WO2014136118A1 - Traitement du syndrome de stress post-traumatique avec un antagoniste des récepteurs de mélanocortines - Google Patents

Traitement du syndrome de stress post-traumatique avec un antagoniste des récepteurs de mélanocortines Download PDF

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WO2014136118A1
WO2014136118A1 PCT/IL2014/050232 IL2014050232W WO2014136118A1 WO 2014136118 A1 WO2014136118 A1 WO 2014136118A1 IL 2014050232 W IL2014050232 W IL 2014050232W WO 2014136118 A1 WO2014136118 A1 WO 2014136118A1
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use according
previous
ptsd
administration
antagonist
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PCT/IL2014/050232
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English (en)
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Esther L. SABBAN
Lidia I. SEROVA
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New York Medical College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/723—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2271—Neuropeptide Y
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • 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

  • Embodiments of the invention relate to treatment of post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • PTSD is a debilitating psychiatric disorder induced by exposure to a severe trauma and is typically associated with functional impairments and increased physical and mental health risks. PTSD patients tend to have a six fold higher risk of suicide than non-PTSD patients.
  • the treatment of PTSD is challenging, and may include many years of individual and group therapy and treatment with medications such as conventional antidepressants, anxiolytic drugs, ⁇ -adrenergic antagonists, opiates, or Cortisol with variable results [rev. in (Kar 2011, Bowirrat et al. 2010)].
  • An aspect of embodiments of the invention relates to a method for preventing and/or treating PTSD by administration to a subject an effective amount of melanocortin receptor antagonist. Additional embodiments relate to a method for preventing and/or treating PTSD by administration to a subject an effective amount of melanocortin receptor four receptor (MC4R) antagonist.
  • M4R melanocortin receptor four receptor
  • a melanocortin receptor antagonist is an agent which binds to a melanocortin receptor thereby blocking, dampening or preventing an agonist-mediated activity of the receptor.
  • An MC4R antagonist is an agent which binds to an MC4 receptor thereby blocking, dampening or preventing an agonist-mediated activity of the receptor.
  • An example of an MC4R antagonist according to an embodiment of the invention is HS014, a synthetic peptide having the CAS number 207678-81-7, comprising 12 amino acids and having the sequence depicted in Figure 2.
  • Melanocortins are involved in a wide range of physiological processes, including memory and/or learning, thermoregulation, analgesia, regulation of cardiovascular and immune systems and feeding behavior. Melanocortins exert their biological effects by binding to specific melanocortin receptors (MCR). There are five differentially expressed melanocortin receptors: MC1R, MC2R, MC3R, MC4R and MC5R. MC4R is predominantly expressed in the brain areas such as the cortex, hippocampus, amygdala, septal region, corpus striatum, thalamus, hypothalamus and brainstem.
  • MCR melanocortin receptors
  • MC4R is a 332 amino acid protein.
  • the sequence of human MC4R, herein designated as SEQ. ID NO. 1 is portrayed in Figure 1. There may be variations of sequences of MC4R when comparing MC4R of different organisms. Antagonists of one or more mammalian varieties of MC4R may be used according to embodiments of the invention to treat PTSD. Many functions have been attributed to MC4R including erectile dysfunction, nociception, food intake and energy expenditure.
  • a melanocortin receptor antagonist is administered through intranasal administration.
  • a melanocortin receptor antagonist is administered to a subject before exposure to a traumatic event. In an embodiment of the invention, a melanocortin receptor antagonist is administered to a subject shortly after exposure to a traumatic event.
