Patent Application
20180110742
The present invention relates to the use of N-Methyl-D-aspartate (NMDA) antagonists at sub-anesthetic doses for the treatment of mental or psychiatric disorders with occurrence of aggressive and/or impulsive behavior, in particular for the treatment of motor dysfunction associated with aggressive and/or impulsive behaviors.
Physicians tend to treat mental or psychiatric disorders with occurrence of aggressive and/or impulsive behavior presenting a symptom of motor dysfunction with psychiatric medication from different groups. Antipsychotics are also used for borderline personality. Stimulants are notably used for attention deficit hyperactivity disorder (ADHD). Drugs such as selective serotonin reuptake inhibitors (SSRIs) can help both depression and impulsivity. Anticonvulsant drugs can help reduce impulsive, angry outbursts. Other drugs such as risperidone (Risperidal) have been helpful with both depression and feelings of depersonalization in people with borderline personality. Antidepressants or anxiolytics (including sedatives) are used for the treatment of anxiety disorders. Mood stabilizers are used primarily in bipolar disorder.
However, these groups of drug can induce major problems with adverse side effects of medication, tolerance and addiction in a patient. Moreover, most of these drugs tend to act on the cognitive dysfunction of a mental or psychiatric disorder and not the motor dysfunction of these disorders, in particular aggressive and/or impulsive behaviors associated with these disorders. Alternative therapies aiming at decreasing side effects, tolerance effect, and toxicity effect are thus needed.
N-Methyl-D-aspartate receptor system is involved in numerous physiological and pathological processes in the central nervous system. Indeed, NMDA receptor overactivation is often associated with mental disorders with occurrence of aggressive and/or impulsive behavior. Therefore inhibition of NMDA receptors has often been considered as a good target to treat these disorders. However, blocking NMDA receptors has demonstrated the enhancement of impulsivity (Malhorta et al Neuropsychopharmacology. 1997 September; 17(3):141-50). In addition, the administration of ketamine in healthy humans and animal models induces schizophrenia (Breier et al Am J Psychiatry. 1997 June; 154(6):805-11.). In particular, most previous studies have shown that ketamine injection increased impulsivity in animals and humans (Cottone et al. Psychopharmacology (Berl). 2013 March; 226(1):127-38).
Contrary to the state of the art, the inventors of the present application discovered that the administration of a low and sub-anesthetic dose of an NMDA receptor antagonist could restore attention, suppress and/or decrease impulsivity and/or aggressiveness in primates. Contrary to rodents, these species constitute a good model to study mental disorders with occurrence of aggressive and/or impulsive behavior since their prefrontal cortex is well developed and organized on the same plan as in humans In addition, the present application demonstrates that a low and sub-anesthetic dose of an NMDA receptor antagonist inhibits or alleviates the motor dysfunction observed in impulsivity and/or aggressiveness of a mental or psychiatric disorder.
One object of the invention is a composition for use in the treatment of motor dysfunction in a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior in a subject in need thereof, comprising a sub-anesthetic dose of a compound antagonizing NMDA receptors.
In one embodiment, said compound is a noncompetitive or an uncompetitive antagonist of the NMDA receptor.
In another embodiment, said compound is ketamine, memantine, amantadine, tiletamine, phencyclidine (PCP), dizocilpine MK-801, Argiotoxin 636, dextrorphan, HU-211, Rhynchophylline, aptiganel, ifenprodil, lanicemine, Remacemide and/or analog and/or functional derivatives thereof.
In another embodiment, said compound is ketamine and/or an analog and/or a functional derivative thereof.
In another embodiment, said compound is memantine and/or an analog and/or a functional derivative thereof.
In another embodiment, said composition further comprises at least one pharmaceutical excipient.
In another embodiment, said composition is to be administered in a subject in need thereof by topical, transdermal, intramuscular, subcutaneous, oral, parenteral, intranasal administration.
In another embodiment, said composition is provided in a sustained-release form.
In another embodiment, said composition is formulated as a patch.
In another embodiment, said disorder is selected from the group comprising personality disorders, anxiety disorders, mood disorders, impulse control and addiction disorders, neurodegenerative disorders and movement disorders.
In another embodiment, said disorder comprises: personality disorders, impulse control and addiction disorders, neurodegenerative disorders and movement disorders.
In a preferred embodiment, said disorder is selected from the group comprising attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), Tourette syndrome, impulse control disorder (ICD), blepharospasm, Tic disorder, dissocial personality disorder, intermittent explosive disorder (IED), bipolar disorder, pyromania, kleptomania, paranoid personality disorders, schizoid personality disorders, schizotypal personality disorders, social anxiety disorder, panic disorder, agoraphobia, post-traumatic stress disorder, antisocial personality disorders, borderline personality disorders, histrionic personality disorders, narcissistic personality disorders, Parkinson's disease, and amyotrophic lateral sclerosis.
In a preferred embodiment, said disorder comprises: attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), Tourette syndrome, impulse control disorder (ICD), blepharospasm, Tic disorder, dissocial personality disorder, intermittent explosive disorder (IED), bipolar disorder, pyromania, kleptomania, paranoid personality disorders, schizoid personality disorders, schizotypal personality disorders, post-traumatic stress disorder, borderline personality disorders, Parkinson's disease, and amyotrophic lateral sclerosis.
