Transporters fpr norepinephrine (NE), serotonin (5-HT) and dopamine (DA); SNRI/selective noradrenaline reuptake inhibitor

The human heart sodium channel (hNav1.5) is interacting with tomoxetine (1-100 µM; 0.5-20 sec; tsA201 cells) in a state- and dose-dependent way [2].

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Atomoxetine Hydrochloride is the hydrochloride salt of atomoxetine, a phenoxy-3-propylamine derivative and selective non-stimulant, norepinephrine reuptake inhibitor with cognitive-enhancing activity. Although its precise mechanism of action is unknown, atomoxetine appears to selectively inhibit the pre-synaptic norepinephrine transporter, resulting in inhibition of the presynaptic reabsorption of norepinephrine and prolongation of norepinephrine activity in the synaptic cleft. The effect on cognitive brain function may result in improved attention and decreased impulsivity and activity levels.

Tomoxetine (0.3-3 mg/kg; i.p.; 0-4 hours; male Sprague-Dawley rats) increases extracellular norepinephrine and dopamine 3-fold and increases intracellular Expression of Fos[1]. Tomoxetine (0.1-5 mg/kg; intraperitoneal injection and oral administration; for 14 days; spontaneously hypertensive rats) can improve ADHD-related behaviors in rats [3].

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Atomoxetine (ATX) is a commonly used non-stimulant treatment for Attention deficit hyperactivity disorder (ADHD). It primarily acts to increase noradrenalin levels; however, at higher doses it can increase dopamine levels. To date there has been no investigations into the effects of orally-administered ATX in the most commonly used model of ADHD, the spontaneously hypertensive rat (SHR). The aim of this study was to describe the effects of doses thought to be selective (0.15 mg/kg) and non-selective (0.3 mg/kg) for noradrenalin on behavioural measures in the SHR. Firstly, we examined the effects of acute and chronic ATX on locomotor activity including sensitisation and cross-sensitisation to amphetamine. Secondly, we measured drug effects on impulsivity using a T-maze delay discounting paradigm. We found no effect of ATX on locomotor activity and no evidence for sensitisation or cross-sensitisation. Furthermore, there were no differences in T-maze performance, indicating no effects on impulsivity at these doses. The absence of behavioural sensitisation supports previous claims of superior safety relative to psychostimulants for the doses administered. There was also no effect on impulsivity; however, we suggest that was confounded by stress specific to SHRs. Implications for future studies, behavioural assessment of SHRs and their use as a model of ADHD are discussed[1].

Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2-3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties[2].

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rat [1]
Doses: 0.3, 1 and 3 mg/kg
Route of Administration: intraperitoneal (ip) injection; 4 hrs (hrs (hours))
Experimental Results: The number of cells expressing Fos-like immunoreactivity increased 3.7-fold in the PFC, extracellular Norepinephrine and dopamine increase 3-fold.

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Animal/Disease Models: Spontaneously hypertensive rat (SHR) [3]
Doses: 0.1, 0.3, 1.25 and 5.0 mg/kg
Route of Administration: intraperitoneal (ip) injection and oral administration; continued for 14 days
Experimental Results: No effect on measurements of locomotor activity.

