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Neurotransmitter transporters and receptors binding profile of viloxazine. Representative results of binding competition assays of viloxazine (10 µM). Viloxazine binding was calculated as a percent inhibition of the binding of a radiolabeled ligand specific for each target (mean ± SEM, n = 2). Targets that presented an inhibition higher than 50% were considered a significant effect for viloxazine binding.
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Background
Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other AD...
Citations
... In addition to norepinephrine and dopamine, viloxazine increases serotonin in the prefrontal cortex at clinically used doses but does not show relevant activity as a serotonin reuptake inhibitor [1]. Additionally, it shows functional activity as a 5HT2C partial agonist and 5HT7 antagonist in preclinical research [4]. Its more modest affinity at norepinephrine transporters (less potent norepinephrine transporter binding affinity than atomoxetine and reboxetine) is consistent with a low incidence of cardiovascular effects observed in ADHD clinical studies [5]. ...
Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics.
Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3–5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student’s t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers.
The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84–102.49), 436.15 (398.87–476.92), and 583.35 (262.41–1296.80), respectively; 150.76 (126.03–180.35), 185.76 (155.01–222.61), and 189.71 (160.37–224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71–121.54), 167.56 (153.05–183.45), and 168.91 (154.38–184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33–142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0–24 125.66 (105.36–149.87)).
Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.
... In in vivo preclinical studies, viloxazine has demonstrated an ability to elevate levels of serotonin (5-HT), norepinephrine, and dopamine in the prefrontal cortex, which is closely associated with ADHD pathophysiology. Importantly, only a small and transient increase in dopamine levels was noted in the nucleus accumbens, a brain region involved in substance use disorders, suggesting a low abuse potential for viloxazine [2,10,11]. Due to its mechanism of action, viloxazine is categorized within the group of non-stimulant ADHD medications. ...
IntroductionViloxazine is an antidepressant medication classified as an SNRI (serotonin and norepinephrine reuptake inhibitor). In April 2021, it received FDA approval in the United States for the treatment of ADHD in children aged 6 to 17. Subsequently, in May 2022, it was also approved for the treatment of adults with ADHD [1]. Viloxazine, available in extended-release capsules, represents novel non-stimulant medication option for patients with ADHD.Aim of the studyOur aim was to review the viloxazine in the fields of ADHD treatment, summarize current knowledge and analyze the first treatment results. Methods and materialsA review of the literature available in the PubMed database was performed, using the key words: „Viloxazine" ; „ADHD treatment" ; „ADHD”, „attention deficit hyperactivity disorder”, „attention deficit hyperactivity disorder treatment”; „ADHD non-stimulant treatment”; „ADHD non-stimulant”; „ADHD non-stimulant drugs”, „SPN-812” Conclusion
Viloxazine presents a promising non-stimulant alternative for ADHD treatment with more favorable pharmacokinetics, new way of possible administration and fewer adverse effects, particularly within the cardiovascular system, than other available ADHD medication options. While these findings are encouraging, continual research is imperative to establish the long-term safety profile.
... Salah satu bahan alam yang dapat digunakan adalah kunyit karena kunyit (Curcuma Longa) memiliki senyawa metabolit skunder yang memiliki bioaktivitas (3). Kunyit dengan dosis 560mg/KgBB menunjukkan efektif sebagai antidepresan pada tikus wistar rat (rattus norvegicus) (4 (6), namun hanya tiga isolat kunyit memiliki aktivitas biologis sebagai antioksidan adalah toluene, 1-(4-hydroxy-3-methoxyphenyl)-(3,4dihydroxyphenyl)-1,6-heptadiene-3,5-dione, curcumin, dandemethoxycurcumin dengan nilai IC50 masing-masing 0.5, 0.8, 0.7 GAE/100mg (7). Aktivitas biologis senyawa sebagai antioksidan dapat dijadikan marker antidepresan karena mekanisme antioksidan dapat mendasari efek neuroprotektif antidepresan (8). ...
A Depression is a mental problem that is common in all communities, including teenagers. It is estimated that 10-20% of teenagers in the world experience mental health problems. Turmeric at a dose of 560mg/KgBW was shown to be effective as an antidepressant in Wistar rats (rattus norvegicus). Computers offer in silico test methods as a complement to in vitro and in vivo methods which are commonly used in the process of discovering and developing the biological activity of chemical compounds or natural materials as drug candidates. The research results show that MD simulations on the serotonin transporter complex protein with the ligand Demethoxycurcumin are more stable than curcumin and fluvoxamine. The results of identifying the molecular dynamics determinant of binding with the native ligand are amino acid SER336 and the reference ligand is amino acid SER438.
