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WO2003039487A2 - Cyclo(prolyl-glycine) et procedes utilises pour traiter des troubles neuronaux - Google Patents

Cyclo(prolyl-glycine) et procedes utilises pour traiter des troubles neuronaux Download PDF

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Publication number
WO2003039487A2
WO2003039487A2 PCT/US2002/036235 US0236235W WO03039487A2 WO 2003039487 A2 WO2003039487 A2 WO 2003039487A2 US 0236235 W US0236235 W US 0236235W WO 03039487 A2 WO03039487 A2 WO 03039487A2
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WIPO (PCT)
Prior art keywords
cpg
disease
injury
administered
animal
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PCT/US2002/036235
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English (en)
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WO2003039487A3 (fr
Inventor
Jian Guan
Peter David Gluckman
Frank Sieg
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Neuronz Limited
Neuronz Biosciences, Inc.
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Priority to AU2002340465A priority Critical patent/AU2002340465A1/en
Publication of WO2003039487A2 publication Critical patent/WO2003039487A2/fr
Publication of WO2003039487A3 publication Critical patent/WO2003039487A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to compositions comprising cyclo(Prolyl-Glycine) "cyclo(Pro-Gly),” “cyclic PG” or “cPG”) and methods for its use in the treatment or prevention of cell damage in animals, and more particularly relates to compositions and methods of treating injury or disease of neurons in the central nervous system (CNS).
  • CNS central nervous system
  • Degeneration and/or death of cells in the nervous system is a substantial medical problem, and results in increased morbidity and mortality among people affected with one or more of a variety of CNS abnormalities.
  • Such abnormalities include traumatic injury, diseases such as Parkinson's Disease, Alzheimer's Disease, stroke, and decreased neural perfusion secondary to cardiac arterial bypass graft surgery ("CABG").
  • CABG cardiac arterial bypass graft surgery
  • CABG cardiac arterial bypass graft surgery
  • IGF-1 Insulin-like growth factor 1
  • IGFBP-2 IGF binding protein-2
  • IGFBP-3 IGF binding protein-3
  • IGF-1 was anticipated to be more efficacious administered at a site distant from the injury than desu IGF-1, which does not bind well to binding proteins. This was indeed the case.
  • Des ⁇ _ 3 IGF-1 was not significantly active as a neuronal rescue agent at a dose equivalent to that at which IGF-1 shows neuroprotection.
  • IGF-1 is a naturally occurring peptide that can decrease binding of glutamate to glutamate receptors of neurons (Bourguinon, U.S. Patent No: 5,804,550, inco ⁇ orated herein fully by reference). IGF-1 also can decrease neuronal degeneration caused by damage and/or disease. IGF-1 can be modified by proteolytic cleavage in nervous and other tissues to des ⁇ - 3 IGF-1 and a 3 amino acid peptide, glycine-proline-glutamate ("Gly-Pro-Glu" or "GPE"), the amino-terminal tripeptide of IGF-1. GPE is also neuroprotective (Gluckman et al., U.S. Patent No: 6,187,906, inco ⁇ orated herein fully by reference).
  • one object of the present invention is to provide compositions and new approaches to therapy for injury and disease, particularly CNS injury and disease.
  • administering cPG can be used to restore damaged tissue in mammals.
  • this invention provides a method of treating an animal to protect neurons otherwise destined to die as a result of an insult from injury or disease, comprising administering to said animal an effective amount of cPG.
  • Certain embodiments of this invention include administering cPG to animals suffering from neuronal or glial cell degeneration.
  • cPG can substantially reverse or prevent neuronal damage in CNS tissues.
  • cPG can be used to treat a variety of conditions characterized by neuronal degeneration and/or neuronal cell death.
  • Such conditions include, by way of example only, hypoxic ischemic damage, damage associated with Parkinson's disease, Alzhemier's disease, damage associated with stroke and/or coronary arterial bypass graft (CABG) surgery, or damage caused by neurotoxins.
  • other embodiments of the invention provide a method of treating a patient with neuronal cell loss as the result of an insult from injury or disease, comprising administering to said patient an amount of cPG effective to stimulate neurite outgrowth.
