US20100069390A1 - Method of treatment of attention deficit/hyperactivity disorder (ADHD) - Google Patents

Method of treatment of attention deficit/hyperactivity disorder (ADHD) Download PDF

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Publication number
US20100069390A1
US20100069390A1 US12/585,157 US58515709A US2010069390A1 US 20100069390 A1 US20100069390 A1 US 20100069390A1 US 58515709 A US58515709 A US 58515709A US 2010069390 A1 US2010069390 A1 US 2010069390A1
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adhd
viloxazine
treatment
activity
antagonistic activity
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US12/585,157
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Christopher D. Breder
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Supernus Pharmaceuticals Inc
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Supernus Pharmaceuticals Inc
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Priority to US12/585,157 priority Critical patent/US20100069390A1/en
Assigned to SUPERNUS PHARMACEUTICALS, INC. reassignment SUPERNUS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BREDER, CHRISTOPHER D.
Publication of US20100069390A1 publication Critical patent/US20100069390A1/en
Assigned to U.S. BANK NATIONAL ASSOCIATION reassignment U.S. BANK NATIONAL ASSOCIATION SECURITY AGREEMENT Assignors: SUPERNUS PHARMACEUTICALS, INC.
Priority to US13/930,051 priority patent/US20130289035A1/en
Priority to US14/634,281 priority patent/US20150290202A1/en
Priority to US15/615,423 priority patent/US11324753B2/en
Priority to US17/718,819 priority patent/US11458143B2/en
Priority to US17/896,774 priority patent/US20230102784A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • Viloxazine (Emovit®, Vivalan®, Vivarin®, Vicilan®) is a bicyclic antidepressant morpholine derivative that inhibits the reuptake of norepinephrine. Viloxazine hydrochloride has been approved in Italy, Belgium, England, Ireland, Germany, Portugal, Spain, the former Yugoslavia, France, Slovakia, for the treatment of major depressive disorder.
  • Viloxazine is known to inhibit noradrenergic reuptake transporters (155 nM) and has very weak activity at the serotonin reuptake inhibitor (17.3 ⁇ m). (Tatsumi et al [1997] Eur J Pharmacol 340 (2-3): 249-58).
  • the present invention is predicated on the unexpected discovery that viloxazine may be effective in the treatment of ADHD in humans with nominal, if any, significant side effects.
  • a method of treating ADHD and ADHD-related disorders in a mammal comprising administering to the mammal a pharmaceutical agent exhibiting 5HT1B and/or 5HT7 antagonistic activity is provided.
  • the invention provides a method for treatment of ADHD and ADHD-related disorders in a mammal comprising administering to the mammal a pharmaceutical agent exhibiting a combination of at least two of the following: noradrenergic reuptake inhibitory activity, 5HT1B antagonistic activity, and 5HT7 antagonistic activity.
  • the invention provides a method for treatment of ADHD and ADHD-related disorders in a mammal comprising administering to the mammal a pharmaceutical agent exhibiting a combination of at least two of the following: noradrenergic reuptake inhibitory activity, ⁇ 4/ ⁇ 2 antagonistic activity, and ⁇ 7 antagonistic activity.
  • the invention provides a method for treatment of ADHD and ADHD-related disorders in a mammal comprising administering to the mammal a pharmaceutical agent exhibiting a combination of at least two of the following: 5HT1B antagonistic activity, 5HT7 antagonistic activity, ⁇ 4/ ⁇ 2 antagonist activity, and ⁇ 7 antagonistic activity.
  • the current invention provides a novel method for treatment of ADHD and related disorders by administering a formulation of viloxazine.
  • the invention also provides a method of identifying compounds for the treatment of ADHD and/or similar disorders.
  • FIG. 1 shows a competition curve obtained with compound viloxazine with human 5-HT7 receptor.
  • FIG. 2 shows the agonist effect of the compound viloxazine with human 5HT7 receptor.
  • FIG. 3 shows the antagonist effect of the compound viloxazine with human 5HT7 receptor.
  • FIG. 4 shows a competition curve obtained with compound viloxazine with human 5-HT1B receptor.
  • FIG. 5 shows the agonist effect of the compound viloxazine with human 5HT1B receptor.
  • FIG. 6 shows the antagonist effect of the compound viloxazine with human 5HT1B receptor.
  • the invention provides a method for treatment of ADHD and ADHD-related disorders.
  • ADHD-related disorders include, but are not limited to, mood or affective disorders such as anxiety, depression or bipolar disorder; or disorders where ADHD may be a co-morbid syndrome, such as obsessive compulsive disorder, Tourette's Syndrome, or Post Traumatic Stress Disorder.