  • Fig. 1 depicts the sequence of a human MC4R
  • FIG. 2 depicts the structure of an MC4R antagonist, the synthetic peptide HS014;
  • Fig. 3A depicts a bar graph representing percentage of time in four 5-minute intervals of rat immobility in rats from 2 treatment groups and one vehicle (control) group, during exposure to the 20 minute forced swim part of a single prolonged stress (SPS) procedure, an indication of perception of the severity of the stress;
  • SPS single prolonged stress
  • Fig. 3B depicts a bar graph representing percentage of time immobility of rats from two treatment groups and one vehicle group, in a 5-minute forced swim test performed 7 days after inducement of stress in a single prolonged stress (SPS) model;
  • Figs. 4A-E depict bar graphs representing parameters relating to an elevated plus maze (EPM) rat test indicative of anxiety-related symptoms of rats administered intranasal vehicle (V), 3.5 nanogram HS014 per rat (3.5HS) or 100 microgram HS014 per rat (100HS) 30 min before SPS when the EPM test was performed 14 days following SPS, the parameters relating to open arm (OA) entries (Figs. 4 A and 4B), closed arm (CA) entries (Figs. 4C and 4D) and anxiety index (Fig. 4E);
  • EPM elevated plus maze
  • Figs. 5A-F depict bar graphs representing parameters relating to an EPM rat test indicative of anxiety-related symptoms of rats administered vehicle (V), 3.5 nanogram HS014 per rat (3.5HS) or 100 microgram HS014 per rat (100HS) when the EPM test was performed 14 days following SPS, the parameters relating to risk assessment (5A and 5B), head dips (5C) and grooming (Figs. 5D-F);
  • Figs. 6A-B depict F depict bar graphs representing parameters relating to an open field rat test indicative of anxiety-related symptoms of rats administered vehicle (V), 3.5 nanogram HS014 per rat (3.5HS) or 100 microgram HS014 per rat (100HS) when the open field test was performed 14 days following SPS, the parameters relating to duration in center of field (6 A) and defecation (6B);
  • FIG. 7 A depicts a method 100 for treatment and/or prevention of PTSD in a human subject.
  • Fig. 7B depicts a method 200 for treatment and/or prevention of PTSD in a human subject.
  • traumatic stress may cause excessive activation of an organism's hypothalamic -pituitary-adrenal (HP A) axis, thereby increasing the risk of PTSD and PTSD-like symptoms.
  • blockage of MC4R may reduce the activation of the HPA axis, thereby reducing, ameliorating or preventing the development and/or progression of PTSD.
  • MC4R antagonists include AGRP (83-132) and SHU09119.
  • AGRP (83-132) is a 50 amino acid multi-cyclic peptide, commercially available from Anaspec, EGT, Fremont, CA, USA.
  • SHU09119 is a selective MC4 receptors antagonist. It is a monocyclic 7 amino acid melanocortin-based peptide, available from Tocris Bioscience, Bristol, United Kingdom.
  • Another exemplary MC4R antagonist is HS028, cyclicfAcCys 11 , dichloro-D-phenylalanine , Cys , Asp-NH 2 ]pMSH 11-22), commercially available from Sigma-Aldrich.
  • Another exemplary MC4R antagonist is monocyclic 6 amino acid aMSH- based peptide HS131 having the sequence [Cys Gly D-Nal Arg Try Cys] and described in (Schioth et al. 2003).
  • Another exemplary MC4R antagonist is JKC-363 (cyclic[Mprl l,D-Nall4, Cysl8,
  • Another exemplary MC4R antagonist is BL-6020/979 (formerly known as SNT207979), described in (Dallmann et al. 2011).
  • MCL0129 Another exemplary MC4R antagonist is MCL0129, available from Clearsynth
  • an MC4R antagonist is administered in combination with Neuropeptide Y (NPY).
  • NPY is a 36- amino acid peptide which functions as a neurotransmitter in the mammalian brain.
  • an MC4R antagonist may be administered in the same composition or in a different composition as NPY.
  • NPY is administered intranasally.
  • NPY is administered before the MC4R antagonist.
  • NPY is administered after the MC4R antagonist.
  • NPY is administered while the effect of the MC4R antagonist is still present in the patient.
  • Example la Treatment of rats with MC4R antagonist before stress in an SPS model and evaluation of short term depressive-like symptoms after stress.
  • Rats in the low dose treatment group received 3.5 nanograms (ng) of HS014 in 10 microliters ( ⁇ ) of water via intranasal infusion.
  • Rats in the high dose treatment group received 100 micrograms ⁇ g) of HS014 in 10 ⁇ of water via intranasal infusion.
  • Rats in the vehicle group were administered an equal volume of vehicle (water) 30 min (minutes) prior to SPS. Animals in the control group were handled for 6 days prior to behavioral testing, but were not subjected to SPS. The body weights were monitored during the experimental procedures. Each group contained 8 to 12 animals.
