WO2001028578A2 - Composition pharmaceutique a base de pglu-glu-pro-nh2 et procede de traitement de maladies et de lesions cerebrales - Google Patents

Composition pharmaceutique a base de pglu-glu-pro-nh2 et procede de traitement de maladies et de lesions cerebrales Download PDF

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WO2001028578A2
WO2001028578A2 PCT/US2000/029278 US0029278W WO0128578A2 WO 2001028578 A2 WO2001028578 A2 WO 2001028578A2 US 0029278 W US0029278 W US 0029278W WO 0128578 A2 WO0128578 A2 WO 0128578A2
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eep
glu
injuries
brain
pglu
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PCT/US2000/029278
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WO2001028578A3 (fr
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James L. Meyerhoff
Michael L. Koenig
Joseph B. Long
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Wrair
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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
    • A61K38/06—Tripeptides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention is directed to a neuroprotectant composition wherein the active ingredient is pGLU-GLU-PRO-NH 2 or a combination of pGLU-GLU-PRO-NH 2 (EEP) and N-tert-Butyl- ⁇ -(2-sulfophenyl)nitrone (SPBN).
  • the present invention is also directed to a method of treating and preventing diseases and injuries of the brain, spinal cord and retina by administering the endogenous tripeptide EEP to a subject as a neuroprotectant or by administering EEP in combination with SPBN or other nitrone.
  • Penetrating head wound have a greater than 50% risk of developing posttraumatic epilepsy. Closed head injuries are more prevalent in the military than in the civilian community, and certain groups (e.g. paratroopers) are at special risk for both head and spinal injury.
  • certain groups e.g. paratroopers
  • DCS air gas embolism or decompression sickness
  • therapies for these conditions There are very few available treatments for brain injury today and the gradual progressive biochemical changes which occur after head trauma can lead to the evolution of permanent neuronal damage.
  • Laser energy could be deliberately directed at the cockpit of U.S. military aircraft (airplanes and/or helicopters) with the intent of impairing the vision of pilots and/or crews (door gunners or medics).
  • the adverse effects on the retina may range from transient impairment which can impact operational performance, to lasting disability or blindness. Reconnaissance troops and TOW missile operators are also at risk.
  • Other potential sources of laser-induced retinal injury include exposure to laser targeting and ranging devices.
  • a common source of laser-induced retinal injury in soldiers is the hand held neodymium (Nd:YAG) laser target designator (range finder), which operates at a wavelength of 1064 nanometers.
  • Ruby lasers operating at a wavelength of 694.3 nm have also been used in military range finders and represent an additional potential source of retinal damage.
  • the normal function of the lens, focussing light onto the retina also serves to concentrate incident laser energy, when exposure occurs. While the magnifying effect of the human lens on intraocular laser energy is large as much as 10,000 fold - the amplification in the case of a soldier using binoculars could reach as much as 10 6 .
  • the amount of laser energy reaching the retina is also directly related to pupil diameter. Thus, soldiers are at greater risk under dark-adapted conditions.
  • the location of the laser-induced lesion is clinically very important, with foveal location being the most severe. Laser injuries near the fovea present a risk of penumbral spread over time to include the fovea.
  • Submarines could become disabled (DISSUB) on the ocean floor, requiring emergency evacuation of the crew.
  • arrival of a rescue ship could take days, during which time crews in a disabled submarine could be exposed to hyperbaric conditions.
  • a submersible rescue vessel would transport the crew to the surface in groups, potentially without decompression. Once on the surface, crew members may be required to wait for access to treatment in a limited- capacity recompression chamber on the surface.
  • some personnel might be at significant risk for neurological complications of DCS.
  • Spinal cord injury is a relatively common sequela of DCS; recompression treatment is not always successful and if delayed, prognosis for recovery is poor.
  • the prolonged delay before submarine crews might be brought to the surface provides a significant window of opportunity for administration of a safe, well-tolerated prophylactic treatment to mitigate risk and severity of possible neurological complications of DCS.
  • AD age-related macular degeneration
  • DR diabetic retinopathy
  • glaucoma cataracts.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • glaucoma cataracts.
  • the prevalence of diabetes in North America is estimated to reach almost 17 million by the year 2000.
  • IDDM insulin- dependent diabetes mellitus
  • DPR proliferative retinopathy
  • a major pathological mechanism in both AMD and DPR is retinal neovascularization.
  • the mechanisms of DPR include excessive retinal vascular permeability, edema, ischemia and the principal causes of loss of vision are hemorrhage into the vitreous and/or retinal detachment.