  • the method comprises the administration to a mammal diagnosed with ADHD or an ADHD-related disorder a pharmaceutical agent exhibiting a combination (at least 2) of: noradrenergic reuptake inhibitory activity, 5HT1B antagonistic activity, and 5HT7 antagonistic activity.
  • the invention comprises a method of treating any of the above-listed disorders with a pharmaceutical agent exhibiting a combination (at least 2) of: noradrenergic reuptake inhibitory activity, ⁇ 4/ ⁇ 2 antagonistic activity, and ⁇ 7 antagonistic activity.
  • the invention comprises a method of treating any of the above-listed disorders with a pharmaceutical agent exhibiting a combination (at least 2) of: 5HT1B antagonistic activity, 5HT7 antagonistic activity, ⁇ 4/ ⁇ 2 antagonistic activity, and ⁇ 7 antagonistic activity.
  • the pharmaceutical agents suitable for invention are identified by a process comprising the steps of: (1) selecting one or a combination of active agents with known activity inhibiting either serotonin or noradrenergic reuptake transporters; (2) conducting a receptor screening assay on the selected agent(s) to identify activity on at least one nicotinic, dopaminergic, serotonergic or gabaergic receptor or binding site where the activity is known to be associated with ADHD; (3) determining if said activity is agonistic or antagonistic; (4) selecting among the screened active agents at least one that targets the most of the different types of ADHD-associated receptors; and (5) optimizing the total dosage of the selected active agent(s).
  • the pharmaceutical agent is viloxazine.
  • viloxazine in addition to noradrenergic activity, viloxazine exhibits specific antagonist activity at the 6-HT7 (serotonin 7) and 5HT1B receptors. It was also discovered that viloxazine exhibits ⁇ 4/ ⁇ 2 and/or ⁇ 7 antagonistic activity. This heretofore unknown receptor activity of viloxazine was evaluated as follows:
  • a heterologous competition assay was used to determine the relative affinity of viloxazine for 5-HT receptors. Briefly, recombinant 5-HT1B OR 5-HT7 receptors were expressed in a CHO cell line. The receptors were then saturated with a tritiated receptor-specific ligand at concentrations known to be saturating. Thereupon, 10 ⁇ M viloxazine was added to the cells in the presence of non-specific ligand and incubated. In this way, viloxazine was allowed to “compete” with the receptor-specific ligand, such that greater displacement (i.e., % inhibition) is indicative of greater binding strength of viloxazine at a given receptor. “Specific binding” refers here to the difference in the binding of the ligand to the receptors in the presence or absence of an excess of the viloxazine. The conditions and results of the assays are summarized in the Table 1.
  • the affinity of viloxazine for 5-HT7 5-HT1B receptors was further characterized by determining the IC50 (i.e., the concentration of viloxazine that can inhibit 50% of control specific binding).
  • IC50 i.e., the concentration of viloxazine that can inhibit 50% of control specific binding.
  • the inhibition constants Ki were calculated using Cheng Prusoff equation. Ki is defined as the concentration of the competing ligand (viloxazine) that bound to half the binding sites at equilibrium in the absence of radioligand or other competitors.
  • Tables 2 and 3 The results of the affinity assay are summarized in Tables 2 and
  • the nature of the binding was next determined. Briefly, an assay was designed that examined the agonist effect on the 5HT7 or 5-HT1B receptor, i.e., the generation of cAMP or the blockade of this effect when stimulated by a 5HT7 agonist, serotonin. This was also done with a range of concentrations to determine the relative agonist versus antagonist binding Ki.
  • the EC50 values concentration producing a half-maximal specific response
  • IC50 values a concentration causing a half-maximal inhibition of the control-specific agonist response
  • the apparent dissociation constants for antagonists Kb were calculated using the modified Cheng Prusoff equation.
  • the conditions of the screening are represented in Table 4. Results of the functional assays are seen in FIGS. 2 ( 5 -HT7 agonist assay) and 3 (5-HT7 antagonist assay). The agonist assay demonstrated no measurable response ( FIG. 2 ). The antagonist assay for 5-HT7 yielded a weak response with an IC50 greater than 3.0 ⁇ 10-5 M.
  • Membrane homogenates of rat cerebral tissue are incubated with 1.5 nM [3H]cystine (for nicotinic acetylcholine ⁇ 4 ⁇ 2 screen) or 1 nM [125I] ⁇ -bungarotoxin (for nicotinic acetylcholine ⁇ 7 screen) in the absence or presence of 10 ⁇ M test compound in buffer.
  • Nonspecific binding is determined in the presence of 10 ⁇ M nicotine for ⁇ 4 ⁇ 2 or 1 ⁇ M ⁇ -bungarotoxin for ⁇ 7.
  • the samples are filtered rapidly under vacuum through glass fiber filters and rinsed several times. The filters are dried, then counted for radioactivity in a scintillation counter.
