYP2D6 metabolism (plasma concentration peak below 200 ng/ml 1-2 hours after ingestion). Low response to atomoxetine (of 60% according to manufacturer). Dose increase may be required, possibly up to over 100 mg/day in adults.36

6.1.2.2. Atomoxetine with concomitant use of CYP2D6 inhibitors

If CYP2D6 metabolism is high and CYP2D6 inhibitors are taken concomitantly, the plasma peak atomoxetine concentration should be monitored after 1-2 hours. CYP2D6 inhibitors may increase aomoxetine blood levels, which increases the likelihood of response as well as the risks of side effects. When CYP2D6 inhibitors are administered alongside atomoxetine in sufferers with genetically elevated CYP2D6 metabolism, atomoxetine blood levels should be monitored regularly.36

6.1.3. CYP2D6 inhibitors

CYP2D6 metabolizes, among others:37

  • Class I antiarrhythmics
  • Beta blocker
  • HT3 receptor antagonists
  • Amphetamine and derivatives
  • Opioids

CYP2D6 inhibitors include:

  • Fluoxetine (strong)3637
  • Paroxetine (strong)3637
    • Paroxetine increased plasma levels of atomoxetine 5.8-fold.38
  • Bupropion (moderate)36
  • Duloxetine (moderate)36
  • Sertraline37; dubious39

7. Long-term effects: No habituation effects of atomoxetine

A meta-analysis of 87 randomized placebo-controlled double-blind trials found no evidence of diminishing effects of methylphenidate, amphetamine medications, atomoxetine, or α2-antagonists with prolonged use.40


  1. Gelbe Liste: Atomoxetin

  2. Kooij, Bijlenga, Salerno, Jaeschke, Bitter, Balázs, Thome, Dom, Kasper, Filipe, Stes, Mohr, Leppämäki, Brugué, Bobes, Mccarthy, Richarte, Philipsen, Pehlivanidis, Niemela, Styr, Semerci, Bolea-Alamanac, Edvinsson, Baeyens, Wynchank, Sobanski, Philipsen, McNicholas, Caci, Mihailescu, Manor, Dobrescu, Krause, Fayyad, Ramos-Quiroga, Foeken, Rad, Adamou, Ohlmeier, Fitzgerald, Gill, Lensing, Mukaddes, Brudkiewicz, Gustafsson, Tania, Oswald, Carpentier, De Rossi, Delorme, Simoska, Pallanti, Young, Bejerot, Lehtonen, Kustow, Müller-Sedgwick, Hirvikoski, Pironti, Ginsberg, Félegeházy, Garcia-Portilla, Asherson (2018): Updated European Consensus Statement on diagnosis and treatment of adult ADHD, European Psychiatrie, European Psychiatry 56 (2019) 14–34, http://dx.doi.org/10.1016/j.eurpsy.2018.11.001, Seite 22, 7.4.4.

  3. Walitza, Romanos, Renner, Gerlach (2016): Psychostimulanzien und andere Arzneistoffe, die zur Behandlung der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) angewendet werden, S. 294, in; Gerlach, Mehler-Wex, Walitza, Warnke (Hrsg,) (2016): Neuro-/Psychopharmaka im Kindes- und Jugendalter: Grundlagen und Therapie.

  4. Bymaster, Katner, Nelson, Hemrick-Luecke, Threlkeld, Heiligenstein, Morin, Gehlert, Perry (2002): Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat: A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder; Neuropsychopharmacology 27, 699–711 (2002); doi:10.1016/S0893-133X(02)00346-9

  5. Stahl (2013): Stahl’s Essential Psychopharmacology, 4. Auflage, Seite 493

  6. Heal, Cheetham, Smith (2009): The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology. 2009 Dec;57(7-8):608-18. doi: 10.1016/j.neuropharm.2009.08.020.

  7. Ding, Naganawa, Gallezot, Nabulsi, Lin, Ropchan, Weinzimmer, McCarthy, Carson, Huang, Laruelle (2014): Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD. Neuroimage. 2014 Feb 1;86:164-71. doi: 10.1016/j.neuroimage.2013.08.001. PMID: 23933039.

  8. Callahan, Plagenhoef, Blake, Terry (2019): Atomoxetine improves memory and other components of executive function in young-adult rats and aged rhesus monkeys. Neuropharmacology. 2019 Sep 1;155:65-75. doi: 10.1016/j.neuropharm.2019.05.016.

  9. Suzuki, Ikeda, Tateno, Okubo, Fukayama, Suzuki (2019): Acute Atomoxetine Selectively Modulates Encoding of Reward Value in Ventral Medial Prefrontal Cortex. J Nippon Med Sch. 2019;86(2):98-107. doi: 10.1272/jnms.JNMS.2019_86-205.

  10. Ludolph, Udvardi, Schaz, Henes, Adolph, Weigt, Fegert, Boeckers, Föhr (2010): Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations; Br J Pharmacol. 2010 May; 160(2): 283–291.; doi: 10.1111/j.1476-5381.2010.00707.x; PMCID: PMC2874851; PMID: 20423340

  11. anders z.B.: Prox-Vagedes, Ohlmeier in Ohlmeier, Roy (Hrsg.) (2012): ADHS bei Erwachsenen – Ein Leben in Extremen, Kapitel 5: Die Suche nach dem Rausch: Substanzabhängigkeit bei ADHS, Seite 101

  12. Steinhausen, Rothenberger, Döpfner (2010): Handbuch ADHS, Seite 84, 85

  13. Krause et al. 2005

  14. Takamatsu, Hagino, Sato, Takahashi, Nagasawa, Kubo, Mizuguchi, Uhl, Sora, Ikeda (2015): Improvement of Learning and Increase in Dopamine Level in the Frontal Cortex by Methylphenidate in Mice Lacking Dopamine Transporter; 1 Curr Mol Med. 2015 Mar; 15(3): 245–252. doi: 10.2174/1566524015666150330144018, PMCID: PMC5384353

  15. Dela Peña, Botanas, de la Peña, Custodio, Dela Peña, Ryoo, Kim, Ryu, Kim, Cheong (2018): The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 17;88:311-319. doi: 10.1016/j.pnpbp.2018.08.012.