... 2,3 The efficacy of viloxazine in the treatment of ADHD has been attributed to its ability to increase norepinephrine (NE) and dopamine (DA) levels by inhibiting the norepinephrine transporter (NET), 4 the major protein responsible for the clearance of catecholamines in the prefrontal cortex (PFC). [5][6][7] In the US, viloxazine ER (viloxazine extendedrelease capsules; Qelbree ® ) is approved by the FDA for the treatment of ADHD in children (≥6 years) and adults. This has led to the labeling of viloxazine as a norepinephrine reuptake inhibitor (NRI). ...
... 5,[8][9][10][11] More recently, a microdialysis study found that viloxazine increased extracellular levels of NE, DA, and 5-HT in the PFC of freely-moving, male rats. 6 The increase in 5-HT found in this study was especially intriguing, as it suggested a potential contribution to the mechanistic action of viloxazine in ADHD; however, this initial study utilized a single dose of viloxazine (50 mg/kg) and did not collect sufficient data to determine whether increases at this dose were clinically relevant. ...
... The effect of viloxazine (1-30 mg/kg) on DA levels found in this experiment was unexpected and contrary to the findings of a previously published microdialysis experiment by our group, in which a 50 mg/kg dose of viloxazine significantly increased extracellular DA levels in the PFC. 6 These time-course experiments were repeated with select doses to verify the effect of viloxazine on DA levels in the PFC (data presented later in the Results section; Figure 4B). ...
Background
Viloxazine ER (viloxazine extended-release capsules; Qelbree®), a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment, has known activity as a norepinephrine (NE) transporter (NET) inhibitor. In vitro studies have also shown direct pharmacological effects on specific serotonin (5-HT) receptors, but not on the serotonin transporter (SERT). An in vivo microdialysis study in rats showed viloxazine (50 mg/kg i.p.) increased extracellular 5-HT, NE, and dopamine (DA) in the prefrontal cortex (PFC), a key brain region in ADHD pathology. This study evaluated whether these effects occur at clinically relevant concentrations.
Methods
Microdialysis experiments were conducted in freely-moving, Sprague-Dawley rats (males, 8 weeks). Viloxazine (1, 3, 10, 30 mg/kg) was administered intraperitoneally to establish the dose range in rats at which viloxazine plasma concentrations aligned with those of individuals with ADHD administered therapeutic doses of viloxazine ER. Concentrations of unbound viloxazine, NE, 5-HT, DA, and NE and 5-HT metabolites (3,5-dihydroxyphenylglycol [DHPG] and 5-hydroxyindoleacetic acid [5-HIAA]) were measured in PFC interstitial fluid. After identifying a therapeutically relevant dose (30 mg/kg), the experiment was repeated using 30 and 50 mg/kg viloxazine (as 50 mg/kg increased NE, 5-HT, and DA in prior studies).
Results
Viloxazine unbound (free drug) plasma concentrations in rats at 30 mg/kg were comparable to free drug concentrations in individuals with ADHD taking clinically effective doses (based on validated population PK models). Viloxazine 30 mg/kg significantly increased extracellular NE, 5-HT, and DA PFC levels compared to vehicle. Concomitant decreases in DHPG, but not 5-HIAA, support the inhibitory effect of viloxazine on NET but not SERT.
Conclusion
At clinically relevant concentrations, viloxazine increases PFC NE, DA, and 5-HT. Prefrontal augmentation of 5-HT does not appear to result from 5-HT reuptake inhibition but may be related to activation of 5-HT neurons. The potential therapeutic role of serotonergic effects in ADHD treatment merits further exploration.
... Esto cobra especial sentido al tomar en cuenta que recientemente se ha sugerido que el mecanismo de acción de la Viloxazina consiste principalmente en la inhibición de los transportadores de norepinefrina, así como en la regulación de la serotonina mediante actividad antagonista en los receptores HT-5 2B , y agonista en los receptores HT-5 2C , aumentando los niveles de serotonina extracelular en la corteza prefrontal; sin embargo, el análisis in vivo en pacientes pediátricos sugirió que el porcentaje de ocupación de receptores no aumenta de forma dosisdependiente en dosis mayores a 200 mg. 20 No obstante, para evaluar la efectividad de cada dosis se requiere de más estudios que evalúen la efectividad a diferentes dosis terapéuticas. ...