Absorption, Distribution and Excretion
The pharmacokinetic characteristics of atormoxetine are highly dependent on individual cytochrome P450 2D6 gene polymorphisms. A significant proportion of the population (up to 10% of Caucasians, 2% of African Americans, and 1% of Asians) are poor metabolizers (PMs) of CYP2D6-metabolized drugs. Compared to individuals with normal CYP2D6 activity, these individuals have reduced activity in this metabolic pathway, resulting in a 10-fold higher AUC, a 5-fold higher peak plasma concentration, and a slower elimination rate (plasma half-life of 21.6 hours). After oral administration, atormoxetine is rapidly absorbed, with an absolute bioavailability of approximately 63% in vigorous metabolizers (EMs) and approximately 94% in poor metabolizers (PMs). The mean maximum plasma concentration (Cmax) is reached approximately 1 to 2 hours after administration, with a maximum concentration of 350 ng/ml and an AUC of 2 mcg·h/ml. Atomoxetine is primarily excreted as 4-hydroxyatoromoxetine-O-glucuronide, mainly in the urine (over 80% of the dose) and a small amount in the feces (less than 17% of the dose). Only a small amount (less than 3%) of atoromoxetine is excreted unchanged, indicating extensive biotransformation. The volume of distribution (VOD) of orally administered atoromoxetine is 1.6–2.6 L/kg. The steady-state VOD of intravenously administered atoromoxetine is approximately 0.85 L/kg. The clearance of atoromoxetine depends on individual CYP2D6 gene polymorphism, ranging from 0.27–0.67 Lh/kg. Steady-state VOD (intravenous administration): 8.5 L/kg. Atomoxetine is primarily distributed in body fluids; after standardization to body weight, the VOD is similar among patients of different weights.
Atomoxetine is rapidly absorbed after oral administration, with an absolute bioavailability of approximately 63% in fast metabolizers and approximately 94% in slow metabolizers. Maximum plasma concentration (Cmax) is reached approximately 1 to 2 hours after administration.
/Milk/ Atomoxetine and/or its metabolites are distributed in rat milk; it is currently unknown whether the drug is distributed in human milk.
…Atomoxetine has high water solubility and biomembrane permeability, enabling rapid and complete absorption after oral administration. Its absolute oral bioavailability ranges from 63% to 94%, primarily influenced by the degree of first-pass metabolism. Systemic clearance of atormoxetine involves three oxidative metabolic pathways: aromatic ring hydroxylation, benzylic hydroxylation, and N-demethylation. Aromatic ring hydroxylation produces the major oxidative metabolite of atormoxetine, 4-hydroxyatormoxetine, which is subsequently glucuronidated and excreted in the urine. The formation of 4-hydroxyatormoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two groups of individuals: those with high metabolic capacity (CYP2D6 fast metabolizers) and those with low metabolic capacity (CYP2D6 slow metabolizers). The oral bioavailability and clearance of atormoxetine are influenced by CYP2D6 activity; however, plasma pharmacokinetic parameters are predictable for both fast and slow metabolizers. Following a single oral dose, atormoxetine reaches peak plasma concentrations approximately 1–2 hours after administration. The plasma half-life is 5.2 hours for fast metabolizers and 21.6 hours for slow metabolizers. The systemic plasma clearance of atormoxetine is 0.35 L/h/kg for fast metabolizers and 0.03 L/h/kg for slow metabolizers. Correspondingly, the mean steady-state plasma concentration is approximately 10 times higher in slow metabolizers than in fast metabolizers. After multiple doses, atormoxetine accumulates in the plasma of slow metabolizers, while almost no accumulation occurs in fast metabolizers. The volume of distribution is 0.85 L/kg, indicating that atormoxetine is distributed in systemic water in both rapid and slow metabolizers. Atomoxetine is highly bound to plasma albumin (approximately 99% plasma binding). Although steady-state concentrations of atormoxetine are higher in slow metabolizers than in rapid metabolizers after administration of the same mg/kg/day dose, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype. Administration of atormoxetine does not inhibit or induce the clearance of other drugs metabolized by CYP enzymes. In rapid metabolizers, potent and selective CYP2D6 inhibitors reduce the clearance of atormoxetine. However, the use of CYP inhibitors in individuals with impaired metabolic capacity does not affect the steady-state plasma concentrations of atormoxetine. For more complete data on the absorption, distribution, and excretion of atormoxetine (8 drugs in total), please visit the HSDB record page.

