Classifications

• • 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
  • A61K38/07—Tetrapeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/401—Proline; Derivatives thereof, e.g. captopril
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
• • 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
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the central nervous system (CNS) of mammals employs many neuroactive peptides to effect specialized signaling within the brain and spinal cord including the neuroactive peptides somatostatin, choiecystokinm, VIP, Substance P, enkephalin, Neuropeptide Y (NPY), Neurotensin, TRH, CCK, and dynorphin.
• somatostatin somatostatin
• NPY Neuropeptide Y
• Neurotensin TRH
• CCK dynorphin
• the disclosure relates to a method of treating, suppressing and/or preventing cortical spreading depression (SD), comprising administering to a patient in need thereof a pharmaceutically effective amount of a GL YX peptide, in certain embodiments, the disclosure relates to treating or ameliorating long-term post migraine sequelae in a patient in need thereof, comprising administering to the patien a pharmaceutic lly effective amount of a GLYX peptide,
• the invention relates to a method of treating, suppressing, and/or preventing cortical spreading depression in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound represented by:
• FIG. 1 shows focal, high [K r ]-indueed spreading depression (SD) in field CA1 of hippoeampai slices resulting in a change in luminance reflecting the spreading wave of mass depolarization of neurons and glia.
• Figures 11A-11B show rescue of blast-induced learning deficits by rapastinel (3 mg/kg IV; 1 hour post-blast) in PEL tests 24 hours post-blast.
• Figure 11A shows blast recovery time (latency to normal ambulation) data.
• Figure 1 I B shows the results of a single 3 min Positive Emotional Learning (PEL) test session conducted 24 hours post-blast using a between subjects design.
• N 4-6 per group. * P ⁇ 0.05 ( Figure 11A) A OVA, or ( Figure 1 IB) fisher's PLSD post hoc test, rapastinel ⁇ TBI vs. vehicle + TBI.
• Probable migraine describes conditions that have some characteristics of migraines, but where there is not enough evidence to diagnose it as a migraine with certainty (in the presence of concurrent medication overuse).
• Chronic migraine is a complication of migraines, and is a headache that fulfills diagnostic criteria for migraine headache and occurs for a greater time interval. Specifically, greater or equal to 15 days/month for longer than 3 months.
• GLYX peptide refers to a peptide haying NMDAR glycine-site partial agonist/antagonist activity. GLYX peptides may be obtained by well-known recombinant or synthetic methods such as those described in US Patents 5,763,393 and 4,086,196 herein incorporated by reference. In some embodiments, GLYX refers to a tetrape tide having the amino acid sequence Thr-Pro-Pro-Thr, or L-threonyl-L-prolyl-L-prolyl- L-ihreonine amide.
• GLYX-13 may act predominantly at NR2B-containing MDARs, and may not display the classic side effects of known NMDAR modulators such as CPC- 101,606 and ketamine.
• an anti-migraine or other therapeutic effect with essentially no sedation may be produced by GLYX-13 when administered to a subject in therapeutically effective amounts.
• GLYX-13 may not have abuse potential (e.g., may not be habit-forming).
• GLYX-13 may increase AMPA GluRl serine-845 phosphorylation.
• glycogen synthase kinase 3 ⁇ (GSK- ⁇ ) may be activated by GLYX-13.
• levels of ⁇ -catentn may be altered after administration of GLYX-13.
• a migraine sufferer that has, or is at risk of, any of these conditions may take medications to treat or to manage these diseases, and these medications may adversely interact with currently used medications for the treatment of migraine with aura.
• some of these conditions are contraindications for triptan therapy (e.g., stroke and sumatriptan therapy).
• the FDA issued a public health advisory in 2006 regarding serotonin syndrome, a life-threatening condition that may occur whe a triptan is used together with certain anti-depressants that are serotonin reuptake inhibitors (SSRls) or selective serotonin/norepinephrine reuptake inhibitors (SNRls). Accordingly, the methods described herein may be useful for the treatment of patients who have depression or patients who have suffered, or are at risk of, stroke.
• SSRls serotonin reuptake inhibitors
• SNRls selective serotonin/norepinephrine reuptake inhibitors
• any compositions of the disclosure will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the disclosure may be readily determined by techniques known to those of skill in the art or as taught herein. In general, satisfactory results can be obtained when the compound is administered to a human at a daily dosage of, for example, between 0.05 nig and 3000 mg (measured as the solid form), e.g. about 10 mg to about 500 nig, or e.g., about 1 to about 200mg/kg.
• the effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.
• Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
• compositions may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an exeipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
• any conventional additive such as an exeipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.
• Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof,
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof,
• Exemplary drags that may be used in combination with a GLYX peptide include Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft, Welibutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), and Ludiomiil.
• GLYX-13 was bath- applied at 1, 10, or 50 ⁇ to hippocampal slices for 30 niin prior to brief ejection of high [K+] (1 fflM in patch pipette) into stratum radiatum of the C Al region and attempted to ehcit SD.

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• Health & Medical Sciences (AREA)
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• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
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• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Immunology (AREA)
• Gastroenterology & Hepatology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Pain & Pain Management (AREA)
• Dermatology (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2015
  • 2015-06-23 WO PCT/US2015/037177 patent/WO2015200322A1/en not_active Ceased
  • 2015-06-23 KR KR1020177001848A patent/KR20170018072A/ko not_active Ceased
  • 2015-06-23 BR BR112016030375A patent/BR112016030375A8/pt not_active IP Right Cessation
  • 2015-06-23 JP JP2016575106A patent/JP6688748B2/ja active Active
  • 2015-06-23 RU RU2017101410A patent/RU2721401C2/ru active
  • 2015-06-23 AU AU2015280108A patent/AU2015280108B2/en not_active Ceased
  • 2015-06-23 EP EP15811633.5A patent/EP3157943A4/en not_active Withdrawn
  • 2015-06-23 CA CA2953170A patent/CA2953170A1/en not_active Abandoned
  • 2015-06-23 MX MX2016017388A patent/MX2016017388A/es unknown
  • 2015-06-23 CN CN201580033913.6A patent/CN106661085A/zh active Pending
• 2020
  • 2020-04-06 JP JP2020068289A patent/JP2020114863A/ja active Pending

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