Another object of the invention is a patch for use in the treatment of motor dysfunction in a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior, comprising the composition of the invention, and an acceptable carrier
Another object of the invention is a method for decreasing aggressive and/or impulsive behavior in a subject with a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior, wherein said method comprises administering a sub-anesthetic dose of a compound antagonizing NMDA receptors to the subject.
In one embodiment, said compound is a noncompetitive or an uncompetitive antagonist of the NMDA receptor.
In another embodiment, said compound is ketamine, or memantine and/or analog and/or functional derivatives thereof.
In another embodiment, said compound is ketamine and/or analog and/or functional derivatives thereof.
In another embodiment, said compound is memantine and/or analog and/or functional derivatives thereof.
In another embodiment, said compound is memantine and said dose is less than about 0.10 mg/kg.
In another embodiment, said compound is comprised in a pharmaceutical composition further comprising at least one pharmaceutical excipient.
In another embodiment, said administration is topical, transdermal, intramuscular, subcutaneous, oral, parenteral, or intranasal administration.
In another embodiment, said compound is provided in a sustained-release form.
In another embodiment, said compound is comprised in a composition formulated as a patch.
In another embodiment, said disorder is selected from the group consisting of personality disorders, impulsive control and addiction disorders, neurodegenerative disorders and movement disorders.
In a preferred embodiment, said disorder is selected from the group consisting of attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), Tourette syndrome, Impulsive control disorder (ICD), Blepharospasm, Tic disorder, Dissocial personality disorder, Intermittent explosive disorder (IED), Pyromania, Kleptomania, paranoid personality disorders, schizoid personality disorders, schizotypal personality disorders, post-traumatic stress disorder, borderline personality disorders, Parkinson's disease, amyotrophic lateral sclerosis.
In the present invention, the following terms have the following meanings:
The present invention relates to a method for decreasing aggressive and/or impulsive behavior in a subject with a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior, wherein said method comprises administering a sub-anesthetic dose of a compound antagonizing NMDA receptors to the subject.
The present invention further relates to a method for treating a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior, wherein said method comprises administering a sub-anesthetic dose of a compound antagonizing NMDA receptors to the subject. In one embodiment, the method of the invention is for reducing aggressive and/or impulsive behavior in the subject.
This invention further relates to a composition for treating or for use in the treatment of motor dysfunction in a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior comprising a sub-anesthetic dose of a compound antagonizing NMDA receptors.
The term “compound” as used throughout the specification includes but is not limited to: active metabolite, enantiomer, isomer, functional derivative, analog or salt of the NMDA antagonist of the invention.
The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, glutamate and glycine must bind to the NMDA receptor. An NMDA receptor that has glycine and glutamate bound to it and has an open ion channel is called “activated”. Chemicals that deactivate the NMDA receptor are called antagonists.
Each receptor subunit has modular design and each structural module also represents a functional unit: the extracellular domain contains two globular structures: a modulatory domain and a ligand-binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. The agonist-binding module links to a membrane domain, which consists of three trans-membrane segments and a re-entrant loop reminiscent of the selectivity filter of potassium channels. The membrane domain contributes residues to the channel pore and is responsible for the receptor's high-unitary conductance, high-calcium permeability, and voltage-dependent magnesium block. Each subunit has an extensive cytoplasmic domain, which contain residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues that interact with a large number of structural, adaptor, and scaffolding proteins.
Activation of NMDA receptors results in the opening of an ion channel that is nonselective to cations. A unique property of the NMDA receptor is its voltage-dependent activation, a result of ion channel block by extracellular Mg2+ ions. This allows voltage-dependent flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell. Activation of NMDA receptors requires binding of glutamate or aspartate (aspartate does not stimulate the receptors as strongly). In addition, NMDA receptors also require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor.
In one embodiment, the compound of the invention has similar selectivity, IC50 values or kinetics properties for the NMDA receptor subtypes than ketamine or memantine.
In another embodiment, the compound of the invention has an IC50 value inferior to about 2 μM for the subunit GluN2C of the NMDA receptor and inferior to about 3 μM for the subunit GluN2D of the NMDA receptor. IC50 values or kinetics properties determination are well known by the skilled artisan. For example, the IC50 of a drug can be determined by constructing a dose-response curve and examining the effect of different concentrations of antagonist on reversing agonist activity.
In another embodiment, the compound of the invention requires the binding of an NMDA agonist and channel opening to access to its binding, allosteric and/or blocking site.
In one embodiment of the invention, the compound inhibits the receptor by binding both in the internal portion of the pore and can remain trapped inside the channel following its closure.
In one embodiment of the invention, the compound is a noncompetitive antagonist of the NMDA receptor. Examples of noncompetitive antagonists include but are not limited to: ketamine; amantadine; tiletamine; phencyclidine (PCP); PCP hydrochloride functional derivatives; dizocilpine MK-801; Argiotoxin 636, dextrorphan, HU-211, Rhynchophylline and analogs or functional derivatives thereof.
In another embodiment, the compound is an uncompetitive channel blocker of the NMDA receptor. Examples of uncompetitive antagonists of the NMDA receptor include but are not limited to: memantine; aptiganel or Cerestat or CNS-1102, ifenprodil, lanicemine, Remacemide and analogs or functional derivatives thereof.