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Metabolism/Metabolites
Atomoxetine is primarily biotransformed via the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. Plasma concentrations of atormoxetine are higher in individuals with reduced CYP2D6 activity (also known as impaired metabolizers or PM) than in those with normal CYP2D6 activity (also known as enhanced metabolizers or EM). In impaired metabolizers, the steady-state AUC of atormoxetine is approximately 10 times that of enhanced metabolizers, and the Cmax is approximately 5 times that of enhanced metabolizers. Regardless of CYP2D6 status, the major oxidative metabolite is 4-hydroxyatormoxetine, which is rapidly glucuronidated. 4-hydroxyatormoxetine has comparable potency as a norepinephrine transporter inhibitor to atormoxetine, but its plasma concentration is significantly lower (1% of atormoxetine concentration in rapid metabolizers and 0.1% in slow metabolizers). In individuals lacking CYP2D6 activity, 4-hydroxyatormoxetine remains the major metabolite, but it is produced by several other cytochrome P450 enzymes at a slower rate. Another minor metabolite, N-demethylatormoxetine, is produced by CYP2C19 and other cytochrome P450 enzymes, but its pharmacological activity is far lower than that of atormoxetine, and its plasma concentration is also lower (5% of atormoxetine concentration in fast metabolizers and 45% in slow metabolizers). Atomoxetine is primarily metabolized via the CYP2D6 enzymatic pathway. Plasma concentrations of atormoxetine are higher in individuals with reduced activity in this pathway (slow metabolizers) than in individuals with normal activity (fast metabolizers). For slow metabolizers, the AUC of atormoxetine is approximately 10 times that of fast metabolizers, and the Css,max is approximately 5 times that of fast metabolizers. Laboratory detection methods are currently available to identify CYP2D6 slow metabolizers. Regardless of the CYP2D6 state, the main oxidative metabolite produced is 4-hydroxyatormoxetine, which is glucuroninated. 4-Hydroxyatormoxetine is comparable to atormoxetine as a norepinephrine transporter inhibitor, but its plasma concentration is much lower (1% of atormoxetine concentration in rapid metabolizers (EM) and 0.1% in slow metabolizers (PM)). 4-Hydroxyatormoxetine is primarily produced by CYP2D6, but in slow metabolizers, several other cytochrome P450 enzymes can also produce it at a slower rate. N-Desmethylatormoxetine is produced by CYP2C19 and other cytochrome P450 enzymes, but its pharmacological activity is much lower than that of atormoxetine, and its plasma concentration is also lower (5% of atormoxetine concentration in rapid metabolizers and 45% in slow metabolizers).
It has been confirmed that the polymorphic cytochrome P450 2D6 (CYP2D6) plays a crucial role in the pharmacokinetics of atormoxetine hydrochloride [(-)-N-methyl-γ-(2-methylphenoxy)amphenicol hydrochloride; LY139603] after single and multiple administrations. This study evaluated the effects of CYP2D6 polymorphism on the overall distribution and metabolism of 20 mg of 14C-atormoxetine in subjects with CYP2D6 rapid metabolizers (EM; n = 4) and slow metabolizers (PM; n = 3) under steady-state conditions. Atormoxetine is well absorbed from the gastrointestinal tract and is primarily eliminated through metabolism, with the majority of the radioactive material excreted in the urine. In rapid metabolizers, the majority of the radioactive