  • HS014 obtained from Tocris Bioscience, Bristol, UK, was dissolved in water in appropriate amounts and 10 ⁇ of HS014 aqueous solution was infused into each nare under light isoflurane anesthesia with an automatic pipette and disposable plastic tip. The head of the animal was tilted back slightly as the dose was delivered. Extreme care was taken to avoid contact with the intranasal mucosa. Following intranasal administration, the head of the animal was held in a tilted back position for approximately 15 seconds to prevent loss of solution from the nares.
  • Rats from two treatment groups and a vehicle group were prepared as in example la.
  • a group of rats was also administered an intermediate dose of 1 ⁇ g, and there was a nearly significant improvement (decrease in immobile time) relative to the vehicle group.
  • EPM test was performed in an EPM chamber which consisted of a cross- shaped platform with two open arms (OA), each open arm enclosed by a 2 cm high plexiglass fence, and two closed arms (CA), each closed arm enclosed by 40 cm high opaque walls on sides, with arms of the same type located opposite each other.
  • the maze was elevated to a height of 50 cm above ground level. Experiments were performed in a room with dim lighting. Each rat was placed on the central-platform facing an open arm and was allowed to explore the maze for 10 min.
  • Unprotected head dips were defined as peering over the edge of an open arm with head, neck, and shoulders. Increase in this parameter expresses decreased anxiety-like behavior. Grooming behavior has been reported to be a response to novelty or other stressors and might vary in accordance with stress intensity. Because appropriate examination of grooming behavior in EPM requires longer than 5 min session, duration (total time spent grooming) and frequency (number of grooming bouts) were scored for 10 min in the EPM. Intervals greater than 5 seconds were considered as two different bouts. Duration of single bout was calculated as duration of grooming divided by frequency.
  • Grooming behavior was observed predominantly in the closed arms and was manifested as washing of snout and head.
  • Total time, frequency and duration of a single bout of grooming in EPM test are shown in Fig. 5D, 5E and 5F respectively.
  • Example Id Treatment of rats with MC4R antagonist before stress in an SPS model and evaluation of long term anxiety-like symptoms after stress in an open field test.
  • the open field test has been used to determine aspects of emotional behavior including anxiety. Several parameters, such as defecation and time in center of open field within the first 5 min, may be linked to anxiety.
  • Rats from two treatment groups and a vehicle group were prepared as in example la. Administration of HS014 or vehicle was followed by a 30 minute acclimation period, then immobilization stress as described above. The rats were then left undisturbed for 7 days.
  • the open-field arena used was a black opaque plastic enclosure measuring 75x 75 cm, with walls 35 cm high and a black floor.
  • the animal's activity was recorded by a video camera (NTSC IR sensitive) suspended two meters above the arena floor.
  • NTSC IR sensitive video camera
  • rats were placed in a central start position in the open field arena and allowed to explore for 5 min. Their behavior was recorded and analyzed with "Bioserve" software.
  • the arena was cleaned with 70% ethanol after each session and individual rats were tested only once.
  • Example le Biochemical impact of MC4R antagonist before stress in an SPS model
  • traumatic stress may cause excessive activation of an organism's HPA axis, thereby increasing the risk of PTSD and PTSD-like symptoms.
  • Activation of the HPA axis in response to external or internal stimuli originates in hypothalamic corticotropin-releasing hormone (CRH) producing PVN neurons by release of CRH into portal circulation, which stimulates biosynthesis and release of adrenocorticotropin hormone (ACTH) in the pituitary and finally leads to elevation of blood corticosterone released from the adrenal gland.
  • CRH hypothalamic corticotropin-releasing hormone
  • ACTH adrenocorticotropin hormone
  • Plasma levels of corticosterone were examined for a control group (non-SPS) and 3 groups of animals which were subjected to SPS, low dose treatment, high dose treatment and vehicle groups. Animals were euthanized 30 minutes after SPS and plasma corticosteroid levels were determined.
  • corticosterone plasma concentrations for high dose treatment animals were slightly, but significantly lower, compared to the vehicle group, indicating that the administration of MC4R antagonist decreases activation of the HPA axis in response to stress, or enhances recovery from the stress.