  • the results can be expressed as a percent inhibition of the control radioligand specific binding.
  • the standard reference compound is nicotine for ⁇ 4 ⁇ 2 and ⁇ -bungarotoxin for ⁇ 7, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 can be calculated.
  • Conditions for the IC50 determination can be the same as for the initial screen, except the test compound is assayed at 8 different concentrations between 10-9 and 10-4 M.
  • the effectiveness of viloxazine for ADHD treatment can be evaluated in a Five-Choice Serial Reaction Time Task (5-CSRTT) assay.
  • This test in typically performed with rats and is designed to show brain regions and neural substrates involved in attention, information processing speed, impulsivity, hyperactivity and preservative behaviors (obsessive compulsive disorder-like).
  • Pharmaceutical agents of the current invention including but not limited to viloxazine, can be tested to measure their effects on attention, impulsivity and reaction time and the outcome analyzed to determine their profile and application to treating ADHD.
  • SmartCubeTM An additional test, SmartCubeTM, can also be performed to obtain a “behavioral signature” for a given compound.
  • the experimental platform of this test combines robotics, computer video capture and analysis (called computer vision), and bioinformatics to capture and analyze data.
  • An animal treated with the test compound under study is placed in an enclosure and presented with a non-invasive behavioral challenge, such as changing the floor's configuration.
  • the animal's behavior is recorded using cameras and electro-mechanical sensors, and data from these recordings are processed using algorithms to reveal the compound's behavioral signature.
  • This “signature” can then be screened against the company's database of signatures from reference compounds to identify candidates predicted to have utility in treating ADHD.
  • ADHD or ADHD-related disorders can be treated in human subjects by administering viloxazine in a total daily dose that is at least 10% lower than the current minimally effective dose of 2.14 mg/kg, which is used to treat major depressive disorder. In other embodiments, the dose is 15% lower, 25% lower, 35% lower, or 50% lower than the current dose. Dosage ranges of 1.1 mg/kg/day to 9.7 mg/kg/day or approximately 20 to 800 mg for pediatric (aged 6 to 17) and adult population are also provided.
  • viloxazine can be administered in the amount of from 10 to 600 mg/day.
  • the daily dose of viloxazine may be from 150 to 400 mg/day.
  • viloxazine is administered in the amount of up to 300 mg/day.
  • the method of the current invention offers a safe and effective treatment of ADHD and related disorders in both children and adults.
  • a term “viloxazine” includes viloxazine and all pharmaceutically acceptable salts thereof, as well as all isomers, stereomers and polymorphs thereof.
  • the invention encompasses a method of treatment of ADHD or ADHD-related disorders with viloxazine that is characterized by an improved adverse effect profile.
  • the adverse effects that are diminished by the method of the present invention include, but are not limited to, nausea, vomiting, insomnia, loss of appetite, increased erythrocyte sedimentation, EKG and EEG anomalies, epigastric pain, diarrhea, constipation, vertigo, orthostatic hypotension, edema of the lower extremities, dysarthria, tremor, psychomotor agitation, mental confusion, inappropriate secretion of antidiuretic hormone, increased transaminases, seizure, and increased libido.
  • the inventive method provides for the treatment of ADHD without, or at least with far less frequency than with conventional viloxazine-treatment, of one, two, six or more of these listed side effects.
  • the efficacy and the adverse effect profile of the lower dose treatment of the current invention can be evaluated in a randomized, placebo controlled trial.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pain & Pain Management (AREA)
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US12/585,157 2008-09-05 2009-09-04 Method of treatment of attention deficit/hyperactivity disorder (ADHD) Abandoned US20100069390A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US12/585,157 US20100069390A1 (en) 2008-09-05 2009-09-04 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US13/930,051 US20130289035A1 (en) 2008-09-05 2013-06-28 Method of treatment of attention deficit/hyperactivity disorder (adhd)
US14/634,281 US20150290202A1 (en) 2008-09-05 2015-02-27 Method of treatment of attention deficit/hyperactivity disorder (adhd)
US15/615,423 US11324753B2 (en) 2008-09-05 2017-06-06 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US17/718,819 US11458143B2 (en) 2008-09-05 2022-04-12 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US17/896,774 US20230102784A1 (en) 2008-09-05 2022-08-26 Method of treatment of attention deficit/hyperactivity disorder (adhd)