dose was eliminated within 24 hours, while in slow metabolizers, the majority was eliminated within 72 hours. The biotransformation of atormoxetine was similar in all subjects, involving aromatic ring hydroxylation, benzylic oxidation, and N-demethylation. No CYP2D6 phenotype-specific metabolites were found. The major oxidative metabolite of atormoxetine was 4-hydroxyatormoxetine, which subsequently conjugated with glucuronic acid to form 4-hydroxyatormoxetine-O-glucuronide. Due to the lack of CYP2D6 activity, the systemic exposure time to radioactive material was prolonged in PM subjects (half-life t_1/2 = 62 hours) compared to EM subjects (t_1/2 = 18 hours). In EM subjects, atormoxetine (t_1/2 = 5 h) and 4-hydroxyatormoxetine-O-glucuronide (t_1/2 = 7 h) were the major circulating drugs, while in PM subjects, atormoxetine (t_1/2 = 20 h) and N-desmethylatormoxetine (t_1/2 = 33 h) were the major circulating drugs. Despite differences observed in metabolite excretion and relative abundance, the main difference between EM and PM subjects lay in the rate of bioconversion of atormoxetine to 4-hydroxyatormoxetine. Atomoxetine was primarily excreted as 4-hydroxyatormoxetine-O-glucuronide, mainly in the urine (over 80% of the dose) and a small amount in the feces (less than 17% of the dose). Only a small fraction of the Strattera dose was excreted unchanged as atormoxetine (less than 3% of the dose), indicating extensive bioconversion. For more complete data on the metabolism/metabolites of atormoxetine (8 metabolites), please visit the HSDB record page. Atomoxetine is primarily metabolized to 4-hydroxyatormoxetine via the CYP2D6 pathway. 4-Hydroxyatormoxetine is comparable in potency to atormoxetine as a norepinephrine transporter inhibitor, but its plasma concentrations are significantly lower (1% of atormoxetine in fast metabolizers and 0.1% in slow metabolizers). Half-life: 5 hours. The reported half-life depends on individual CYP2D6 gene polymorphisms and ranges from 3 to 5.6 hours. The plasma elimination half-life in normal (fast metabolizer) individuals is approximately 5 hours. In individuals with reduced metabolic capacity (7% Caucasians and 2% Blacks), plasma drug concentrations are significantly elevated, with an elimination half-life of 24 hours. In adult rapid metabolizers (EM), the mean apparent plasma clearance of atormoxetine after oral administration was 0.35 L/hr/kg, with a mean half-life of 5.2 hours. In slow metabolizers (PM), the mean apparent plasma clearance was 0.03 L/hr/kg, with a mean half-life of 21.6 hours. The AUC of atormoxetine in slow metabolizers was approximately 10 times that in rapid metabolizers, and the Css,max was approximately 5 times that in rapid metabolizers. In rapid metabolizers (EM), the elimination half-life of 4-hydroxyatormoxetine was similar to that of N-desmethylatormoxetine (6 to 8 hours), while in slow metabolizers (PM), the half-life of N-desmethylatormoxetine was much longer (34 to 40 hours). ...In rapid metabolizers, the plasma half-life of atormoxetine was 5.2 hours, while in slow metabolizers, it was 21.6 hours. ...
...Twenty-one patients with cytochrome P450 2D6 rapid metabolizer status participated in these single-dose and steady-state pharmacokinetic evaluations. Atormoxetine is rapidly absorbed, reaching peak plasma concentrations 1 to 2 hours after administration. The mean half-life after a single dose and at steady state were 3.12 hours and 3.28 hours, respectively. ...