  • Example If: Biochemical impact of MC4R antagonist before stress in an SPS model, ventral hippocampus glucocorticoid receptor
  • Intranasal infusion has several advantages such as its non-invasiveness, ease of application, and avoidance of hepatic first-pass that indicate that it can serve as a viable strategy for delivering peptides such as HS014 into the CNS.
  • the potential usefulness of nasal administration also derives from the fact that biological effects can be achieved in the human brain with low concentrations without potential side effects associated with peripheral administration.
  • the results of this study demonstrate, for the first time, that rapid delivery of a MC4R antagonist to the brain by single intranasal infusion has a pronounced resilient effect on both short term and prolonged responses to traumatic events.
  • Intranasal HS014 pretreatment reduced depressive-like behavior in forced swim immediately after immobilization stress.
  • a number of long term PTSD-like symptoms such as anxiety-like and depressive-like behavior evaluated 7 days or longer after SPS, were dramatically reduced or even eliminated by the single intranasal HS014 pre-treatment.
  • Example 2a Methods of treating a human subject to prevent and/or treat PTSD comprising MC4R antagonists.
  • Figure 7 A shows a flow-diagram depicting a method 100 for treating and/or preventing PTSD in a human subject according to an embodiment of the invention.
  • Method 100 comprises identifying a subject at risk of PTSD in a block 110 and administering MC4R antagonists in a block 120.
  • subject is exposed to a potentially traumatic event.
  • subject is tested for a symptom of PTSD.
  • a subject at risk of PTSD in block 110 has not experienced a traumatic event. In an embodiment of the invention, a subject at risk of PTSD in block 110 has experienced a traumatic event.
  • a subject at risk of PTSD in block 110 is a subject who is likely to encounter a traumatic event.
  • the traumatic event is one or more than one of: abuse, domestic violence, violent crime, fire, natural disaster, combat, vehicular accident, medical emergency, death of friend or relative or terror.
  • the subject is a combat soldier, a firefighter, a law-enforcement officer, a police officer, a medical practitioner or an emergency medical responder.
  • the MC4R antagonist in block 120, is HS014.
  • the MC4R antagonist is: AGRP (83-132), SHU09119, HS131, JKC-363, BL-6020/979 or MCL0129.
  • MC4R antagonist in block 120, is administered in an amount sufficient to antagoize MC4 receptors in the CNS. In an embodiment of the invention, in block 120, MC4R antagonist is administered in an amount sufficient to treat a symptom of PTSD. In an embodiment, MC4R antagonist is administered in amount between 10 ng and 1 g per day. In an embodiment, MC4R antagonist is administered in amount between 0.1 mg and 200 mg per day.
  • MC4R antagonist in block 120, is administered intranasally. In an embodiment of the invention, in block 120, MC4R antagonist is administered orally, intravenously, intramuscularly or subcutaneously.
  • MC4R antagonist in block 120, is administered in an aqueous solution. In an embodiment of the invention, MC4R antagonist is administered intranasally to contact the nasal epithelium. In an embodiment of the invention, MC4R antagonist is administered to the upper third of the nasal cavity of the subject. In an embodiment, MC4R antagonist is administered intranasally and transported into the brain.
  • MC4R antagonist in block 120, is administered using a device which focuses administration to the maxillary sinus. Administration to the maxillary sinus is further described in United States Patent Application Publication 2011/0151393, hereby incorporated by reference.
  • MC4R antagonist is administered by a nasal drug delivery device.
  • a nasal drug delivery device examples of such devices are made by Impel Neuropharma, and devices described in PCT application publication WO 2012/119153, hereby incorporated by reference.
  • MC4R antagonist in block 120, is administered between 1 minute and about 24 hours before the subject is expected to be exposed to trauma. In an embodiment of the invention, MC4R antagonist is administered about 30 minutes before the subject is expected to be exposed to trauma.
  • a subject is tested for a symptom of PTSD in block 140.
  • the subject in block 140 the subject is tested using a PTSD symptom scale.
  • a symptom of PTSD is an anxiety-related symptom and/or a depression-related symptom.
  • a symptom of PTSD comprises trauma related flashbacks, nightmares, memory loss or distress.