There are many different conditions that are recognized as mental disorders with occurrence of aggressive and/or impulsive behavior or psychiatric disorders with occurrence of aggressive and/or impulsive behavior. Aggressive and impulsive behaviors in a mental or psychiatric disorder include two components: a motor and a cognitive dysfunction.
As used herein, the terms “aggressive and/or impulsive behaviors in a mental or psychiatric disorder” are related to behaviors or symptoms of aggressive and/or impulsive motor dysfunction. In particular, such behaviors or symptoms involve involuntary movements that include without limitation fidgeting, squirming, having trouble sitting still (e.g. during dinner, school, or story time), being constantly in motion, punding, tremors, muscle stiffness, joint stiffness, spasm, low muscle control, movement difficulty, rigidity in arms, rigidity in legs, reduced locomotor activity, reduced movement coordination, or a combination thereof.
Tests to assess such behaviors are well known to the skilled artisan and include without limitation, Barratt Impulsiveness Scale which can detect motor impulsiveness: “acting on the spur of the moment”, Impulsive/Premeditated Aggression Scale, the 3 clap test.
Mental or psychiatric disorders with aggressive and/or impulsive behaviors having motor dysfunction include without limitation, personality disorders, impulse control and addiction disorders, neurodegenerative disorders, and movement disorders.
Other examples of mental or psychiatric disorders with aggressive and/or impulsive behaviors having motor dysfunction include without limitation, anxiety disorders and mood disorders.
People with anxiety disorders respond to certain objects or situations with fear and dread, as well as with physical signs of anxiety or nervousness, such as a rapid heartbeat and sweating. An anxiety disorder is diagnosed if the person's response is not appropriate for the situation, if the person cannot control the response, or if the anxiety interferes with normal functioning. Examples of anxiety disorders include but are not limited to: generalized anxiety disorder, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, and specific phobias.
Mood disorders, also called affective disorders, involve persistent feelings of sadness or periods of feeling overly happy, or fluctuations from extreme happiness to extreme sadness. Examples of mood disorders include but are not limited to: Intermittent explosive disorder (IED), depression, mania, and bipolar disorder.
In one embodiment, the disease to be treated is not an anxiety disorder. Examples of anxiety disorders include but are not limited to: generalized anxiety disorder, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, and specific phobias.
In another embodiment, the disease to be treated is not a mood disorder. Examples of mood disorders include but are not limited to: Intermittent explosive disorder (IED), depression, mania, and bipolar disorder.
The present invention also relates to a pharmaceutical composition for treating or for use in treating motor dysfunction in a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior in a subject in need thereof, wherein said pharmaceutical composition comprises a sub-anesthetic dose of an NMDA antagonist and at least one pharmaceutically acceptable excipient.
The present invention also relates to a pharmaceutical composition for treating of or for use in treating a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior in a subject in need thereof, wherein said pharmaceutical composition comprises a sub-anesthetic dose of an NMDA antagonist and at least one pharmaceutically acceptable excipient. In one embodiment, treating means decreasing the occurrence of aggressive and/or impulsive behavior.
Another object of the invention is a medicament for treating or for use in treating motor dysfunction in a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior comprising a sub-anesthetic dose of an NMDA antagonist.
Another object of the invention is a medicament for treating or for use in treating a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior comprising a sub-anesthetic dose of an NMDA antagonist. In one embodiment, treating means decreasing the occurrence of aggressive and/or impulsive behavior.
In one embodiment, the compound of this invention may be provided in the form of a pharmaceutically acceptable salt. Examples of such a salt include, but are not limited to, those formed with organic acids (e.g. acetic, lactic, citric, malic, formaric, tartaric, stearic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloridic, nitric, diphosphoric, sulphuric, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or co-polymers of polylactic-glycolic acids).
In another embodiment, the composition, pharmaceutical composition or medicament of the invention further comprises some excipients, such as, for example, surfactants (e.g. hydroxypropylcellulose); suitable carriers, such as, for example, solvents and dispersion media containing, for example, water, monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride, ethanol, polyol (e.g. glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, such as, for example, peanut oil and sesame oil; isotonic agents, such as, for example, sugars or sodium chloride; coating agents, such as, for example, lecithin; agents delaying absorption, such as, for example, aluminum monostearate and gelatin; preservatives, such as, for example, benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like; buffers, such as, for example, boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate and the like; tonicity agents, such as, for example, dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride; antioxidants and stabilizers, such as, for example, sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like; nonionic wetting or clarifying agents, such as, for example, polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol; viscosity modifying agents, such as, for example dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose; and the like.
In one embodiment of the invention, the composition, the pharmaceutical composition or the medicament comprises a sub-anesthetic dose of an NMDA antagonist.
In one embodiment, the administration to a subject in need thereof of the composition of the invention results in the alleviation or inhibition of symptoms of mental disorders with occurrence of aggressive and/or impulsive behavior.
In one embodiment, the administration of the composition results in the suppression or in a decrease of aggressive behaviors. In one embodiment, the administration of the composition results in the suppression or in a decrease of impulsive behaviors. In one embodiment, the administration of the composition results in restoring attention.
According to the invention, the sub-anesthetic dose of an NMDA antagonist is calculated in order to reach a desired behavior such as improvement in attention level, decrease in impulsivity and/or aggressiveness. Methods for assessing the efficacy of the treatment are readily measurable by routing procedures familiar to a physician.