  • cPG The effects of cPG are dose-related. At certain doses (about 10 nM), cPG can restore glutamate-induced death of cerebellar cells to values undistinguishable from those found in vehicle-treated controls. Increasing the dose of cPG by about 100 fold also can result in substantial neuroprotection in the light of a neurotoxic insult. Additionally and su ⁇ risingly, at lower doses (e.g., 1 nM), cPG can actually increase neuronal cell numbers compared to vehicle-treated controls. Thus, cPG can also be used to promote neuroregeneration. cPG can also have potent neuroprotective effects in cerebellar neurons exposed to hypoxic or ischemic damage. Thus, cPG can be an effective therapeutic agent to treat neural degeneration, damage or neuronal cell death associated with hypoxia, stroke or CABG.
  • certain embodiments of the invention include a method of treating a patient with neuronal cell loss as the result of an insult from injury or disease, comprising administering to said patient cPG in an amount sufficient to stimulate neural fasiculation.
  • kits including, in some embodiments, a kit comprising cPG formulated in a pharmaceutically acceptable buffer, a container for holding said cPG formulated in a pharmaceutically acceptable buffer, and instructions.
  • this invention provides a method of treating an animal having neural degeneration, comprising providing an animal having a functional deficit associated with said neural degeneration; administering a therapeutically effective amount of cPG to said animal; and monitoring a change in said functional deficit in said animal.
  • this invention provides a method for preparing a medicament for treating an animal having a functional deficit associated with neural degeneration, comprising mixing cPG in a pharmaceutically acceptable buffer.
  • Figure 1 depicts a graph showing effects of cPG on neuronal survival after exposure to glutamate.
  • Figure 2 depicts a graph showing effects of cPG on neuronal survival and neurite outgrowth.
  • Figures 3 a and 3b are photomicrographs of cerebellar explants showing effects of cPG on fascicle formation in vitro.
  • Figure 4 depicts a graph showing effects of cPG on functional recovery of motor behaviour in vivo following a 6-OHDA lesion.
  • Figure 5 depicts neuronal rescue due to cPG following hypoxic-ischemic brain injury in adult rats.
  • Figure 6 depicts a graph showing effects of cPG on brain regions following hypoxic-ischemic injury in rats.
  • compositions are provided that can also include one or more other agents that promote neural regeneration, decrease cell degeneration or death, or are neuroprotective.
  • methods of treatment or prevention of cell damage and death in animals are provided, that comprise providing a composition comprising cPG in response to injury or disease.
  • kits for the method of treatment or prevention of cell damage and death in mammals in response to injury or disease, where the kit comprises a dosage form of cPG formulated in a pharmaceutically acceptable buffer, a container holding the dosage form, and instructions.
  • the kit may further comprise one or more other compounds.
  • Such other compounds may be selected from the group consisting of for example, growth factors and associated derivatives, e.g., insulin-like growth factor-I [IGF-I], insulin-like growth factor-II [IGF-II], the tripeptide GPE, transforming growth factor- ⁇ l, activin, growth hormone, nerve growth factor, growth hormone binding protein, and/or IGF-binding proteins. It can be readily appreciated that other compounds may be used along with cPG
  • compositions and methods of promoting fasiculation of axons By promoting formation of nerve bundles, cPG may be useful in treating conditions in which nerve processes (axons and/or dendrites) have become severed, such as in sha ⁇ force injuries, local areas of necrosis or disease, or other localized injuries to nerve processes.
  • kit for restoring neural function comprising a dosage form of cPG formulated in a pharmaceutically acceptable buffer, a container holding said dosage form, and instructions.
  • kits may further comprise cGP along with another neuroprotective compound.
  • Such compounds include IGF-I, GPE, interferon beta lb (Betaseron®) or consensus interferon (Infergen®, interferon alfacon-1).
  • compositions and methods to treat or prevent cell damage and death in response to injury and disease comprise administration of a therapeutic amount of cPG alone or in combination with other agents, after the insult.
  • cPG can be used either alone or in combination with other agents to prevent adverse effects of planned brain injury.
  • Such conditions include CABG or other planned surgeries such as brain surgery, vascular surgery or other interventions that may lead to decreased perfusion of the nervous system.
  • adverse neurological effects can be ameliorated.
  • the present invention is broadly based upon the applicant's su ⁇ rising finding that cPG can protect cells, particularly nerve cells, against damage, loss of neurites, and/or apoptotic or necrotic cell death. These capabilities of cPG are achieved through increasing the effective concentration or amount of cPG in the affected tissue of a patient.
  • the amount of cPG may be increased by providing precursors of cPG.