  • a symptom of PTSD comprises loss of interest in life, difficulty falling asleep, irritability, hypervigilance, suicidal thoughts and fears.
  • a symptom of PTSD is ameliorated in a subject.
  • Example 2b Methods of treating a human subject to prevent and/or treat PTSD comprising administering MC4R antagonist.
  • Figure 7B shows a flow-diagram depicting a method 200 for treating and/or preventing PTSD in a human subject according to an embodiment of the invention.
  • Method 200 comprises identifying a subject exposed to a trauma in a block 220 and administering MC4R antagonist in a block 230.
  • subject is tested for a symptom of PTSD.
  • the subject exposed to a trauma was exposed to one or more than one of: abuse, domestic violence, violent crime, fire, natural disaster, combat, vehicular accident, medical emergency, death of friend or relative or terror.
  • the subject is a combat soldier, a firefighter, a law-enforcement officer, a police officer, a medical practitioner or an emergency medical responder.
  • the MC4R antagonist is HS014.
  • is an MC4R antagonist of block 230 is as described above regarding block 120.
  • the dosage of the MC4R antagonist of block 230 is as described above regarding block 120.
  • the route of administration of the MC4R antagonist of block 230 is as described above regarding block 120.
  • MC4R antagonist according to block 230 is administered following the trauma. In an embodiment, MC4R antagonist is administered immediately after the trauma. In an embodiment, MC4R antagonist is administered between 1 minute and 1 week after the trauma.
  • the subject is exposed to imaginal exposure of trauma before administration of MC4R antagonist according to block 230. In an embodiment of the invention, the subject is exposed to imaginal exposure of trauma between 6 hours and 1 second before administration of MC4R antagonist. In an embodiment of the invention, the subject is exposed to imaginal exposure of trauma after administration of MC4R antagonist according to block 230. In an embodiment of the invention, the subject is exposed to imaginal exposure of trauma between 1 second and 6 hours after administration of MC4R antagonist.
  • imaginal exposure of trauma comprises one or more than one of the following: revisiting the traumatic memory, recounting it aloud, and processing the revisiting experience.
  • the subject has not experienced symptoms of PTSD at the time of administration. In an embodiment of the invention, the subject has experienced symptoms of PTSD at the time of administration.
  • a subject is tested for a symptom of PTSD in block 240.
  • the subject in block 240 the subject is tested using a PTSD symptom scale.
  • a symptom of PTSD is an anxiety-related symptom and/or a depression-related symptom.
  • a symptom of PTSD comprises trauma related flashbacks, nightmares, memory loss or distress.
  • a symptom of PTSD comprises loss of interest in life, difficulty falling asleep, irritability, hypervigilance, suicidal thoughts and fears.
  • a symptom of PTSD is ameliorated in a subject.
  • compositions according to an embodiment of the invention are conveniently presented in unit dosage form and are prepared by any of the methods well known in the art of pharmacy.
  • the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, patch, ampoule, vial or pre-filled syringe.
  • compositions of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one active component together with a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes.
  • compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the components of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • compositions according to embodiments of this invention may also be administered in a controlled release formulation such as a slow release or a fast release formulation.
  • a controlled release dosage composition may be prepared using methods well known to those skilled in the art.
  • solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • compositions according to embodiments of the invention may contain an active amount of 0.1%-95% of the MC4R antagonist (s), preferably l%-70%.
  • the daily dosage of the MC4R antagonist is between 0.1 milligram (mg) and 1500 mg.
  • a MC4R antagonist is a sole active pharmaceutical agent used to treat a disease.
  • combination therapies in which a MC4R antagonist is used in combination with another active pharmaceutical agent to treat a disease.
  • “In combination with” refers to both drugs being substantially effective in the body at a same time. Both drugs can be administered substantially at the same time, or both drugs can be administered at different times but have effect on the body at the same time.
  • a method for the treatment or prevention of a symptom of PTSD comprising administering to a patient in need thereof, of a melanocortin receptor antagonist.
  • the melanocortin receptor antagonist is a melanocortin receptor 4 (MC4R) antagonist.
  • the method comprises preventing a symptom of PTSD in a subject at risk of experiencing a symptom of PTSD.