The composition, pharmaceutical composition or medicament of the invention may be administered by several routes of administration. Examples of adapted routes of administration include, but are not limited to: intramuscular (i.m.), subcutaneous, intravenous, intraocular, transdermal, topical, parenteral, intranasal and oral administration. Parenteral administration may be by intravenous (IV) injection, subcutaneous (s.c.) injection, intramuscular (i.m) injection, intra-arterial injection, intrathecal (i.t.) injection, intra-peritoneal (i.p.) injection, or direct injection or other administration to the subject.
In one embodiment of the invention, the sub-anesthetic dose of the NMDA antagonist is inferior or equal to about 15 mg/kg body weight/day, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of the NMDA antagonist is inferior or equal to about 15 mg/kg body weight, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of the NMDA antagonist is superior to 0 or superior to about 0.001, 0.01 or 0.1 mg/kg body weight/day, and inferior or equal to about 15 mg/kg body weight/day, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of the NMDA antagonist is superior to 0 or superior to about 0.001, 0.01 or 0.1 mg/kg body weight, and inferior or equal to about 15 mg/kg body weight, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is inferior to about 0.5 mg/kg body weight/day, preferably inferior to about 0.25 mg/kg body weight/day, more preferably inferior to about 0.05 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is inferior to about 0.5 mg/kg body weight, preferably inferior to about 0.25 mg/kg body weight, more preferably inferior to about 0.05 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight/day, and inferior to about 0.5 mg/kg body weight/day, preferably inferior to about 0.25 mg/kg body weight/day, more preferably inferior to about 0.05 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight, and inferior to about 0.5 mg/kg body weight, preferably inferior to about 0.25 mg/kg body weight, more preferably inferior to about 0.05 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight/day, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 mg/kg body weight/day, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 mg/kg body weight, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight/day, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is superior to 0 or superior to about 0.001 mg/kg body weight/day, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is superior to 0 or superior to about 0.001 mg/kg body weight, and inferior to about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In one embodiment of the invention, the sub-anesthetic dose of ketamine is about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight/day, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 mg/kg body weight/day, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is superior to 0 or superior to about 0.001 mg/kg body weight, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of an NMDA antagonist is about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of memantine is inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of memantine is inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of memantine is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight/day, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of memantine is superior to 0 or superior to about 0.001 or 0.01 mg/kg body weight, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of memantine is superior to 0 or superior to about 0.001 mg/kg body weight/day, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of memantine is superior to 0 or superior to about 0.001 mg/kg body weight, and inferior to about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
In another embodiment of the invention, the sub-anesthetic dose of memantine is about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight/day.
In another embodiment of the invention, the sub-anesthetic dose of memantine is about 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.10, 0.08, 0.05, 0.025, 0.01 mg/kg body weight.
It will be understood that the sub-anaesthetic dose of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific sub-anaesthetic dose for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific peptide employed; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
According to an embodiment, the composition, pharmaceutical composition or medicament of the invention is in a form adapted for injection, preferably selected from the group comprising solutions, such as, for example, isotonic solution, saline solution, sterile aqueous solutions, dispersions, emulsions, suspensions, solid forms suitable for using to prepare solutions or suspensions upon the addition of a liquid prior to use, such as, for example, powder, freeze-dried compositions, liposomal forms and the like. Sterile injectable solutions are prepared by incorporating the composition of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized composition into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
According to an embodiment, the composition, pharmaceutical composition or medicament of the invention is in a form adapted to oral administration. According to a first embodiment, the form adapted to oral administration is a solid form selected from the group comprising tablets, pills, capsules, soft gelatin capsules, sugar-coated pills, orodispersing tablets, effervescent tablets or other solids. According to a second embodiment, the form adapted to oral administration is a liquid form, such as, for example, a drinkable solution, a buccal spray, liposomal forms and the like. The oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
According to an embodiment, the composition, pharmaceutical composition or medicament of the invention is in a form adapted for local delivery via the nasal and respiratory routes. Examples of formulations suitable for nasal administration include but are not limited to, nasal solutions, sprays, aerosols and inhalants.
According to an embodiment, the composition, pharmaceutical composition or medicament of the invention is in the form of, or comprises, liposomes and/or nanoparticles.
In one embodiment, the composition of the invention is in a form adapted for a topical administration.
In one embodiment, the composition of the invention is formulated as a patch for topical or transdermal administration.
Examples of formulations adapted to topical administration include, but are not limited to: patches, sticks, lipsticks, waxes, creams, lotions, ointments, balms, gels, glosses, masks, leave-on washes or cleansers and/or the like.
In one embodiment, the composition of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. In addition, the compositions can contain polyethylene glycol 400. They can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox II (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol). Woven pads or rolls of bandaging material, e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application.
In another embodiment of the invention, the composition of the invention is in a form adapted for transdermal administration.
In one embodiment, the transdermal composition is an ointment, paste, cream; film, balm, patch, such as, for example, transdermal patch, gel, liposomal forms or the like.
In one embodiment of the invention, the ointment is an oleaginous ointment; an emulsified ointment such as, for example, oil-in-water or a water-in-oil ointment; or a water-soluble ointment, preferably is an oleaginous ointment.
In one embodiment of the invention, the oleaginous ointment uses bases such as, for example, plant and animal oils; plant and animal fats; waxes; Vaseline, such as, for example, white Vaseline or Vaseline oil; and paraffin such as, for example, liquid paraffin or paraffin oil.