  • CyclicPG has been isolated from the rat brain tissue and has been shown to improve memory in animal models (US 5,439,930; Gudasheva et al., 1996 FEBS Lett 391: 149-152; Gudasheva et al., 1999 Biull Eksp Biol Med 128: 411-3; Gudasheva et al., 2001, Bull Exp Biol Med 131: 464-6), and cPG has been found in coffee.
  • cPG exhibits neuroprotection in both cell culture and in animal models of neurodegenerative disease and can therefore be an effective addition or alternative to conventional therapies for neural degeneration.
  • the mechanism of cPG's protective effects are not known, one possible mechanism involves protecting cells from apoptotic and necrotic cell death.
  • cPG can be used as an effective therapy for a variety of neurological diseases, including hypoxia, ischemia and neurotoxin-induced nerve damage.
  • cPG can be used in the absence of any particular neurological deficit to promote neurite outgrowth and fasiculation of nerves.
  • cPG may be an effective way of promoting neurite regeneration.
  • compositions and methods of the invention find use in the treatment of animals, such as human patients, suffering from neural injury or disease. Still more generally, the compositions and methods of the invention find use in the treatment of mammals, such as human patients, suffering from nerve damage or potential apoptotic and/or necrotic cell death, due to injuries and diseases.
  • Specific conditions and diseases include septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, allograft rejection, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataract, retinal disorders, age-related macular degeneration, optic neuritis ileitis, inflammation induced by ove ⁇ roduction of inflammatory cytokines, hemorrhagic shock, anaphylactic shock, burn, infection leading to the ove ⁇ roduction
  • the invention has application in the induction of nerve bundle formation following insult in the form of trauma, toxin exposure, asphyxia or hypoxia-ischemia. And has application in the treatment or prevention of apoptosis in response to injury or disease in the form of cancers, viral infections, autoimmune diseases, neurological diseases and injuries and cardiovascular diseases.
  • Injuries to and diseases of the cerebellum include cerebellar infarction, cerebellar hemorrhage, adult onset hereditary ataxias including SCA1, SCA2, SCA3/MJD, SCA4, SCA5, SCA6, SCA7, dominantly inherited olivopontocerebellar atrophy, recessively inherited olivopontocerebellar atrophy; sporadic cerebellar degeneration including sporadic olivopontocerebellar atrophy, multiple system atrophy; drug induced, metabolic and endocrine disorders affecting the cerebellum including cerebellar dysfunction and loss of Purkinje cells due to the administration of the chemotherapeutic agents 5-fluorouracil and cytosine arabinoside, cerebellar atrophy in patients suffering from epilepsy exposed to phenytoin, alcoholic cerebellar degeneration and Wemicke's encephalopathy.
  • cPG treatment may be given before an injury, for example, before elective surgery.
  • relevant elective procedures include neural surgery, in which retraction of lobes of the brain may lead to cerebral oedema, or heart operations, such as valve replacement, in which inevitable small emboli are said to lead to detectable impairment of brain function in some 75% of cases.
  • Cyclo(Pro-Gly) cPG's anti-apoptotic and anti-necrotic activity can be measured by in vivo using cell counts by methods such as those discussed in Klempt et al, 1992.
  • cPG can also be measured in vitro using mass spectroscopy, immunological, or chromatographic methods known in the art.
  • CNS damage may for example be measured clinically by the degree of permanent neurological deficit cognitive function, and/or propensity to seizure disorders.
  • the therapeutic ratio of a compound can be determined, for example, by comparing the dose that gives effective anti-apoptotic and anti-necrotic activity in a suitable in vivo model such as experimental immune encephalomyelitis (Mendel et al., 1995 Ewr. J. Immunol. 25: 1951-1959) in a suitable animal species such as the mouse, with the dose that gives significant weight change (or other observable side-effects) in the test animal species.
  • a suitable in vivo model such as experimental immune encephalomyelitis (Mendel et al., 1995 Ewr. J. Immunol. 25: 1951-1959) in a suitable animal species such as the mouse
  • the total pharmaceutically effective amount of the cPG agonist compound administered parenterally per dose will be in a range that can be measured by a dose response curve.
  • the amount of cPG agonist to be employed can be calculated on a molar basis based on these serum levels of cPG.