  • the only effective treatment known for either AMD or DPR is coagulation via exposure to focussed laser irradiation (Vinding, 1995). Laser photocoagulation in a grid pattern is an effective treatment for the macular edema seen in diabetic retinopathy, as well as the neovascularization.
  • ganglion cells are the output neurons of the retina and axons projecting from these cells form the optic nerve and project to the lateral geniculate nucleus of the brain. In one study, 12 hours after laser exposure, ganglion cells in monkey retina were liquefied. Ganglion cells are also destroyed in glaucoma, and continue to perish even after institution of standard glaucoma therapy.
  • glucocorticoids can exacerbate the excitotoxic phase of neural injury.
  • Postulated mechanisms of GC-mediated synergy with excitotoxic effects of glutamic acid include: (1) GCs inhibition of reuptake inactivation of synaptic GLU, thereby increasing synaptic GLU levels; (2) GCs inhibition of calcium efflux from the postsynaptic neuron (McEwen & Sapolsky, 1995).
  • methylprednisolone has recently been proven to exacerbate laser-induced lesions of the retina (Schuschereba et al., 1997).
  • Other possible condidates, such as drugs which block the effects of glutamate at its NMDA receptor or the associated ion channel are associated with unacceptable behavioral toxicity (Tricklebank et al., 1989).
  • TRH thyrotropin-releasing hormone
  • TRH thyrotropin-releasing hormone
  • TRH is a tripeptide comprised of the amino acids pyroglutamate-histidine-proline-amide.
  • TRH has been shown to be neuroprotective, analeptic, anticonvulsant and antidepressive.
  • TRH was initially recognized as a peptide released by the brain to stimulate secretion of thyroid-stimulating hormone from the pituitary gland. Subsequently, TRH was identified in many brain regions and associated with numerous physiological functions. When injected, TRH was found to have many behavioral effects, including, analeptic, anticonvulsant and antidepressant ( Sato et al., 1984; Sattin et al., 1987).
  • TRH farnesoid X-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe II
  • Another limitation on therapeutic use of TRH might be potential for excessive activation of the thyroid gland.
  • TRH is not a suitable neuroprotectant because it is hydrolyzed by serum enzyme thyroliberinase which limits its bioavailability. Also TRH elevates plasma levels of thyroid hormone, which could potentially be problematic.
  • nitrone based free radical traps such as ⁇ -Phenyl-N-tert- butylnitrone (PBN) which offer an ROS scavenging mechanism which differes from vitamin E and other endogenous compounds (*Althaus et al., 1998).
  • PBN ⁇ -Phenyl-N-tert- butylnitrone
  • the nitrones react covalently with ROS to form stable nitroxides and as such have been used to measure ROS. They have also been shown to be neuroprotective against glutamate-induced toxicity in cultured neurons (Zeevalk et al.
  • SPBN N-tert-Butyl- ⁇ -(2-sulfophenyl)nitrone
  • NXY-059 was shown to be effective in both tempory (Kuroda et al., 1999) and permanent focal ischemia models in the rat, and was effective when given 3 hours (Kuroda et al,1999) or even 5 hours (Maples et al., 1999) after start of recirculation in the former.
  • NXY-059 administered either 15 min prior or 30 min post TBI was effective in decreasing volume of necrosis in the controlled cortical impact model (Cheng, et al., 1999). This compound is currently beind developed for treatment of stroke by Centaur Pharmaceuticals and Astra/Zeneca.
  • the object of the invention is to provide such a neuroprotectant to fill the current needs.
  • the invention solves the above problems associated with known neuroprotectants by providing a neuroprotectant composition wherein the active ingredient is pGLU-GLU- PRO-NH 2 (EEP) or a combination of pGLU-GLU-PRO-NH 2 (EEP) and N-tert-Butyl- ⁇ -(2- sulfophenyl)nitrone (SPBN).
  • EEP pGLU-GLU- PRO-NH 2
  • SPBN N-tert-Butyl- ⁇ -(2- sulfophenyl)nitrone
  • the present invention is also directed to a method of treating and preventing diseases and injuries of the brain, spinal cord and retina by administering the endogenous tripeptide EEP to a subject as a neuroprotectant or by administering EEP in combination with SPBN or other nitrone.
  • EEP treatment is effective as a treatment for a wide range of injuries and diseases of the brain and spinal cord in the military and civilian sector.
  • EEP treatment can be given at the first sign of spinal injury in service members such as divers, seals and submariners, as well as paratroopers, sport divers and victims of automobile accidents.
  • EEP treatment can also be given for degenerative diseases of the spinal cord, such as amyotrophic lateral sclerosis and multiple sclerosis; neuronal degeneration due to traumatic brain injury, stroke; and degenerative brain diseases such as Parkinson's, Huntington's and Alzheimer's.