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US9450208P 2008-09-05 2008-09-05
US12/585,157 US20100069390A1 (en) 2008-09-05 2009-09-04 Method of treatment of attention deficit/hyperactivity disorder (ADHD)

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US13/930,051 Abandoned US20130289035A1 (en) 2008-09-05 2013-06-28 Method of treatment of attention deficit/hyperactivity disorder (adhd)
US14/634,281 Abandoned US20150290202A1 (en) 2008-09-05 2015-02-27 Method of treatment of attention deficit/hyperactivity disorder (adhd)
US15/615,423 Active US11324753B2 (en) 2008-09-05 2017-06-06 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US17/718,819 Active US11458143B2 (en) 2008-09-05 2022-04-12 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US17/896,774 Pending US20230102784A1 (en) 2008-09-05 2022-08-26 Method of treatment of attention deficit/hyperactivity disorder (adhd)

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US14/634,281 Abandoned US20150290202A1 (en) 2008-09-05 2015-02-27 Method of treatment of attention deficit/hyperactivity disorder (adhd)
US15/615,423 Active US11324753B2 (en) 2008-09-05 2017-06-06 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US17/718,819 Active US11458143B2 (en) 2008-09-05 2022-04-12 Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US17/896,774 Pending US20230102784A1 (en) 2008-09-05 2022-08-26 Method of treatment of attention deficit/hyperactivity disorder (adhd)

