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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
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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

Definitions

• Dopaminergic therapies are among the most prescribed for these behavioral syndromes, and include such molecules as haloperidol and other antipsychotics.
• the dopamine receptors for these molecules are grouped into two families: the Dl , which includes the Dl and D5 receptors, and the D2, which includes the D2, D3 and D4 receptors.
• the two families differ by the manner in which the receptor protein is incorporated into the cell membrane, and by the pharmacology of the molecules that have an affinity for each type.
• Each receptor type is a distinct entity with its unique gene, anatomy in the brain, and affinity for different molecules.
• Some dopamine receptor subtypes, such as the D2 receptor have further modifications in the protein structure, giving rise to further sub-classification, e.g., D2 S hort and D2
• the D5 receptor has very specific localization in the brain, and is found in such areas as the parafascicular nucleus of the thalamus, as well as the prefrontal cortex, hippocampus, ventral tegmental area, substantia nigra and raphe nucleus (Hartman DS, Civelli O. Molecular attributes of dopamine receptors: new potential for antipsychotic drug development. Ann Med 1996; 28(3):21 1 -9).
• the parafascicular nucleus is involved in the behavioral process of attention to critical sensory input and activation of the subject toward that stimulus.
• One of the important paradigms in which the parafascicular nucleus participates is the activation of the fight or flight response.
• the parafascicular nucleus is likely involved in activating early components of aggressive behavior (Matsumoto , Minamimoto T, Graybiel AM, Kimura M. Neurons in the thalamic CM-Pf complex supply striatal neurons with information about behaviorally significant sensory events. J
• DRD5 D5 receptor
• DRD5 is also associated with genetic transmission of a number of disorders associated with aggression, irritability and impulsivity, including schizophrenia, Tourette's, and ADHD (Maher BS, Marazita ML, Ferrell RE, Vanyukov MM. Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet 2002;12(4):207-15). Blockade of the D5 receptor in a knockout model is associated with decreased motor activity, which may be akin to decreased aggression (Holmes A, Hollon TR, Gleason TC, et al. Behavioral characterization of dopamine D5 receptor null mutant mice. Behav Neurosci 2001 ; 1 15(5): 1 129-44).
• Molindone is a typical antipsychotic drug that has high affinity for the D2 family of dopamine receptors, where it is thought to exert its therapeutic action. Molindone was previously suggested for the treatment of aggression in both adult and pediatric patients (Greenhill LL, Barmack JE, Spalten D, Anderson M, Halpern F. Molindone Hydrochloride in the treatment of aggressive, hospitalized children [proceedings]. Psychopharmacol Bull 1981 ;17(1): 125-7; Itil TM, Wadud A. Treatment of human aggression with major tranquilizers, antidepressants, and newer psychotropic drugs. J Nerv Ment Dis 1975; 160(2- l):83-99).
• Molindone was also evaluated for children with the early-onset schizophrenia spectrum disorders (J Am Acad Child Adolesc Psychiatry, 2007, August, 46:8, p.969 - 978 and Am J Psychiatry, 165: 1 1 , Nov. 2008).
• WO 2010/080603 describes the use of molindone for the treatment of aggression, the disclosure of which is incorporated herein in its entirety by reference.
• the dose of molindone may range from 100 to 225mg per day (Bagnall A, Fenton M, Kleijnen J, Lewis R. Molindone for schizophrenia and severe mental illness. Cochrane Database Syst Rev 2007(1 ):CD002083 .
• the dose of other antipsychotics used for the treatment of aggressive behavior are about 50% relative to those used for the treatment of psychosis in schizophrenia (J Am Acad Child Adolesc Psychiatry. 2006 Jul;45(7):792-800).
• the current invention offers a method of treatment of aggression in a human subject suffering from ADHD, Tourette's and/or autism, comprising: (a) determining the weight or age of the human subject; (b) calculating a dose of molindone needed to achieve a plasma concentration, or other parameter (e.g., brain concentration), based on body weight or age, that does not saturate the molindone receptors; (c) administering the dose of step (b) to the human subject.
• the molindone receptors may comprise D2 receptors, D5 receptors, or both, or others.
• the dose may be calculated such that the molindone administered would comprise less than 90%, 80%, 70%, 60%, 50%, even less than 20% of the molindone dose required for treatment of schizophrenia.
• the invention also provides a method of treating aggression in a human subject suffering from ADHD, Tourette's and/or autism comprising administering a daily dose of molindone between 15 mg and 60 mg for human subjects weighing over 30 kg and a daily dose of molindone less than 25mg for human subjects weighing less than 30 kg.
• the low, medium, and high doses for the under 30 kg group were 12 mg, 24 mg, and 36 mg, respectively.
• the low, medium, and high doses for the 30 kg and over group were 18 mg, 36 mg, and 54 mg, respectively.
• the low dose met all secondary endpoints of Clinical Global Impression for severity and improvement, and of Oppositional Defiant Disorder with statistical significance vs placebo with p-values of 0.007, 0.017 and 0.039, respectively.
• the high dose did not show efficacy across any of the measures.
• the low (12 mg or 18 mg) and medium (24 mg or 36 mg) doses of molindone met the efficacy endpoint of rate of remission of aggression for all patients with statistical significance vs placebo and p-values of 0.009 and 0.043, respectively.
• the low and medium doses showed a reduction in score for the R-MOAS with p-values of 0.071 and 0.1 15.
• the clear and consistent trend for both arms reinforces the statistically significant remission scores.
• the magnitude of the score reductions seen in both arms was in a range that would be clearly clinically significant in patients.
• Molindone was well tolerated throughout the study across all doses. The patients may also suffer from Tourette's and/or autism. Preferable ranges for low, medium, and high doses for the under 30 kg group are 10 - 14 mg, 22-26 mg, and 34-38 mg, respectively.
• preferable ranges for the low, medium, and high doses for the 30 kg and over group are 16 - 20 mg, 34-38 mg, and 52-56 mg, respectively.

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• 2013
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• 2018
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