Toxicity Summary
Identification and Use: Atomoxetine (brand name: Strattera) is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). Human Exposure and Toxicity: In short-term studies in children or adolescents with ADHD, atomoxetine increased the risk of suicidal ideation. Acute or chronic overdose of atomoxetine may be accompanied by gastrointestinal symptoms, somnolence, dizziness, tremor, behavioral abnormalities, hyperactivity, agitation, and signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, elevated blood pressure, dilated pupils, dry mouth). Less commonly, QT interval prolongation and altered mental status, including disorientation and hallucinations, have been reported. Atomoxetine may cause clinically significant hepatotoxicity through metabolic-specific reactions or by inducing autoimmune hepatitis. There have been reports of death resulting from combined overdose of atomoxetine (Stratera) and at least one other medication. Sudden death, stroke, and myocardial infarction have been reported in children and adults with structural heart abnormalities or other serious heart conditions. Animal studies: The estimated median lethal dose (LD50) of atormoxetine hydrochloride in animals via oral administration is: 25 mg/kg for cats, >37.5 mg/kg for dogs, and 0.190 mg/kg for rats and mice. Prodromal symptoms of atormoxetine toxicity following a single oral dose in animals include mydriasis and decreased pupillary light reflex, mucus in stool, salivation, vomiting, ataxia, tremor, myoclonus, and convulsions. Chronic toxicity studies were conducted in adult rats and dogs for up to one year. No major target organ toxicity was observed in dogs at oral doses up to 16 mg/kg/day, or in rats with a time-weighted average dose of up to 47 mg/kg/day when atormoxetine was added to their diet. These doses are 4–5 times the maximum recommended daily oral dose for adults. Mild hepatotoxicity was observed in male rats at a time-weighted average dose ≥14 mg/kg/day, manifested as mottled and pale liver, increased relative liver weight, hepatocyte vacuolation, and a slight increase in serum ALT levels. No hepatotoxicity was observed in dogs. Dogs exhibited clinical signs such as dilated pupils, decreased pupillary light reflex, vomiting, and tremors, but these symptoms were milder in adult dogs at daily doses ≥8 mg/kg. During organogenesis, oral administration of atormoxetine hydrochloride to rabbits and rats at doses up to 100 mg/kg/day and 150 mg/kg/day (13 times the maximum recommended daily oral dose for adults) did not reveal evidence of drug-related teratogenicity or fetal growth retardation. In a rat fertility study, decreased pup weight and survival were observed, primarily occurring in the first week postpartum, following a time-weighted average dose of atormoxetine ingested by the mother of 23 mg/kg/day or higher. Atomoxetine hydrochloride showed negative results in a series of genotoxicity studies, including the Ames test (reverse point mutation assay), in vitro mouse lymphoma assay, Chinese hamster ovary cell chromosomal aberration assay, rat hepatocyte unplanned DNA synthesis assay, and mouse in vivo micronucleus assay. However, a slight increase in the proportion of bichromosomal cells was observed in Chinese hamster ovary cells, suggesting internal duplication (chromosomal number abnormality). In rats and mice, no carcinogenicity was observed after two consecutive years of dietary administration of atormoxetine hydrochloride at a weighted average dose of up to 47 and 458 mg/kg/day, respectively. The exact mechanism of action of atormoxetine in treating attention deficit hyperactivity disorder (ADHD) is unclear, but in vitro studies suggest its action may be related to selective inhibition of presynaptic norepinephrine transporters. Atormoxetine appears to have very low affinity for other norepinephrine receptors or other neurotransmitter transporters or receptors. Interactions Atomoxetine should be used with caution in patients receiving systemic (oral or intravenous) salbutamol (or other β2-receptor agonists) therapy, as salbutamol may enhance cardiovascular effects, leading to increased heart rate and blood pressure. Salbutamol (600 mcg, intravenously, over 2 hours) can cause increased heart rate and blood pressure. Atomoxetine (60 mg twice daily for 5 days) enhances these effects, and is most pronounced after the first concurrent use of salbutamol and atomoxetine. However, another study in 21 healthy Asian subjects (excluded due to poor metabolic capacity) did not observe these effects on heart rate and blood pressure after concurrent inhalation of salbutamol (200-800 mcg) and atomoxetine (80 mg once daily for 5 days). The manufacturer states that atomoxetine is contraindicated in patients currently receiving or recently (within 2 weeks) receiving monoamine oxidase (MAO) inhibitor therapy. Furthermore, at least a 2-week interval should be maintained after discontinuing atomoxetine before initiating MAO inhibitor therapy. Patients receiving other medications that affect the concentration of monoamine neurotransmitters in the brain, especially when concurrently taking monoamine oxidase inhibitors (MAO inhibitors), have been reported to have experienced severe and even fatal reactions (including high fever, muscle rigidity, myoclonus, autonomic dysfunction with rapid fluctuations in vital signs, and altered mental status, such as extreme agitation, which can progress to delirium and coma). When atormoxetine is used concomitantly with drugs that inhibit the activity of the cytochrome P-450 2D6 (CYP2D6) isoenzyme, pharmacokinetic interactions may occur (slowing atormoxetine metabolism). CYP2D6 inhibitors can increase plasma atormoxetine concentrations in fast-metabolizing patients to levels similar to those in slow-metabolizing patients. When atormoxetine is used in combination with potent CYP2D6 inhibitors (such as paroxetine, fluoxetine, quinidine), or in patients with impaired CYP2D6 isoenzyme metabolism, the manufacturer recommends considering dose adjustments for atormoxetine. However, in vitro studies have shown that co-administration of atormoxetine with CYP2D6 inhibitors does not increase plasma atormoxetine concentrations in patients with impaired CYP2D6 metabolism.
There may be potential drug interactions (enhanced hypertension) when atormoxetine is used co-administered with vasopressors (e.g., dopamine, dobutamine). Use with caution.
For more complete data on drug interactions of atormoxetine (6 in total), please visit the HSDB record page.