In one embodiment of the invention, the transdermal composition further comprises one or more excipients. Suitable pharmaceutically acceptable excipients are well known from the skilled person. Examples of suitable excipients include, but are not limited to, carriers, emulsifying agents, stiffening agents, rheology modifiers or thickeners, surfactants, emollients, preservatives, humectants, buffering agents, solvents, moisturizing agents and stabilizers.
Those of skill in the art are well aware of general technologies for administration of transdermal or topical composition. Transdermal drug delivery offers controlled release of a drug to the patient and transdermal patches are user-friendly, convenient, painless, and offer multi-day dosing which usually results in improved patient compliance.
Such composition can be administered to the skin of the face, scalp, temporal region, arms, stomach, thighs, back, neck and the like. Suitable skin of the face includes skin of the chin, the upper lip, the lower lip, the forehead, the nose, the cheek, the skin around the eyes, the upper eyelid, the lower eyelid or combinations thereof. Suitable skin of the scalp includes the front of the scalp, the scalp over the temporal region, the lateral part of the scalp, or combinations thereof. Suitable skin of the temporal region includes the temple and the scalp over the temporal region and combinations thereof. The composition may be formulated into a bioadhesive patch or a bioadhesive strip with an occlusive covering. Alternatively, the transdermal composition for administration to the skin can be applied as a topical ointment, a topical gel, a lotion, a cream, a solution, a spray, a paint, a varnish, a film, a foil, to be applied to the skin in a layer with or without an occlusive dressing.
In another embodiment, the composition of the invention can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
The present invention also relates to a patch comprising the composition of the invention, more particularly as a sustained-release patch. Patches can include any conventional form such as, for example, adhesive matrix, polymeric matrix, reservoir patch, matrix or monolithic-type laminated structure, and are generally comprised of one or more backing layers, adhesives, penetration enhancers, an optional rate controlling membrane and a release liner which is removed to expose the adhesives prior to application. Polymeric matrix patches also comprise a polymeric-matrix forming material. Suitable transdermal patches are described in more detail in, for example, U.S. Pat. Nos. 5,262,165; 5,948,433; 6,010,715 and 6,071,531; the disclosure of each of which are incorporated herein in their entirety.
In one embodiment, the composition of the invention is to be administered in a sustained-release form.
Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing ketamine or memantine, which matrices are in the form of shaped articles, e.g., patches, films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the Lupron Depot™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compounds remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at about 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S—S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
The formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, or sustained-releasing as described herein. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.
In one embodiment of the invention, the composition comprises a delivery system that controls the release of the composition. Examples of suitable carriers for sustained or delayed release include, but are not limited to, gelatin; gum Arabic; xanthane polymers; thermoplastic resins such as, for example polyvinyl halides, polyvinyl esters, polyvinylidene halides and halogenated polyolefins; elastomers such as, for example, brasiliensis, polydienes, and halogenated natural and synthetic rubbers; and flexible thermoset resins such as polyurethanes, epoxy resins; biodegradable polymers and the like.
In one embodiment of the invention, the composition, pharmaceutical composition or medicament of the invention may be used in conjunction with delivery systems that facilitate delivery of the agents to the central nervous system. For example, various blood brain barrier (BBB) permeability enhancers may be used to transiently and reversibly increase the permeability of the blood brain barrier to a treatment agent. Such BBB permeability enhancers include but are not limited to leukotrienes, bradykinin agonists, histamine, tight junction disruptors (e.g., zonulin, zot), hyperosmotic solutions (e.g., mannitol), cytoskeletal contracting agents, and short chain alkylglycerols (e.g., 1-O-pentylglycerol). Oral, sublingual, parenteral, implantation, nasal and inhalational routes can provide delivery of the active agent to the central nervous system. In some embodiments, the compounds of the present invention may be administered to the central nervous system with minimal effects on the peripheral nervous system.
The blood-brain barrier (BBB) is a physical barrier and system of cellular transport mechanisms between the blood vessels in the central nervous system (CNS) and most areas of the CNS itself. The BBB maintains homeostasis by restricting the entry of potentially harmful chemicals from the blood, and by allowing the entry of essential nutrients. However, the BBB can pose a formidable barrier to delivery of pharmacological agents to the CNS for treatment of disorders or maintaining or enhancing normal and desirable brain functions, such as cognition, learning, and memory.
The present invention can also relate to a prodrug of the NMDA antagonist or an encapsulation of said antagonist.
In one embodiment, the composition, pharmaceutical composition or medicament of the invention is a prodrug of the selective NMDA antagonist.
In another embodiment, the composition, pharmaceutical composition or medicament of the invention is a prodrug of ketamine and/or analog and/or functional derivative thereof.
In another embodiment, the composition, pharmaceutical composition or medicament of the invention is a prodrug of memantine and/or analog and/or functional derivative thereof.
Prodrugs as described herein are capable of passage across the blood-brain barrier and may undergo hydrolysis by CNS esterases to provide the active compound.
Prodrugs provided herein may also exhibit improved bioavailability, improved aqueous solubility, improved passive intestinal absorption, improved transporter-mediated intestinal absorption, protection against accelerated metabolism, tissue-selective delivery, less (or fewer) side effects, lessened or no deleterious drug interaction with other medications, and/or passive enrichment in the target tissue.