Introducción. El Trastorno por Déficit de Atención e Hiperactividad (TDAH) es el problema psiquiátrico más frecuente en niños y adolescentes, el cual se expresa como niveles patológicos de inatención e hiperactividad que repercuten en la vida del paciente pediátrico. Actualmente la terapia más habitual incluye terapia con fármacos estimulantes, los cuales causan varios efectos secundarios que pueden afectar el desarrollo del niño. Recientemente la FDA aprobó el uso de viloxazina oral en cápsulas de liberación prolongada, un tratamiento no estimulante para el TDAH, en niños y adolescentes. Objetivo. Presentar una síntesis del conocimiento sobre la eficacia de la viloxazina oral de liberación prolongada en la disminución de los síntomas del TDAH en pacientes pediátricos, evaluada mediante el instrumento TDAH-RS-5. Método. Se llevó a cabo una búsqueda en PubMed, Web Of Science, Scopus, ScienceDirect, y SciELO, hasta el 8 de noviembre de 2022. Se realizó un meta-análisis de los estudios que cumplieron con los criterios de elegibilidad, así como homogeneidad en cuanto diseño, dosis y tiempo de tratamiento, basado en la diferencia de medias en la puntuación TDAH-RS-5 al final del tratamiento. Resultados. Se identificaron 4 ensayos clínicos aleatorizados de los cuales 4 fueron incluidos en el meta-análisis. El SPN-812 en dosis de 200 mg mostró una disminución en la puntuación TDAH-RS-5 (DM=-5.84, IC95%: -7.93 a -3.75, p<0.00001, n=715) con respecto al placebo. Por su parte, el SPN-812 de 400 mg también mostró una disminución en la puntuación TDAH-RS-5 (DM=-4.4, IC95%=-6.73 a -2.08, p<0.001, n= 596) Conclusión. Los resultados sugieren que la administración de Viloxazina oral de liberación prolongada en pacientes pediátricos puede disminuir los síntomas del TDAH en niños y adolescentes, sin embargo, es necesario realizar más ensayos clínicos aleatorizados, debido al alto riesgo de sesgo de patrocinio, ya que los 4 ensayos clínicos fueron financiados por el laboratorio que fabrica el SPN-812.
... (a) Mechanism of action: the mechanism of SPN-812 is unique, as a serotonin-norepinephrine modulating agent (SNMA), compared with other ADHD and depression pharmacotherapies. As a selective 5-HT 2B receptor antagonist and 5-HT2C receptor agonist, SPN-812 modulates serotonergic activity and moderately inhibits norepinephrine transporter (NET), thus blocking the reuptake of norepinephrine [19]. (b) US Food and Drug Administration (FDA) Approval: in 2021, SPN-812 has been approved for treatment of ADHD in children aged 6-17 [20]. ...
Background:
SPN-812 has been approved for attention-deficit/hyperactivity disorder (ADHD) treatment in children and adolescents.
Objective:
We aimed to analyze the efficacy and safety of different doses of SPN-812 for ADHD pediatric patients of different ages, verify its clinical efficacy, and evaluate its safety.
Methods:
Up until 30 August 2023, randomized controlled trials (RCTs) were searched in EMBASE, MEDLINE, the Cochrane Library, and clinicaltrials.gov to evaluate different doses of SPN-812 and a placebo.
Results:
We pooled 1619 patients from five RCTs with a duration of 6-8 weeks. Patients (6-17 years old) in SPN-812 (100, 200, and 400 mg/d) groups were superior to the control group in all efficacy outcomes with lower attention-deficit/hyperactivity disorder rating scale-5 (ADHD-RS-5), Conners 3-parent short form composite T score (Conners 3-PS), Weiss functional impairment rating scale-parent (WFIRS-P), and increased clinical global impression-improvement (CGI-I) score (both p < 0.05). At the same time, only SPN-812 300 mg/d did not show a significantly high risk of the adverse events (AEs) such as somnolence and decreased appetite (p = 0.09). There was no significant difference between placebo and SPN-812 groups (100, 200, and 400 mg/d) in serious adverse events (SAEs) such as syncope. The subgroup analyses showed that, both in children and adolescents subgroups, SPN-812 showed better efficacy than the placebo. The two age subgroups showed a significantly higher risk of AEs and an insignificant risk of SAEs than the placebo.
Conclusion:
At present, SPN-812 (100, 200, and 400 mg/d) is superior to the corresponding control in efficacy measures. However, the safety problem cannot be ignored.