[1]. Effects of atomoxetine on locomotor activity and impulsivity in the spontaneously hypertensive rat. Behav Brain Res. 2013 Apr 15;243:28-37.

[2]. Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner. Front Pharmacol. 2021 Feb 25;12:622489.

[3]. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology. 2002 Nov;27(5):699-711.

Therapeutic Uses

Adrenergic Reuptake Inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Atomoxetine is listed in the database.
Atomoxetine (Stratera) is indicated for the treatment of attention deficit hyperactivity disorder (ADHD). /Included in US Product Labelling/
/Exploratory Treatment/ /The purpose of this study is to/observe the efficacy and safety of atormoxetine hydrochloride in the treatment of childhood narcolepsy. This study included 66 patients with narcolepsy who met the diagnostic criteria of the International Classification of Sleep Disorders (ICSD-2) and received atormoxetine hydrochloride between November 2010 and December 2014. There were 42 males and 24 females, with a mean age of onset of 7.5 years (range 3.75–13.00 years) and a mean duration of illness of 1.75 years (range 0.25–5.00 years). Each patient underwent complete blood count, liver and kidney function tests, multiple sleep latency tests (MSLT), polysomnography (PSG), neuroimaging, and electroencephalography (EEG). Some children also underwent HLA-DR2 gene testing and serum infection marker testing. The 66 patients were followed up for 2 to 49 months (mean 18 months) to observe clinical efficacy and adverse reactions. Of the 62 patients, daytime sleepiness improved, with 11 (16.7%) showing improvement, 29 (43.9%) showing significant improvement, and 22 (33.3%) showing improvement. Of the 54 patients, sudden collapse occurred, with 18 (33.3%) showing improvement, 19 (35.2%) showing significant improvement, and 10 (18.5%) showing improvement. Of the 55 patients with nocturnal sleep disturbances, 47 showed symptom improvement, 14 (25.5%) had symptom control, 20 (36.4%) showed significant treatment efficacy, and 13 (23.6%) showed effective treatment. Thirteen patients experienced hypnagogic or waking hallucinations, with only 4 experiencing symptom control. Four patients developed sleep paralysis, with only 1 experiencing control. Eighteen patients showed improved attention and learning efficiency. Eighteen patients experienced anorexia, five experienced mood disorders, and two experienced depression. One patient each experienced nocturia, muscle tremors, and involuntary tongue movements. One patient experienced prolonged PR interval and premature atrial contractions. Atormoxetine hydrochloride is effective for excessive daytime sleepiness, cataplexy, and nocturnal sleep disturbances in patients with narcolepsy, but its efficacy against hallucinations and sleep paralysis is not significant. Adverse reactions are mild, with anorexia and mood disorders being relatively common. As a non-central nervous system stimulant, atomoxetine hydrochloride does not cause drug dependence and has no prescription restrictions; it is well-tolerated, safe, and effective, and can be considered a good alternative for the treatment of childhood narcolepsy. For more complete data on the therapeutic uses of atomoxetine (6 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Suicidal ideation in children and adolescents. In short-term studies in children or adolescents with attention deficit/hyperactivity disorder (ADHD), atomoxetine (Strattera) increased the risk of suicidal ideation. Anyone considering the use of atomoxetine in children or adolescents must weigh this risk against clinical need. ADHD comorbid with other conditions may increase the risk of suicidal ideation and/or behavior. Patients starting treatment should be closely monitored for suicidal tendencies (suicidal thoughts and behaviors), worsening of clinical symptoms, or changes in unusual behavior. Family members and caregivers should be informed of the need for close monitoring and communication with the prescribing physician. Atomoxetine (Stratera) is approved for the treatment of ADHD in children and adults. Atomoxetine is not approved for the treatment of major depressive disorder. A pooled analysis of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine in children and adolescents (12 trials involving more than 2,200 patients, 11 for ADHD and 1 for enuresis) showed that patients in the atomoxetine group had a higher risk of suicidal ideation early in treatment compared to the placebo group. The mean risk of suicidal ideation was 0.4% in patients receiving atomoxetine (5 out of 1,357 patients), while no suicidal ideation was observed in the placebo group (851 patients). No suicide events occurred in these trials. Post-marketing reports indicate that atomoxetine may cause serious liver injury. Although no evidence of liver injury was detected in clinical trials involving approximately 6,000 patients, there have been rare, clinically significant cases of liver injury in post-marketing experience that are considered possibly or suspected to be related to atomoxetine use. In addition, there have been rare reports of liver failure, including one case that ultimately led to a liver transplant. Due to the possibility of underreporting, the true incidence of these adverse reactions cannot be accurately estimated. Most reports of liver injury occurred within 120 days of starting atormoxetine, with some patients experiencing significantly elevated liver enzymes (>20 times the upper limit of normal) and jaundice, accompanied by significantly elevated bilirubin levels (>2 times the upper limit of normal), which resolved upon discontinuation of atormoxetine. One patient experienced a recurrence of liver