The term “prodrug” as used herein refers to a compound that is converted under physiological conditions, by solvolysis or metabolically to a specified compound that is pharmaceutically/pharmacologically active. The “prodrug” can be a compound of the present invention that has been chemically derivatized such that it retains some, all or none of the bioactivity of its parent drug compound and is metabolized in a subject to yield the parent drug compound. The prodrug of the present invention may also be a “partial prodrug” in that the compound has been chemically derivatized such that it retains some, all or none of the bioactivity of its parent drug compound and is metabolized in a subject to yield a biologically active derivative of the compound.
Prodrugs can be formed by attachment of biocompatible polymers, such as those previously described including polyethylene glycol (PEG), to compounds of the present invention using linkages degradable under physiological conditions. See also Schacht, et al. (1997) Poly(ethylene glycol) Chemistry and Biological Applications, American Chemical Society, San Francisco, Calif. 297-315. Attachment of PEG to proteins can be employed to reduce immunogenicity and/or extend the half-life of the compounds provided herein. Any conventional PEGylation method can be employed, provided that the PEGylated agent retains at least some pharmaceutical activity.
In one embodiment, the antagonist, preferably the selective antagonist, of the invention is PEGylated.
In one embodiment, the present invention further provides prodrugs comprising the compounds described herein. The prodrugs can be formed utilizing a hydrolyzable coupling to the compounds described herein. Ettmayer, et al. (2004) J. Med. Chem. 47(10): 2394-2404; Testa and Mayer (2003) Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry and Enzymology Wiley-Verlag Helvetica Chimica Acta, Zuerich (Chapters 1-1): 1-780.
In one embodiment, the composition, the pharmaceutical composition or the medicament of the invention is sterile. Advantageously, it comprises a preservative in order to prevent the growth of microorganisms. The prevention of the action of microorganisms may be brought about by various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
In one embodiment, the sub-anesthetic dose of the compound of the invention is administered once a month, twice a month, once a week, twice a week, at least once a day, twice, or three times a day.
In another embodiment, the sub-anesthetic dose of the compound of the invention is administered once a day on consecutive days for at least a week, at least a month, at least a year, or on as needed basis for the rest of the patient's life.
In another embodiment, the sub-anesthetic dose of the compound of the invention is administered once a week on consecutive weeks for at least two weeks, one month, at least a year, or more as needed basis for the rest of the patient's life.
In another embodiment, the sub-anesthetic dose of the compound of the invention is administered once a month on consecutive months for at least two months, a year, or more as needed basis for the rest of the patient's life.
According to one embodiment of the invention, the administration dose of the pharmaceutical composition is determined by the skilled artisan and personally adapted to each subject.
In one embodiment of the invention, sub-anesthetic dose of the compound of the invention is to be administered for a chronic treatment.
In another embodiment of the invention, sub-anesthetic dose of the compound of the invention is to be administered for an acute treatment.
In one embodiment, the composition, the pharmaceutical composition or the medicament of the invention is to be administered alone, i.e., is not administered in combination with another therapeutic agent for treating mental disorder with occurrence of aggressive and/or impulsive behavior.
In one embodiment, the composition, the pharmaceutical composition or the medicament of the present invention is to be administered with other active agents. In one embodiment, the composition, the pharmaceutical composition or the medicament and the other active agent may be administered separately or in conjunction with the compound of the invention.
In one embodiment of the invention, the subject is a young child. As used herein, the term “young child” refers to a child from 0 to 3 years old.
In another embodiment of the invention, the subject is a child. In one embodiment, the term “child” may refer to subjects aged from 0 to 12, preferably from 3 to 12. More generally, the term child refers to a subject which is not yet an adolescent.
In another embodiment of the invention, the subject is an adolescent. In one embodiment, the term “adolescent” may refer to subjects aged from about 12 to 17, but the skilled artisan will appreciate that the length of adolescence may vary from one individual to another.
In another embodiment, the subject is an adult. In one embodiment, the term “adult” may refer to subjects of more than 17 years old. More generally, the term adult refers to a subject which is no more an adolescent.
In one embodiment of the invention, the subject to be treated is diagnosed with a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior.
In another embodiment, the subject diagnosed with a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior is already treated with other active agents as described herein to alleviate symptoms of a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior.
In another embodiment of the invention, the subject to be treated is at risk of developing a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior.
Increased risks factors increasing the development of mental or psychiatric disorders with occurrence of aggressive and/or impulsive behavior, include but are not limited to: parental treatment such as parental rejection, lack of parental warmth, high hostility, harsh discipline, high maternal negative affect, anxious childrearing, modeling of dysfunctional and drug-abusing behavior, and child abuse (emotional, physical and sexual), migration and discrimination, childhood trauma, bereavement or separation in families, drug abuse, family history (e.g., of anxiety), temperament and attitudes.
In one embodiment of the invention, the subject has a genetic or a familial predisposition to a mental or psychiatric disorder with occurrence of aggressive and/or impulsive behavior.
Examples of genetic predisposition include but are not limited to: linkage to chromosome bands 16p13, on chromosome 2p23.2, mutations involving genes dopamine receptor D3 (DRD)3, DRD4, dopamine active transporter (SLC6A3) (DAT1), dopamine beta-hydroxylase (DBH), SLIT and NTRK-like family, member 1 (SLITRK1), alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1, APOEc4, TREM2, TDP-43, Tau, CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, S1C24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, ATP13A2, MAPT, CD2AP, VAPB, SETX, ALS2, SOD1, huntingtin.