  • one method for determining appropriate dosing of the compound entails measuring cPG levels in a biological fluid such as a body or blood fluid. Measuring such levels can be done by any means, including RIA and ELISA. After measuring cPG levels, the fluid is contacted with the compound using single or multiple doses. After this contacting step, the cPG levels are re-measured in the fluid. If the fluid cPG levels have fallen by an amount sufficient to produce the desired efficacy for which the molecule is to be administered, then the dose of the molecule can be adjusted to produce maximal efficacy.
  • This method can be carried out in vitro or in vivo. Preferably, this method is carried out in vivo, i.e.
  • the compound herein is administered to the mammal using single or multiple doses (that is, the contacting step is achieved by administration to a mammal) and then the cPG levels are remeasured from fluid extracted from the mammal.
  • compositions and Routes of Administration cPG may be administered using any suitable means.
  • a shunt into a ventricle of the animal may be used.
  • peripheral administration via a blood vessel, such as a vein may be used.
  • direct injection into the site of therapy may be desirable.
  • cPG may be injected directly into a site of neural damage.
  • Such routes of administration may be especially desired in situations in which perfusion of that location is compromised either by decreased vascular perfusion or by decreased cerebral spinal fluid (CSF) flow to that area.
  • CSF cerebral spinal fluid
  • the effective amount of cPG in the CNS can be increased by administration of a pro-drug form of cPG which comprises cPG and a carrier, cPG and the carrier being joined by a linkage which is susceptible to cleavage or digestion within the patient. Any suitable linkage can be employed which will be cleaved or digested to release cPG following administration. Additionally, analogs of cPG, naturally occurring precursors of cPG may be administered and converted to cPG by endogenous means.
  • cPG levels can be increased through an implant which is or includes a cell line which is capable of expressing cPG in an active form within the CNS of the patient.
  • cPG can be administered as part of a medicament or pharmaceutical preparation. This can involve combining cPG with any pharmaceutically appropriate carrier, adjuvant or excipient. The selection of the carrier, adjuvant or excipient will of course usually be dependent upon the route of administration to be employed.
  • cPG cPG
  • administration route can vary widely.
  • An advantage of cPG is that it can be administered peripherally. This means that it need not be administered directly to the CNS of the patient in order to have effect in the CNS.
  • peripheral route can include parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracisternal, topical, infusion (using eg. slow release devices or minipumps such as osmotic pumps or skin patches), implant, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, oral, buccal, pulmonary, rectal or vaginal.
  • the compositions can be formulated for parenteral administration to humans or other mammals in therapeutically effective amounts (eg. amounts which eliminate or reduce the patient's pathological condition) to provide therapy for the neurological diseases described above.
  • Convenient administration routes include subcutaneous injection (e.g. dissolved in a physiologically compatible carrier such as 0.9% sodium chloride) or orally (in a capsule).
  • Cyclic PG can be administered using any convenient route. Examples include administration by lateral cerebroventricular injection or through a surgically inserted shunt into the lateral cerebroventricle of the brain of the patient, intraveneously, direct injection into the desired location or other routes.
  • a suitable dose range may for example be between about l ⁇ g to lOOmg of cPG per lOOg of body weight where the dose is administered centrally.
  • the amount of cPG can be from about l ⁇ g per Kg body weight to about lOOmg of cPG per kg of body weight of the animal.
  • restoring nerve function in an animal can comprise administering a therapeutic amount of cPG in combination with another neuroprotective agent, such as IGF-1.
  • IGF-1 can be administered in a dose range of about 0.1 to lOOO ⁇ g of IGF-1 per lOOg body weight of the mammal or an interferon from about 0.1 to 1000/xg of interferon per lOOg of body weight of the mammal.
  • the interferon is interferon beta.
  • the interferon is interferon beta lb (Betaseron®).
  • the interferon comprises consensus interferon (Infergen®, interferon alfacon-1).
  • cPG compounds can be obtained from a suitable commercial source.
  • cPG can be directly synthesized by conventional methods such as the stepwise solid phase synthesis method of Merryfield et al, 1963.
  • synthesis can involve the use of commercially available peptide synthesizers such as the Applied Biosystems model 430 A.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polylactides (U.S. Pat. No.
  • Liposomes containing the compound are prepared by methods known per se: DE 3,218,121; Epstein et al, 1985; Hwang et al, 1980; EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appln. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324.
  • the liposomes are of the small (from or about 200 to 800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the most efficacious therapy.
  • PEGylated peptides having a longer life can also be employed, based on, e.g., the conjugate technology described in WO 95/32003 published November 30, 1995.