injury after restarting atormoxetine, with liver enzymes elevated to 40 times the upper limit of normal and bilirubin levels elevated to 12 times the upper limit of normal, which resolved upon discontinuation of the drug, suggesting that atormoxetine was likely the cause of the liver injury. Such reactions may occur several months after starting treatment, but laboratory abnormalities may persist for weeks after discontinuation. The aforementioned patient recovered from the liver injury without requiring a liver transplant. For patients experiencing jaundice or laboratory tests indicating liver injury, atormoxetine should be discontinued and should not be restarted. If the first symptoms or signs of liver dysfunction appear (such as itching, dark urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms), laboratory testing of liver enzyme levels should be performed immediately. The manufacturer states that atormoxetine is contraindicated in patients currently receiving or recently (within 2 weeks) receiving monoamine oxidase (MAO) inhibitor therapy. Furthermore, at least a 2-week interval should be maintained between discontinuing atormoxetine and initiating MAO inhibitor therapy. Serious and even fatal reactions (including high fever, muscle rigidity, myoclonus, autonomic dysfunction with rapid fluctuations in vital signs, and altered mental status, such as extreme agitation, eventually progressing to delirium and coma) have been reported in patients receiving other medications that affect the concentration of monoamine neurotransmitters in the brain, especially when concurrently receiving monoamine oxidase inhibitors (MAO inhibitors). For more complete data on atormoxetine (26 total), please visit the HSDB record page. Pharmacodynamics Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor used to treat attention deficit hyperactivity disorder (ADHD). Studies have shown that atormoxetine specifically increases norepinephrine and dopamine levels in the prefrontal cortex, thereby improving ADHD symptoms. Due to its noradrenergic activity, atormoxetine can also affect the cardiovascular system, such as increasing blood pressure and tachycardia. Sudden death, stroke, and myocardial infarction have been reported in patients taking commonly administered doses of atormoxetine for ADHD. Atomoxetine should be used with caution in patients whose underlying conditions may be exacerbated by elevated blood pressure or heart rate, such as certain patients with hypertension, tachycardia, or cardiovascular/cerebrovascular disease. Atomoxetine should not be used in patients with severe cardiac or vascular disease whose condition is expected to worsen with a clinically significant increase in blood pressure or heart rate. Although the role of atormoxetine in these cases is unclear, treatment of patients with clinically significant cardiac abnormalities should be considered. Patients experiencing exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atormoxetine treatment should undergo immediate cardiac evaluation. Treatment with caution is generally advised in patients with ADHD and concurrent bipolar disorder, as there is concern that atormoxetine may induce mixed/manic episodes in high-risk individuals for bipolar disorder. During treatment, psychotic or manic symptoms, such as hallucinations, delusions, or mania, may occur in children and adolescents without a history of psychosis or mania when taking the usual dose of atormoxetine. If such symptoms occur, atormoxetine should be considered as a contributing factor, and discontinuation of the drug should be considered. Short-term studies have shown that atormoxetine capsules may increase the risk of suicidal ideation in children and adolescents with attention deficit/hyperactivity disorder (ADHD). All pediatric patients receiving atormoxetine should be appropriately monitored for worsening conditions, suicidal tendencies, and changes in abnormal behavior, especially during the first few months of treatment or during dose adjustments (increases or decreases). Post-marketing reports indicate that atormoxetine may cause serious liver injury. Although no evidence of liver injury was detected in clinical trials involving approximately 6,000 patients, rare, clinically significant cases of liver injury have been reported in post-marketing experience, which are considered possibly or suspected to be related to atormoxetine use. In addition, rare cases of liver failure have been reported, including one case that ultimately led to a liver transplant. Atormoxetine should be discontinued immediately in patients who develop jaundice or whose laboratory tests confirm liver injury, and should not be restarted. Laboratory testing of liver enzyme levels should be performed immediately upon the onset of the first symptoms or signs of liver dysfunction (such as itching, dark urine, jaundice, right upper quadrant tenderness, or unexplained "flu-like" symptoms).

C17H21NO

255.354744672775

255.162

C, 79.96; H, 8.29; N, 5.49; O, 6.27

83015-26-3

Atomoxetine hydrochloride;82248-59-7;(Rac)-Atomoxetine-d7 hydrochloride;Atomoxetine-d3 hydrochloride;1217776-38-9

54841

Typically exists as solid at room temperature

1.0±0.1 g/cm3

389.0±37.0 °C at 760 mmHg

161-165 ºC

164.1±16.0 °C

0.0±0.9 mmHg at 25°C

1.552

3.28

1

2

6

19

237

1

[C@H](C1C=CC=CC=1)(CCNC)OC1C=CC=CC=1C

VHGCDTVCOLNTBX-QGZVFWFLSA-N

InChI=1S/C17H21NO/c1-14-8-6-7-11-16(14)19-17(12-13-18-2)15-9-4-3-5-10-15/h3-11,17-18H,12-13H2,1-2H3/t17-/m1/s1

(3R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine

Atomoxetine; 83015-26-3; Tomoxetine; (-)-Tomoxetine; Tomoxetina; Tomoxetinum; Strattera; Tomoxetinum [Latin];

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)