The present invention also relates to a method for treating motor dysfunction in mental or psychiatric disorders with occurrence of aggressive and/or impulsive behavior in a subject in need thereof, wherein said method comprises administering to the subject in need thereof of a sub-anesthetic dose of an NMDA antagonist.
In one embodiment of the invention, said sub-anesthetic dose is calculated in order to reach a desired behavior such as good attention level, less impulsivity and/or less aggressiveness.
In one embodiment of the invention, the method for treating motor dysfunction in mental or psychiatric disorders with occurrence of aggressive and/or impulsive behavior in a subject in need thereof comprises a chronic treatment.
In another embodiment of the invention, the method for treating motor dysfunction in mental or psychiatric disorders with occurrence of aggressive and/or impulsive behavior in a subject in need thereof comprises an acute treatment. In one embodiment of the invention, the method of treating comprises administering to the subject the composition, the pharmaceutical composition or the medicament of the invention.
In one embodiment of the invention, the method is for treating behavioral and/or cognitive symptoms of mental disorders with occurrence of aggressive and/or impulsive behavior.
Another object of the present invention is a method for inhibiting visually-guided saccades in a subject in need thereof comprising the administration of a sub-anesthetic dose of the compound of the invention.
Another object of the present invention is a method for increasing the latency of anticipatory saccades in a subject in need thereof comprising the administration of sub-anesthetic dose of the compound of the invention.
Another object of the present invention is a method for reducing the occurrence of saccades in a subject in need thereof comprising the administration of sub-anesthetic dose of the compound of the invention.
Another object of the present invention is a method for reducing anticipatory or premature saccades occurrence in a subject in need thereof comprising the administration of sub-anesthetic dose of the compound of the invention.
The present invention is further illustrated by the following examples.
The experimental paradigm was designed to create a conflict between the urge to make a saccade to the peripheral box and the necessity to maintain fixation until the eccentric target appeared (
A total of 14104 saccades were analyzed in the three monkeys of the present study (L, S, Y). We found that a 0.25 mg/kg dose of ketamine altered saccadic latency.
Indeed, there was no significant interaction between injected product and the random factor (monkey identity) on saccadic latency (F2;6.001=3.647; p=0.092). Table 1 summarizes observed effects.
Dependent Variable: Saccadic Latency (ms)
As shown above, negative average saccadic latencies in controls (blues curve on
The result of the analysis on average latencies seems contradictory. Indeed, the significant interaction effect of ketamine and delay duration on saccadic latencies vanished when anticipatory and visually-guided saccades were analyzed separately. In order to further investigate this result, cumulative latency distributions of all saccades for the different delay durations were computed.
Product * Premature saccades Crosstabulation
This reduction was particularly strong for long delay durations (1400 ms and 1900 ms). Indeed, during long delays, a longer period of inhibition of a reflexive saccade to the eccentric box was required, and ‘false alarms’ (premature saccades) increased. This is future exemplified on
Cumulative latency distributions show that ketamine injection did not simply increase the latency of anticipatory saccades on average but reduced their occurrence. As a result, latency variance decreased.
The suppression of anticipatory saccades manifested itself very rapidly.
In order to more precisely determine how long it took for ketamine to start modifying saccade latency, the cumulated sum of latencies is represented on
It could be suggested that saccades during ketamine injection experiments were abnormal. However, ketamine injection did not reduce saccade amplitude in group data (monkeys L and Y). An ANOVA with injected product (ketamine or vehicle) as fixed-factor (n=5137 saccades) and monkey as random factor did not show a significant main effect of ketamine [F(1,1)=0.003; p=0.963] or monkey identity [F(1,1)=1.204; p=0.471]. On average in group data amplitude was not affected. However, a significant interaction between product and monkey identity was found [F(1,5169)=41.421; p=0.000]. This effect was due to a different influence of ketamine on saccade amplitude. Indeed, saccade amplitude was reduced by ketamine in monkey L (control: 5.7±0.05 deg; 5.2±0.05 deg; n=4014) and increased in monkey Y (control: 5.7±0.03 deg; 6.2±0.04 deg; n=1159). Note that all amplitude changes amounted to only 10% approximately.
The dose of ketamine used in the present study (0.25 mg/kg) did not evoke spontaneous nystagmus or centripetal drift of the eye as could be observed with higher doses (e.g. 0.6 mg/kg; see Condy et al. Biol Psychiatry 2005; 57: 366-372). Therefore, sedation is a very unlikely hypothesis to explain observed results. However, in order to further test the potential influence of a light sedation in the present results, we compared the proportion of valid trials with and without ketamine During valid trials, monkeys made a saccade towards the eccentric target (premature or visually-guided). However, a trial could be aborted if the animal did not foveate the initial fixation target rapidly enough, or moved away from the eccentric target when it appeared or simply failed to react to the appearance of the fixation point (trial omission). It could be suggested that light sedation could increase the proportion of aborted trials. However,
In conclusion, the effect of ketamine injection on premature (=anticipatory) saccades reduction was consistent in the 2 subjects who generate anticipatory saccades frequently. Ketamine modestly reduced saccadic amplitude. This small amplitude reduction cannot explain the reduction of anticipatory saccades observed. Moreover, reduction of anticipatory saccades cannot be attributed to light sedation.