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CA (1) CA2735934C (fr)
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WO2010127120A1 (fr) * 2009-04-30 2010-11-04 Supernus Pharmaceuticals, Inc. Procédé de traitement d'une dépression
US9358204B2 (en) 2012-02-08 2016-06-07 Supernus Pharmaceuticals, Inc. Formulations of viloxazine
US10160733B2 (en) * 2010-04-12 2018-12-25 Supernus Pharmaceuticals, Inc. Methods for producing viloxazine salts and novel polymorphs thereof
US10544117B2 (en) 2014-09-10 2020-01-28 Temple University—Of the Commonwealth System of Higher Education 5-hydroxytryptamine receptor 7 activity modulators and their method of use
US10858368B2 (en) 2016-11-15 2020-12-08 Temple University—Of the Commonwealth System of Higher Education Modulators of the 5-hydroxytryptamine receptor 7 and their method of use
US11220505B2 (en) 2017-03-21 2022-01-11 Temple University-Of The Commonwealth System Of Higher Education 5-hydroxytryptamine receptor 7 modulators and their use as therapeutic agents
US11324753B2 (en) 2008-09-05 2022-05-10 Supernus Pharmaceuticals, Inc. Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US11897870B2 (en) 2013-03-11 2024-02-13 Temple University-Of The Commonwealth System Higher Education 5-hydroxytryptamine receptor 7 activity modulators and their method of use

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Cited By (16)

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Publication number Priority date Publication date Assignee Title
US11458143B2 (en) 2008-09-05 2022-10-04 Supernus Pharmaceuticals, Inc. Method of treatment of attention deficit/hyperactivity disorder (ADHD)
US11324753B2 (en) 2008-09-05 2022-05-10 Supernus Pharmaceuticals, Inc. Method of treatment of attention deficit/hyperactivity disorder (ADHD)
WO2010127120A1 (fr) * 2009-04-30 2010-11-04 Supernus Pharmaceuticals, Inc. Procédé de traitement d'une dépression
US10160733B2 (en) * 2010-04-12 2018-12-25 Supernus Pharmaceuticals, Inc. Methods for producing viloxazine salts and novel polymorphs thereof
US9662338B2 (en) 2012-02-08 2017-05-30 Supernus Pharmaceuticals, Inc. Formulations of viloxazine
US10265319B2 (en) 2012-02-08 2019-04-23 Supernus Pharmaceuticals, Inc. Formulations of viloxazine
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US9358204B2 (en) 2012-02-08 2016-06-07 Supernus Pharmaceuticals, Inc. Formulations of viloxazine
US11897870B2 (en) 2013-03-11 2024-02-13 Temple University-Of The Commonwealth System Higher Education 5-hydroxytryptamine receptor 7 activity modulators and their method of use
US10544117B2 (en) 2014-09-10 2020-01-28 Temple University—Of the Commonwealth System of Higher Education 5-hydroxytryptamine receptor 7 activity modulators and their method of use
US11192871B2 (en) 2014-09-10 2021-12-07 Temple University-Of The Commonwealth System Of Higher Education 5-hydroxytryptamine receptor 7 activity modulators and their method of use
US10858368B2 (en) 2016-11-15 2020-12-08 Temple University—Of the Commonwealth System of Higher Education Modulators of the 5-hydroxytryptamine receptor 7 and their method of use
US11319327B2 (en) 2016-11-15 2022-05-03 Temple University—Of the Commonwealth System of Higher Education Modulators of the 5-hydroxytryptamine receptor 7 and their method of use
US11220505B2 (en) 2017-03-21 2022-01-11 Temple University-Of The Commonwealth System Of Higher Education 5-hydroxytryptamine receptor 7 modulators and their use as therapeutic agents
US11807642B2 (en) 2017-03-21 2023-11-07 Temple University—Of the Commonwealth System of Higher Education 5-hydroxytryptamine receptor 7 modulators and their use as therapeutic agents

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WO2010028207A2 (fr) 2010-03-11
ES2459322T3 (es) 2014-05-09
US20150290202A1 (en) 2015-10-15
US20230102784A1 (en) 2023-03-30
CA2735934A1 (fr) 2010-03-11
EP2341912B1 (fr) 2014-01-22
US20170266195A1 (en) 2017-09-21
CA2735934C (fr) 2014-01-07
US20130289035A1 (en) 2013-10-31
US20220233548A1 (en) 2022-07-28
WO2010028207A9 (fr) 2010-07-01
US11458143B2 (en) 2022-10-04
EP2341912A2 (fr) 2011-07-13
US11324753B2 (en) 2022-05-10
EP2341912A4 (fr) 2012-02-29

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