  • This invention can also prevent or minimize DCS-induced spinal cord injury, as well as injury due to blast overpressure, or blunt and/or penetrating trauma.
  • EEP treatment can be made available to combat medics in an appropriate delivery mode to achieve high retinal concentrations of EEP rapidly, even when delivered to a casualty at a far- forward echelon. Pre-treatment of DPR patients with EEP prior to laser retinal therapy will limit the penumbral spread of laser injury beyond the intended zones of therapy, thus preventing enlargement of laser scars.
  • chronic treatment with EEP of patents would also slow the progression of glaucoma, treat temporal arteritis or retinitis pigmentosa and serve as adjuvant therapy before, during and after cataract surgery or retinal photocoagulation treatments for either age-related macular degeneration or diabetic retinopathy.
  • Additional uses for EEP treatment include minimizing collateral damage before, during and after therapeutic exposure to ionizing radiation for malignacies, especially of the head and neck. Protection against exposure to ionizing radiation and/or high-energy particles or plasmas such as iron-26. Protection against retinal damage during eye surgery or in occupational exposures such as in welders and firefighters.
  • EEP is found in brain, pituitary and reproductive tissues of rodents, and in serum of both rat and man. Although EEP has a structure very similar to that of thyrotropin-releasing hormone (TRH), it has both similarities and important differences in physiological effects.
  • TRH thyrotropin-releasing hormone
  • the three amino acid structure of EEP is pyroglutamate-glutamate-proline-amide - a structure very similar to that of thyrotropin-releasing hormone (TRH).
  • Thyrotropin- releasing hormone (TRH) is a tripeptide comprised of the amino acids pyroglutamate- histidine-proline-amide (EHP), differing from EEP only in having histidine, rather than glutamate in the number 2 position.
  • EEP has some similarities in physiological effects. For example, like TRH, if administered to rats, it increases locomotor activity, and decreases immobility in the Porsolt swim test (Lloyd et al., 1997). Regional brain levels of EEP are markedly increased by electroconvulsive shock (Pekary et al., 1997), another similarity with TRH (Sattin et al., 1987; Meyerhoff et al., 1990 ). But there are also significant contrasts between the two peptides. Regional brain levels of EEP tend to be consistently higher than levels of TRH in the same region. For example, a comparison of reported levels of EEP vs.
  • TRH in ng/g wet weight
  • TRH are 2.31 vs 1.45 in the amygdala and 0.96 vs. 0.3 in cortex (Pekary et al., 1998).
  • EEP has been reported to be more stable than TRH in follicular fluid (Ashworth et al, 1991).
  • EEP is reportedly not degraded at all in human serum (Cockle et al, 1994; Klootwijk et al., 1997 ), and therefore its bioavailability is far superior to that of TRH.
  • EEP increases as follows: in amygdala, 7 fold; in cortex, 14 fold; in the medulla, 4 fold; and in the hypothalamus, 2 fold.
  • levels in the pituitary increased 11 fold and, especially relevant to proposed uses in ophthalmology, levels in the eye increased Over one hundred fold (Pekary et al., 1998).
  • EEP increases locomotor activity, and decreases immobility in the Porsolt swim test.
  • Regional brain levels of EEP are also markedly increased by electroconvulsive shock, another similarity with TRH.
  • EEP is not hydrolyzed by serum enzyme thyroliberinase so its bioavailability is not limited like TRH. Since EEP is not attacked by that enzyme, it has exceptionally good bioavailability. For example, parenteral administration of EEP to rats elicits regional brain increases ranging rom 4 fold to > 100 fold. Also EEP does not elivate plasma levels of thyroid hormone, like TRH, which can be problematic.
  • TRH was reported to be neuroprotective (Faden et al., 1989 ), its vulnerability to hydrolysis in the bloodstream, limits its bioavailability. As noted, EEP is not degraded in the bloodstream, and has good bioavailability, and gains access to the eye as well as the central nervous system, as detailed in section on description of invention.
  • EEP has potential as treatment for diseases and injuries to the brain and spinal cord in the civilian sector, including: injuries to commercial and sport divers, as well as sport parachutists and victims of automobile accidents; degenerative diseases of the spinal cord, such as Amyotrophic Lateral Sclerosis and Multiple Sclerosis; neuronal degeneration due to traumatic brain injury, stroke, and degenerative brain diseases such as Parkinson's, Huntington's and Alzheimer's.
  • EEP offers potential for treatment of epilepsy, as well.