Consequently, anticipatory saccades occurrence could be reduced by ketamine
We suggest that beneficial effects of low doses of ketamine on impulsivity will be found in all tasks where there is a challenging competition between alternative goals, as it is often the case in real-life situations. Treating impulsivity is an important intervention strategy in psychiatry. Impulsivity scores based on questionnaires should be compared with premature saccades occurrence in human subjects with low doses of ketamine or placebo i.m. We suggest that the frequency of occurrence of premature saccades might be a particularly useful tool in impulsivity evaluation and study in primates and in a clinical environment.
Neuronal activity of two animals was recorded on neurons with phasic discharge during the saccade (saccadic-relayed neurons,
These data clearly show that ketamine decreases the activity of premotor saccadic neurons but increases the activity of fixation neurons. Therefore, these data can be interpreted as a decrease in motor preparation and an increase in inhibition. This neuronal activity could therefore form the basis of a behavioral decrease of impulsivity, since neurons leading to movement are less active and those which inhibit the movement are more active. Therefore, administration of ketamine induces a modification in the balance between excitation and inhibition of the movement in favor of the latter. Consequently, these results support the hypothesis that sub-anesthetic doses of ketamine could reduce the symptom of a motor dysfunction observed in a mental or psychiatric condition.
To investigate the influence of memantine on impulsivity, experiments are carried out using the simple oculomotor paradigm as described above.
The rate of occurrence anticipatory (=premature) saccades or visually-guided saccades are determined following the oral administration of memantine or saline (placebo, vehicle) in rhesus monkeys at a dose of 2 mg/kg, 1.5 mg/kg, 1 mg/kg, 0.5 mg/kg, 0.25 mg/kg and 0.1 mg/kg.
Materials and Methods
Three monkeys participated in the present study (referred to as L, S, Y). Apparatus
Subjects sat in darkness, facing a CRT screen, which presented stimuli at a frequency of 60 Hz. An EyeLink 1000 infrared eye tracking system (SR Research, Mississauga, Ontario) was used to record movements of the right eye at 1 KHz. All experiments were run with homemade stimulus generation software based on a real time Linux kernel (Xenomaï). Stimulus display and oculomotor data collection were synchronized on a frame-by-frame basis. Saccades were detected offline in MATLAB (MathWorks, Natic, Mass.) with a velocity threshold of 30 deg/sec.
Each trial started with an initial fixation period (referred to as ‘initial fixation’), with a small cross (0.7 deg) appearing on the CRT screen for a random duration (850±100 ms; see ‘X’ on
Each experimental session started with a block of 200 trials before injection to measure the baseline saccadic latency on a day-by-day basis. On a randomly selected day ketamine (0.250 mg/kg) was injected i.m. or a placebo saline solution (NaCl 0.9%) of the same volume (0.3 ml). Only saccadic latencies less than 600 ms were considered for further analysis.
Subjects
One male and one female rhesus monkey were used in this study. All procedures were approved by the Institutional Animal Care and Use Committee and were in compliance with the guidelines set forth in the United States Public Health Service Guide for the Care and Use of Laboratory Animals.
Surgeries
A celux recording chamber (Crist Instruments, Hagerstown, Md.) was positioned at 24 mm anterior in Horsley-Clark stereotaxic coordinates and centered on the midline of the brain in both monkeys. At the completion of the surgeries, animals were returned to their home cages. Antibiotics and analgesics were administered as needed during the recovery period under the direction of a veterinarian.
Animal Training
The monkeys were seated in a primate chair with their head restrained for the duration of the testing sessions. They were trained to execute the behavioral task described above for liquid reward and were allowed to work to satiation. Records of each animal's weight and health status were kept, and supplemental water was given as necessary. The monkeys had their heads immobilized and were trained to pursue spots of light projected on a tangent screen in front of them.
Single-Neuron Recordings
To record neuronal activity, a single tungsten microelectrode (FHC, Bowdoinham, Me.) of approximately 6 MΩ impedance at 1 kHz was lowered into the cortex through the dura using a Narishige microdrive. The position of the electrode was determined using a grid system (Crist et al., 1988). Action potentials of single units were isolated using an on-line spike-sorting system that uses a template-matching algorithm (Plexon Inc). A pulse was generated each time an action potential was detected and stored with a 1 ms resolution.
Analysis of Neuronal Activity
To analyze the time course of neuronal activity, spike trains were convolved with a Gaussian probability density in steps of 1 ms to generate the spike-density function (Richmond et al., 1987). The SD of the Gaussian function was set to 20 ms. The average spike density in each experimental condition was computed from all trials in which subjects pursued the target until the end of its trajectory.
Statistical Analyses
All analyses were performed using the univariate General Linear Model analysis of variance (ANOVA) in SPSS (SPSS, International Business Machines, Armonk USA). The significance threshold a for all analysis was 0.05. Monkey identity was used as a random factor to take into account the influence of uncontrolled variability observed between subjects. Fixed factors will be given in the text for each analysis. The dependent variable measured was saccadic latency or amplitude.
| Number | Date | Country | Kind |
|---|---|---|---|
| 15164724.5 | Apr 2015 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/EP2016/059032 | Apr 2016 | US |
| Child | 15789269 | US |