  16. Takahashi, Ohmiya, Honda, Ni (2018): The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder. PLoS One. 2018 Nov 21;13(11):e0207750. doi: 10.1371/journal.pone.0207750. eCollection 2018.

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  18. Nagy, Häge, Coghill, Caballero, Adey, Anderson, Sikirica, Cardo (2015): Functional outcomes from a head-to-head, randomized, double-blind trial of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder and an inadequate response to methylphenidate.Eur Child Adolesc Psychiatry. 2016 Feb;25(2):141-9. doi: 10.1007/s00787-015-0718-0. n = 200

  19. Guanfacin, Wirkstoff Aktuell, Ausgabe 2/2016, Stand 11.04.2015, Information der KBV, randomisierte placebokontrollierte Doppelblindstudie mit n = 337

  20. z.B. unter http://www.adhs-anderswelt.de/viewtopic.php?f=39&t=57585

  21. Arnold: Journal of Attention Disorders Vol. 3(4):200-211 (2000) Methylphenidate vs. amphetamine: Comparative review

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  24. Kooij, Bijlenga, Salerno, Jaeschke, Bitter, Balázs, Thome, Dom, Kasper, Filipe, Stes, Mohr, Leppämäki, Brugué, Bobes, Mccarthy, Richarte, Philipsen, Pehlivanidis, Niemela, Styr, Semerci, Bolea-Alamanac, Edvinsson, Baeyens, Wynchank, Sobanski, Philipsen, McNicholas, Caci, Mihailescu, Manor, Dobrescu, Krause, Fayyad, Ramos-Quiroga, Foeken, Rad, Adamou, Ohlmeier, Fitzgerald, Gill, Lensing, Mukaddes, Brudkiewicz, Gustafsson, Tania, Oswald, Carpentier, De Rossi, Delorme, Simoska, Pallanti, Young, Bejerot, Lehtonen, Kustow, Müller-Sedgwick, Hirvikoski, Pironti, Ginsberg, Félegeházy, Garcia-Portilla, Asherson (2018): Updated European Consensus Statement on diagnosis and treatment of adult ADHD, European Psychiatrie, European Psychiatry 56 (2019) 14–34, http://dx.doi.org/10.1016/j.eurpsy.2018.11.001, Seite 22, 7.4.4.

  25. Snircova, Marcincakova-Husarova, Hrtanek, Kulhan, Ondrejka, Nosalova (2016): Anxiety reduction on atomoxetine and methylphenidate medication in children with ADHD. Pediatr Int. 2016 Jun;58(6):476-81. doi: 10.1111/ped.12847. PMID: 26579704. n = 69

  26. McBurnett, Clemow, Williams, Villodas, Wietecha, Barkley (2017): Atomoxetine-Related Change in Sluggish Cognitive Tempo Is Partially Independent of Change in Attention-Deficit/Hyperactivity Disorder Inattentive Symptoms. J Child Adolesc Psychopharmacol. 2017 Feb;27(1):38-42. doi: 10.1089/cap.2016.0115. n = 124; this article is a reaction to the criticism of Yang, Li (2014): Could atomoxetine improve sluggish cognitive tempo symptoms? J Child Adolesc Psychopharmacol. 2014 Oct;24(8):462. doi: 10.1089/cap.2014.0052. PMID: 25285785, in which the original article Wietecha, Williams, Shaywitz, Shaywitz, Hooper, Wigal, Dunn, McBurnett (2013): Atomoxetine improved attention in children and adolescents with attention-deficit/hyperactivity disorder and dyslexia in a 16 week, acute, randomized, double-blind trial. J Child Adolesc Psychopharmacol. 2013 Nov;23(9):605-13. doi: 10.1089/cap.2013.0054. had been criticized for a failure to exclude ADHD symptoms from the evaluation of the effect of atomoxetine on SCT symptoms.

  27. Froehlich, Becker, Nick, Brinkman, Stein, Peugh, Epstein (2018): Sluggish Cognitive Tempo as a Possible Predictor of Methylphenidate Response in Children With ADHD: A Randomized Controlled Trial. J Clin Psychiatry. 2018 Feb 27;79(2). pii: 17m11553. doi: 10.4088/JCP.17m11553.

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  29. Newcorn, Kratochvil, Allen, Casat, Ruff, Moore, Michelson, (2008): Atomoxetine and Osmotically Released Methylphenidate for the Treatment of Attention Deficit Hyperactivity Disorder: Acute Comparison and Differential Response, Am J Psychiatry 165:721-730; n = 516

  30. Chiarenza, Chabot, Isenhart, Montaldi, Chiarenza, Torto, Prichep (2016): The quantified EEG characteristics of responders and non-responders to long-term treatment with atomoxetine in children with attention deficit hyperactivity disorders. Int J Psychophysiol. 2016 Jun;104:44-52. doi: 10.1016/j.ijpsycho.2016.04.004.

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