  • the subject has been exposed to a traumatic event.
  • the traumatic event is selected from the group consisting of: abuse, domestic violence, violent crime, fire, natural disaster, combat, vehicular accident, medical emergency, death of friend or relative and terror.
  • the symptom of PTSD is an anxiety-related symptom.
  • the symptom of PTSD is a depression-related symptom.
  • the symptom of PTSD is selected from the group consisting of: trauma related flashbacks, nightmares, memory loss or distress, loss of interest in life, difficulty falling asleep, irritability, hypervigilance, suicidal thoughts and fears.
  • the method comprises administration of the melanocortin receptor antagonist within 24 hours prior to the exposure of the subject to a potentially traumatic event.
  • the method comprises administration of the melanocortin receptor antagonist between immediately after a traumatic event and 24 hours after a traumatic event.
  • the method comprises administration of the melanocortin receptor antagonist about half an hour after a traumatic event.
  • the melanocortin receptor antagonist is an MC4R antagonist, and is selected from the group consisting of: HS014, AGRP (83-132), SHU09119, HS131, JKC-363, BL-6020/979 and MCL0129.
  • the MC4R antagonist is HS014.
  • the administration is via the oral, intravenous, intramuscular or subcutaneous route.
  • the administration is via the intranasal route.
  • the administration is to the maxillary sinus.
  • the administration reaches the brain via the intranasal route.
  • the treatment reduces corticosterone plasma concentrations in the subject.
  • a dose of the melanocortin receptor antagonist is between 10 ng and 1 g.
  • a dose of the melanocortin receptor antagonist is between 0.1 mg and 200 mg per day.
  • the method comprises administration in combination with another active agent.
  • the active agent is Neuropeptide Y.
  • the method comprises administering a melacortin receptor antagonist with at least one pharmaceutically acceptable excipient.
  • the method further comprises imaginal exposure of a trauma.
  • a pharmaceutical composition comprising a melanocortin receptor antagonist for the treatment or prevention of a symptom of PTSD.
  • each of the verbs, "comprise,” “include” and “have,” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.

Abstract

Selon un aspect des modes de réalisation, l'invention concerne une méthode destinée à prévenir et/ou à traiter le syndrome de stress post-traumatique (SSPT) par administration à un sujet d'une quantité efficace d'antagoniste des récepteurs de mélanocortines. D'autres modes de réalisation concernent une méthode destinée à prévenir et/ou à traiter le SSPT par administration à un sujet d'une quantité efficace d'antagoniste du récepteur de la mélanocortine de type 4 (MC4R). Eventuellement, l'antagoniste des récepteurs de mélanocortines peuvent être administrés par voie intranasale.
PCT/IL2014/050232 2013-03-08 2014-03-09 Traitement du syndrome de stress post-traumatique avec un antagoniste des récepteurs de mélanocortines WO2014136118A1 (fr)

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Cited By (3)

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EP3078383A1 (fr) * 2015-04-10 2016-10-12 Consejo Superior De Investigaciones Cientificas Utilisation d'un peptide qbp1 pour l'inhibition de la consolidation de la mémoire
WO2017066754A1 (fr) * 2015-10-15 2017-04-20 The Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions et méthodes de traitement de la dépression et de l'anxiété
US11542302B2 (en) 2015-10-15 2023-01-03 Arizona Board Of Regents On Behalf Of The University Of Arizona Modulators of melanocortin receptors for the treatment of depression and anxiety

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WO2016162506A1 (fr) * 2015-04-10 2016-10-13 Consejo Superior De Investigaciones Cientificas Utilisation de peptide qbp1 pour inhiber une consolidation mnésique
WO2017066754A1 (fr) * 2015-10-15 2017-04-20 The Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions et méthodes de traitement de la dépression et de l'anxiété
US10653743B2 (en) 2015-10-15 2020-05-19 Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for the treatment of depression and anxiety by a melanocortin 5 receptor antagonist, PG-20N
US11542302B2 (en) 2015-10-15 2023-01-03 Arizona Board Of Regents On Behalf Of The University Of Arizona Modulators of melanocortin receptors for the treatment of depression and anxiety

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