  • the compound is formulated generally by mixing each at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically, or parenterally, acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • a pharmaceutically, or parenterally, acceptable carrier i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides.
  • the formulations are prepared by contacting the compound uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation.
  • the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein.
  • the carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability.
  • additives such as substances that enhance isotonicity and chemical stability.
  • Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, trehalose, or dextrins; chelating agents such as EDTA; sugar alcohols such as
  • the compound is typically formulated in such vehicles at a pH of from or about 4.5 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of salts of the compound.
  • the final preparation may be a stable liquid or lyophilized solid.
  • Formulations of the peptide in pharmaceutical compositions can also include adjuvants.
  • Typical adjuvants which may be inco ⁇ orated into tablets, capsules, and the like are a binder such as acacia, com starch, or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavoring agent such as peppermint, wintergreen, or cherry.
  • a binder such as acacia, com starch, or gelatin
  • an excipient such as microcrystalline cellulose
  • a disintegrating agent like corn starch or alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose or lactose
  • a flavoring agent such as peppermint, wintergreen, or cherry.
  • a liquid carrier such as a fatty oil.
  • a syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent, and a flavoring agent such as cherry.
  • a sweetener such as sucrose
  • preservatives like propyl paraben a coloring agent
  • a flavoring agent such as cherry.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants, and the like can be inco ⁇ orated according to accepted pharmaceutical practice.
  • kits are also contemplated for this invention.
  • a typical kit would comprise a container, preferably a vial, for the cPG formulation comprising cPG agonist compound in a pharmaceutically acceptable buffer, and instructions, such as a product insert or label, directing the user to utilize the pharmaceutical formulation.
  • the pharmaceutical formulation ordinarily will be stored in unit or multi-dose containers, for example, in sealed ampules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution.
  • a lyophilized formulation 10-mL vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous solution of compound, and the resulting mixture is lyophilized.
  • the infusion solution is prepared by reconstituting the lyophilized compound using bacteriostatic Water-for-Injection. It can be readily appreciated that other dosage forms and types of preparations can be used, and all are considered to be part of this invention.
  • Combination therapy with the cPG agonist compound herein and one or more other appropriate reagents that increase total cPG in the blood or enhance the effect of the cPG agonist is also part of this invention. These reagents generally allow the cPG agonist compound herein to release the generated cPG.
  • glutamate is a neurotransmitter in the CNS of mammals, including humans.
  • glutamate is neurotoxic, resulting in neuronal cell death. Because glutamate is a naturally occurring neurotransmitter in the CNS of mammals, including humans, it is a valuable predictive tool useful for identifying and characterizing agents used to treat neurotoxicity.
  • the tissue was sieved through (125 ⁇ m pore size gauze) and centrifuged (2 minutes at 60g) twice to exchange the medium into serum-free BSA-supplemented START V medium (Biochrom). The second centrifugation step was done with 1ml of START V medium.
  • the microexplants were reconstituted into 500 ⁇ l of START V medium and put on ice.
  • FIG. 2 The results of Study 2 are shown in Figure 2.
  • glutamate (1 mM) caused substantial decrease in cells having neurites.
  • Six hours after addition of glutamate substantially increased the appearance of cells with neurites in a dose range of 10-lOOnM.
  • cPG significantly increased neurite outgrowth compared to vehicle-treated controls.
  • cPG promoted neuronal survival in the presence of neurotoxic amounts of glutamate.
  • FIG 3. The top panel ( Figure 3 a) shows fascicle formation in a cerebellar explant in the presence of 1 mM glutamate for 6 hours, followed by 42 hours incubation with 1 nM cPG.
  • a bundle of nerve processes (a fascicle) can be seen in the middle of Figure 3a, extending toward the right from a group of surviving neurons.
  • Cyclic PG prevented (Study 1) and reversed (Study 2) glutamate- induced neurotoxicity, indicating that cPG is neuroprotective of neurons exposed to a highly toxic dose of glutamate. Moreover, in the presence of glutamate, cPG significantly increased neurite outgrowth compared to explants treated with glutamate plus the vehicle for cPG, indicating that cPG treatment substantially improves neurite outgrowth or neural maturation. Moreover, the finding that cerebellar explants formed fasciles after exposure to cPG indicates that cPG can be useful for promoting neurite and nerve regeneration. In particular, cPG can be desirably used to promote neurite regeneration after, for example, axonal damage. Many conditions are characterized by loss of neural function.