... Therapeutic interventions to specifically stimulate these areas are currently limited either by the multiple and sometimes diffuse actions of various pharmacotherapies (non-selective receptor or neurotransmitter stimulation translated in adverse reactions, most frequently agitation) or by trivial, practical considerations -e.g., neurofeedback can be performedonly with the child's cooperation, and many kids are too agitated to participate and achieve medium term results; however, a recent study showed that viloxazine has superior results to atomoxetine in ADHD kids [61] and gives hope for such a specific intervention in ASD. Viloxazine increases activity in the prefrontal cortex, possibly via differential actions on 5-HT receptors: antagonistic on 5-HT2B and agonistic on 5-HT2C receptors, and also acts on the norepinephrine transporter [62],causing an important modulation of the cortico-basal tracts involved in the cortical control of the enlarged ASD amygdala [29][30][31], with improvement of the fear and anxiety symptoms which are present in a majority of ASD kids. ...
Autistic spectrum disease (ASD) is an increasingly common diagnosis nowadays with a prevalence of 1–2% in most countries. Its complex causality—a combination of genetic, immune, metabolic, and environmental factors—is translated into pleiomorphic developmental disorders of various severity, which have two main aspects in common: repetitive, restrictive behaviors and difficulties in social interaction varying from awkward habits and verbalization to a complete lack of interest for the outside world. The wide variety of ASD causes also makes it very difficult to find a common denominator—a disease biomarker and medication—and currently, there is no commonly used diagnostic and therapeutic strategy besides clinical evaluation and psychotherapy. In the CORDUS clinical study, we have administered autologous cord blood to ASD kids who had little or no improvement after other treatments and searched for a biomarker which could help predict the degree of improvement in each patient. We have found that the neuron-specific enolase (NSE) was elevated above the normal clinical range (less than 16.3 ng/mL) in the vast majority of ASD kids tested in our study (40 of 41, or 97.5%). This finding opens up a new direction for diagnostic confirmation, dynamic evaluation, and therapeutic intervention for ASD kids.
... The PFC has highly unusual neuroanatomy with a low density of dopamine reuptake transporter (DAT) sites (Hitri et al. 1991;Sesack et al. 1998). For this reason, a substantial proportion of released dopamine is transported into noradrenergic neurons via norepinephrine reuptake transporters (NET) (Morón et al. 2002;Stahl 2003) and, as a consequence, selective NARIs increase the synaptic concentrations of norepinephrine and dopamine (Bymaster et al. 2002;Yu et al. 2020), thereby potentiating signaling of both catecholamines. ...
Research into the involvement of adrenoceptor subtypes in the cause(s) of psychiatric disorders is particularly challenging. This is partly because of difficulties in developing animal models that recapitulate the human condition but also because no evidence for any causal links has emerged from studies of patients. These, and other obstacles, are outlined in this chapter. Nevertheless, many drugs that are used to treat psychiatric disorders bind to adrenoceptors to some extent. Direct or indirect modulation of the function of specific adrenoceptor subtypes mediates all or part of the therapeutic actions of drugs in various psychiatric disorders. On the other hand, interactions with central or peripheral adrenoceptors can also explain their side effects. This chapter discusses both aspects of the field, focusing on disorders that are prevalent: depression, schizophrenia, anxiety, attention-deficit hyperactivity disorder, binge-eating disorder, and substance use disorder. In so doing, we highlight some unanswered questions that need to be resolved before it will be feasible to explain how changes in the function of any adrenoceptor subtype affect mood and behavior in humans and other animals.KeywordsAdrenoceptor subtypesAnxietyAttention-deficit hyperactivity disorderBinge-eating disorderCognitionDepressionNeurogenesisOpiate/opioid withdrawal syndromeSchizophrenia
... Potential advantages of VER are improvements in ADHD symptoms by 1 week in children and by 2 weeks in adults, no adjustment required for CYP2D6 (it is a CYP1A2 inhibitor), and the ability to open capsules [2,3]. Although both medications are norepinephrine reuptake inhibitors (NRIs), viloxazine demonstrates less inhibition of norepinephrine (NE) reuptake (Ki = 2300 nM) than atomoxetine (Ki = 3.4 nM), negligible serotonin (5-HT) reuptake inhibition (Ki > 10,000 nM) versus atomoxetine (Ki = 390 nM), and no dopamine (DA) reuptake inhibition versus atomoxetine (Ki = 1750 nM) [4]. In contrast, viloxazine is a 5-HT 2B antagonist, 5-HT 2C partial agonist, and 5-HT 7 antagonist associated with increases in prefrontal cortex 5-HT, NE, and DA levels in vivo [5]. ...