  • cPG By promoting neurite and nerve regeneration, cPG can be a useful therapeutic agent to treat spinal cord injuries, and other conditions in which neural processes are lost, due either to cell death or to injury to peripheral nerve processes.
  • Example 2 Effects of CycIo(Pro-Gly) on 6-Hydroxy Dopamine-Induced Motor Deficits
  • 6-OHDA was injected through a 25G needle connected via a polyethylene catheter to a lOO ⁇ l Hamilton syringe.
  • the 6-OHDA was infused by a microdialysis infusion pump at a rate of 0.5 ⁇ l/min.
  • the needle was left in the brain for a further 3 minutes before being slowly withdrawn.
  • the skin was sutured with 2.0 silk and the rats were allowed to recover from anaesthesia.
  • the rats were housed in a holding room with free access to food and water at all times except during behavioural testing.
  • Cyclic PG was dissolved in saline.
  • Four different doses of cPG (0, 0.1 0.5 lmg/kg, Bachem) were administered intraperitoneally 2h after injecting the 6-OHDA.
  • rats Seven days after administering the 6-OHDA, rats were injected with 0. lmg/kg apomo ⁇ hine, and the number of contralateral rotations/hour was recorded and calculated using a computerised Rotameter (St Diego Instruments). The experimenters were blinded from the treatment groups.
  • Cyclic PG improved functional recovery after a 6-OHDA induced nigral-striatal lesions in a dose-dependent manner.
  • the highest dose tested (lmg/kg) reduced the functional deficit (apomo ⁇ hine induced rotations) by 47%.
  • This data indicates cPG has potential value as a treatment for neuromotor deficits, such as those characteristic of Parkinson's disease.
  • the cerebellum is responsible for promoting and maintaining smoothness of motion by inhibiting overactivity of motoneuron pathways in the cerebrum and spinal cord, these results indicate an important therapeutic role of cPG in treatment of a variety of conditions involving the cerebellum and associated structures.
  • CABG cardiac arterial bypass graft surgery
  • HI hypoxic-ischemic injury
  • a guide cannula was stereotaxically placed on the top of the dura 1.5mm to the right of the mid- line and 7.5mm anterior to the interaural zero plane under halothane anaesthesia.
  • the right carotid artery was double ligated one day after the cannulation.
  • each of the rats were placed in an incubator where the humidity (90 ⁇ 5%) and temperature (31° ⁇ 0.5°C) were controlled for another hour, then exposed to hypoxia (6% oxygen) for lOmin. The animals were kept in the incubator for an additional 2 hours before treatment.
  • a first study twenty two pairs of rats were treated intracerebral ventricularly (icv) with either cPG (0.2 ⁇ g and 2 ⁇ g) or its vehicle (normal saline) alone.
  • cPG 0.2 ⁇ g and 2 ⁇ g
  • vehicle normal saline
  • nine pairs of rats were treated with either cPG (20ng; icv) or the vehicle 2 hours after hypoxic-ischemic insult. Rats in each group were simultaneously infused with cPG or its vehicle under light anaesthesia (1.5% halothane) 2 hours after the insult. A total volume of 20 ⁇ l was infused (icv) over 20 minutes by a micro-infusion pump.
  • Histological examination was performed on rats 5 days after the hypoxic-ischemic injury.
  • the rats were killed with an overdose of sodium pentobarbital and were perfused transcardially with normal saline followed by 10% formalin.
  • the brains were kept in the same fixative for a minimum of 2 days before being processed using a standard paraffin imbedding procedure.
  • corthelial sections 8 ⁇ m in thickness were cut from the striatum, cerebral cortex and hippocampus and were stained with thionin and acid fuchsin. The histological outcome was assessed at three levels: (1) the mid level of the striatum, (2) where the completed hippocampus first appeared and (3) the level where the ventral horn of the hippocampus just appears.
  • the severity of tissue damage was scored in the striatum, cortex and the CAl-2, CA3, CA4 and dentate gyrus of the hippocampus. Tissue damage was identified as neuronal loss (acidophilic (red) cytoplasm and contracted nuclei), pan-necrosis and cellular reactions. Tissue damage was scored using the following scoring system: 0: tissue showed no tissue damage, 1: ⁇ 5% tissue was damaged, 2: ⁇ 50% tissue was damaged, 3: >50% tissue was damaged and 4: >95% tissue was damaged.
  • Figure 5 shows that hypoxic-ischemic injury (left bars of each set) resulted in significant damage scores in each of the areas of the brain studied.
  • Figure 5 also shows that central administration of a relatively low dose of cPG (middle bars of each set; 0.2 ⁇ g) significantly reduced the tissue damage in each brain region examined compared to the vehicle treated group (p ⁇ 0.001).
  • Figure 5 also shows that in some regions of the brain, a higher dose of cPG (2 ⁇ g; right bars of each set) decreased brain damage.
  • FIG. 6 shows that hypoxia/ischemia produces tissue damage (left bars of each set), and that at a dose of 20 ng (right bars of each set), cPG selectively reduced tissue damage in the striatum CA 1-2 and CA4, and by more than 50% in the dentate gyrus and the cortex.
  • cPG can be neuroprotective against neural damage caused by hypoxic-ischemic injury, even when administered after hypoxic- ischemic injury. This su ⁇ rising finding indicates that cPG can be a useful agent to treat a variety of conditions characterized by neural degeneration or cell death, including stroke and cardiac arterial bypass graft surgery, and can stimulate neural regeneration though increased neurite outgrowth and increased formation of nerve bundles.
  • compositions and methods of this invention are useful for preparing medicaments useful for treating neural degeneration and reversing functional neurological deficits in animals afflicted with neurodegenerative conditions including hypoxic-ischemic injury, diseases such as Parkinson's Disease and Alzheimer's Disease.

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Abstract

L'invention concerne des modes de réalisation de compositions pharmaceutiques comprenant cyclo(Pro-Gly) et des procédés de leur utilisation dans le traitement de la dégénérescence neuronale. Les cyclo-PG empêchent sensiblement la dégénérescence neuronale toxique et la mort cellulaire et favorisent la croissance des neurites dans les neurones, notamment dans les neurones cérébelleux. Les effets neuroprotecteurs et neurorégénératifs des cPG sont utiles pour traiter les carences neurologiques comportementales liées aux voies de régulation de l'activité motrice.
PCT/US2002/036235 2001-11-09 2002-11-12 Cyclo(prolyl-glycine) et procedes utilises pour traiter des troubles neuronaux WO2003039487A2 (fr)

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US7232798B2 (en) 2001-11-13 2007-06-19 Tran Loi H Neuroprotection and neuroegenisis by administering cyclic prolyl glycine
WO2011037644A1 (fr) * 2009-09-25 2011-03-31 Neuren Pharmaceuticals Limited Glycyl-2-allylproline cyclique et son utilisation dans le traitement d'une neuropathie périphérique
US8067425B2 (en) * 2003-09-03 2011-11-29 Neuren Pharmaceuticals Limited Neuroprotective bicyclic compounds and methods for their use
CN102348683A (zh) * 2009-03-10 2012-02-08 参天制药株式会社 含有4,6-二氯-1h-吲哚-2-羧酸衍生物或其盐作为有效成分的视神经损伤的预防或治疗剂
US20140309230A1 (en) * 2003-09-03 2014-10-16 Neuren Pharmaceuticals Limited Cyclic Glycyl-2-Allyl Proline Improves Cognitive Performance in Impaired Animals
CN105879005A (zh) * 2016-02-01 2016-08-24 四川好医生攀西药业有限责任公司 一种治疗溃疡性结肠炎的药物组合物及其制备方法和应用
CN105879006A (zh) * 2016-02-01 2016-08-24 四川好医生攀西药业有限责任公司 一种治疗糖尿病足溃疡的药物组合物及其制备方法和应用
CN105902999A (zh) * 2016-02-01 2016-08-31 四川好医生攀西药业有限责任公司 一种治疗消化性溃疡的药物组合物及其制备方法和应用
WO2019222339A1 (fr) * 2018-05-15 2019-11-21 Tran Lloyd Hung Loi Composition d'agent thérapeutique et procédé d'utilisation, pour le traitement d'un trouble cognitif léger, de la dépression et de troubles psychologiques
CN111278451A (zh) * 2017-08-28 2020-06-12 维泰利特健康(新西兰)有限公司 非神经学和/或神经学病症的igf-1分析、调整和疾病管理的改进