Background and objective:
In our outpatient pediatric and adult psychiatry centers, we reserve psychostimulants for predominantly inattentive attention deficit hyperactivity disorder (ADHD) due to the potential for appetite and growth suppression, insomnia, wear off, exacerbation of mood, anxiety, and tics, or misuse. We utilize extended-release (ER) alpha-2 agonists primarily for hyperactivity/impulsivity but find them less effective for inattention, and they can cause sedation and hypotension. Oftentimes, we need to combine an alpha-2 agonist for behavior with psychostimulants for inattention. We employ atomoxetine or viloxazine ER (VER) for combined ADHD. However, our patients' insurers mandate a trial of generic atomoxetine prior to covering branded VER. The objective of this study was to determine whether pediatric and adult patients taking atomoxetine for DSM-5-TR ADHD combined type would experience improvement in ADHD symptoms following voluntary, open-label switch to VER.
Methods:
50 patients (35 children) received mean doses of atomoxetine 60 mg (25-100 mg once daily) followed by VER 300 mg (100-600 mg once daily) after a 5-day atomoxetine washout. Both atomoxetine and VER were flexibly titrated according to US Food and Drug Administration (FDA) guidelines. The pediatric ADHD-Rating Scale-5 (ADHD-RS-5) and the Adult Investigator Symptom Rating Scale (AISRS) were completed prior to starting atomoxetine, and 4 weeks after treatment with atomoxetine or upon earlier response or discontinuation due to side effects, whichever occurred first; the same protocol was used after treatment with VER. We conducted a blinded, de-identified, retrospective review of charts from these 50 patients in the regular course of outpatient practice. Statistical analysis was performed using a within-subject, 2-tailed t-test with significance level of p < 0.05.
Results:
From the baseline total ADHD-RS-5 mean score (40.3 ± 10.3), improvements were greater on VER (13.9 ± 10.2) than atomoxetine (33.1 ± 12.1; t = - 10.12, p < 0.00001) in inattention (t = - 8.57, p < 0.00001) and in hyperactivity/impulsivity (t = - 9.87, p < 0.00001). From the baseline total AISRS mean score (37.3 ± 11.8), improvements were greater on VER (11.9 ± 9.4) than atomoxetine (28.8 ± 14.9; t = - 4.18, p = 0.0009) in inattention (t = - 3.50, p < 0.004) and in hyperactivity/impulsivity (t = - 3.90, p < 0.002). Of patients on VER, 86% reported positive response by 2 weeks versus 14% on atomoxetine. A total of 36% discontinued atomoxetine for side effects, including gastrointestinal (GI) upset (6 patients), irritability (6), fatigue (5), and insomnia (1), versus 4% who discontinued VER due to fatigue. A total of 96% preferred VER over atomoxetine, with 85% (22 out of 26) choosing to taper psychostimulants following stabilization on VER.
Conclusions:
Pediatric and adult ADHD patients who have experienced less than optimal response to atomoxetine demonstrate rapid improvement in inattention and in hyperactivity/impulsivity with greater tolerability on extended-release viloxazine.
... Hence, it elevates extracellular norepinephrine levels in multiple brain areas. [2,3] The FDA approved an extended-release version A B S T R A C T A R T I C L E I N F O of viloxazine under the brand name QELBREE for the treatment of ADHD in April 2021. [4] It was prescribed as an antidepressant for the treatment of major depressive disorder. ...
This research describes a novel technique for the selective separation of degradants from API employing HPLC and online coupling of a triple quadrupole mass analyzer and PDA detector with a SCIEX QTRAP 5500 mass spectrometer. Chromatography was used to separate all degradants on the column Agilent eclipse XDB (150 mm x 4.6 mm, 3.5 μ) with mobile phase ACN: 0.1% TEA (40:60) %v/v. The highest absorption was found to occur at 220 nm, which allows for simultaneous detection without being impacted by the placebo matrix. According to the general ICH recommendations, the suggested RP-HPLC method was accepted. All of the metrics- specificity, linearity, LoD, LoQ, accuracy, precision and robustness of validation were deemed sufficient. The proposed method exhibits strong correlation and great linearity over the range of (12.5–75 μg/mL). The accuracy trials produced consistent recoveries (95–105%), while the precision experiments' percent RSD was less than 2%. The intrinsic stability of the drug molecules in the current formulation could be ascertained by conducting forced degradation studies to assess the degradation products produced under various stress settings. The degradants produced were well separated and further characterized by MS/MS studies. The newly devised approach was demonstrated to be stable and sensitive to all degradants during validation tests. Validation trials demonstrate that the newly developed method was also accurate, precise, resilient, selective, and linear within the necessary operating range.