JP2020196686A (ja) * 2019-06-04 2020-12-10 ゼライス株式会社 認知機能改善用食品
WO2023113623A1 (fr) * 2021-12-17 2023-06-22 The Cgp Lab Limited Sources animales, fongiques et marines de cgp et concentration de cgp accrue pour la gestion de maladies et pour le traitement d'états non neurologiques et/ou neurologiques
US12239629B2 (en) 2020-04-20 2025-03-04 Lloyd Hung Loi Tran Methods for the prophylaxis and treatment of COVID and COVID-19

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BR9913457A (pt) * 1998-09-03 2001-10-16 Neuronz Ltd Neuroproteção

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US7232798B2 (en) 2001-11-13 2007-06-19 Tran Loi H Neuroprotection and neuroegenisis by administering cyclic prolyl glycine
US8067425B2 (en) * 2003-09-03 2011-11-29 Neuren Pharmaceuticals Limited Neuroprotective bicyclic compounds and methods for their use
US20140309230A1 (en) * 2003-09-03 2014-10-16 Neuren Pharmaceuticals Limited Cyclic Glycyl-2-Allyl Proline Improves Cognitive Performance in Impaired Animals
US9119851B2 (en) * 2003-09-03 2015-09-01 Neuren Pharmaceuticals, Ltd. Cyclic Glycyl-2-Allyl Proline improves cognitive performance in impaired animals
CN102348683A (zh) * 2009-03-10 2012-02-08 参天制药株式会社 含有4,6-二氯-1h-吲哚-2-羧酸衍生物或其盐作为有效成分的视神经损伤的预防或治疗剂
EP2407454A4 (fr) * 2009-03-10 2012-05-30 Santen Pharmaceutical Co Ltd Agent prophylactique ou thérapeutique destiné à des troubles du nerf optique comprenant un dérivé ou un sel de l'acide 4,6-dichloro-1h-indole-2-carboxylique comme principe actif
WO2011037644A1 (fr) * 2009-09-25 2011-03-31 Neuren Pharmaceuticals Limited Glycyl-2-allylproline cyclique et son utilisation dans le traitement d'une neuropathie périphérique
CN105879005A (zh) * 2016-02-01 2016-08-24 四川好医生攀西药业有限责任公司 一种治疗溃疡性结肠炎的药物组合物及其制备方法和应用
CN105879006A (zh) * 2016-02-01 2016-08-24 四川好医生攀西药业有限责任公司 一种治疗糖尿病足溃疡的药物组合物及其制备方法和应用
CN105902999A (zh) * 2016-02-01 2016-08-31 四川好医生攀西药业有限责任公司 一种治疗消化性溃疡的药物组合物及其制备方法和应用
EP3675890A4 (fr) * 2017-08-28 2021-11-03 Vitality Wellness (NZ) Limited Améliorations de l'analyse d'igf-1, de l'ajustement et de la gestion de maladie d'états non neurologiques et/ou neurologiques
CN111278451A (zh) * 2017-08-28 2020-06-12 维泰利特健康(新西兰)有限公司 非神经学和/或神经学病症的igf-1分析、调整和疾病管理的改进
US12216119B2 (en) 2017-08-28 2025-02-04 The Cgp Lab Limited IGF-1 analysis, adjustment and disease management of non-neurological and/or neurological conditions
CN112423774A (zh) * 2018-05-15 2021-02-26 L·H·L·特兰 用于治疗轻度认知障碍、抑郁和心理障碍的治疗剂组成及使用方法
US11090303B2 (en) 2018-05-15 2021-08-17 Lloyd Hung Loi Tran Therapeutic agent composition and method of use, for treatment of mild congnitive impairment, depression, and psychological disorders
WO2019222339A1 (fr) * 2018-05-15 2019-11-21 Tran Lloyd Hung Loi Composition d'agent thérapeutique et procédé d'utilisation, pour le traitement d'un trouble cognitif léger, de la dépression et de troubles psychologiques
US12070458B2 (en) 2018-05-15 2024-08-27 Lloyd Hung Loi Tran Therapeutic agent composition and method of use, for treatment of mild congnitive impairment, depression, and psychological disorders
JP2020196686A (ja) * 2019-06-04 2020-12-10 ゼライス株式会社 認知機能改善用食品
US12239629B2 (en) 2020-04-20 2025-03-04 Lloyd Hung Loi Tran Methods for the prophylaxis and treatment of COVID and COVID-19
WO2023113623A1 (fr) * 2021-12-17 2023-06-22 The Cgp Lab Limited Sources animales, fongiques et marines de cgp et concentration de cgp accrue pour la gestion de maladies et pour le traitement d'états non neurologiques et/ou neurologiques

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