  • EEP also has therapeutic potential as an treatment for ophthalmologic conditions such as: retinal injury due to accidental laser exposure; glaucoma, temporal neuritis or retinitis pigmentosa; and as adjuvant therapy before, during and after cataract surgery or retinal photocoagulation treatments for either age-related macular degeneration or diabetic retinopathy.
  • EEP neuroprotective efficacy is enhanced by the co administration of SPBN.
  • the tripeptide EEP which acts, at least in part, by reducing glutamate receptor-mediated calcium influx, is significantly enhanced by the addition of free radical scavenger N-tert-butyl-(2 sulfophenyl)-nitrone (SPBN) which was previously unknown.
  • SPBN free radical scavenger N-tert-butyl-(2 sulfophenyl)-nitrone
  • Co-treatment with the neuroprotectant SPBN which acts via a different mechanism (e.g. free radical scavenger) synergizes with EEP, thereby enhancing its neuropotective properties.
  • SPBN offers an ROS scavenging mechanism which differs from vitamin E and other endogenous compounds.
  • nitrones react covalently with ROS to form stable nitroxide and as such they differ from endogenous scavengers.
  • SPBN has also been shown to be neuroprotective against glutamate-induced toxicity in cultured neurons as well as in several rodent models of cerebral ischemia. In the rat focal ischemia model, it is neuroprotective even when initiation of treatment was delayed. Therefore, it enhances efficacy of EEP when administered together.
  • compositions are of special value in seizures, global hypoxic ischemic insults, in hypoxia, alone or in combination with blood flow reduction (ischemia) as well as in cases of cardiac arrest and in cases of abrupt occlusion of cerebral arteries (stroke) and laser induced retinal injury.
  • One aspect of the present invention relates to pharmaceutical compositions for the purposes set out above, in which the active ingredient is a compound EEP or also known as PGLU-GLU-PRO-NH 2 .
  • Another aspect of the present invention relates to pharmaceutical compositions for the purposes set forth above in which the active ingredients are the compound EEP and SPBN.
  • compositions for oral administration such as tablets, pills, capsules or the like may be prepared by mixing the active ingredient with conventional, pharmaceutically acceptable ingredients such as starcheds, sugars, flavoring agents and preservatives and the like.
  • the tablets or pills can be coated or otherwise compounded with pharmaceutically acceptable materials known in the art to provide a dosage form affording prolonged action or sustained release.
  • Other solid compositions can be prepared as suppositories, for rectal administration.
  • Liquid forms may be prepared for oral administration, as eye drops, intranasal or rectal administration or for injection, the term including subcutaneous, transdermal, intravenous, intrathecal, and other parenteral routes of administration.
  • the liquid compositions include aqueous solutions, with or without organic cosolvents, aqueous or oil suspensions, flavored emulsions with edible oils, as well as elixirs and similar pharmaceutical vehicles, such as isotonic saline or buffered saline, glucose in saline, etc. with pharmaceutically acceptable diluents.
  • agents might be administered as non- irratating ointments or salves.
  • the compositions of the present invention may be formed as aerosols, for intranasal and like administration.
  • EEP has minimal efficacy as a releaser of thyroid stimulating hormone or triiodothyronine, compared to the effect of throtropin releaseing hormone.
  • the dosage range will depend on the method of administration and the age, size and condition of the patient as would be recognized by one of ordinary skill in the art.
  • the active dose for humans is generally in the range of from 0.5 - 10 mg per kg body weight, in a regimen of four times per day, orally or parenterally. However, it is evident to the man skilled in the art that dosages would be determined by the attending physician, according to the disease to be treated, method of administration, patient's age, weight, contraindications and the like.
  • SPBN nitrone SPBN
  • PBN nitrone
  • SPBN is soluble in aqueous solutions and could be delivered in the same vehicles and routes as are appropriate for delivery of EEP. SPBN may be given in doses up to 300 mg/kg, four times per day, orally or parenterally.
  • the invention also relates to methods of treatment of the various pathological conditions described above, by administering to a patient a therapeutically effective amount of the compositions of the present invention.
  • administration as used herein encompasses oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, intrathecal, rectal and intranasal administration.
  • TRH inhibited glutamate-induced elevations in intracellular calcium (Koenig, Yourick & Meyerhoff, 1996), and proposed that this might be the mechanism of neuroprotective effects. Accordingly, having confirmed our initial hypothesis that EEP was neuroprotective, we examined the hypothesis that it would affect glutamate-induced calcium flux in a manner similar to TRH. We found, however, that pre-incubation with EEP does not affect glutamate-stimulated Ca2 + dynamics, whereas TRH clearly does, demonstrating that EEP acts via a different mechanism than TRH. This is consistent with the reported low affinity of EEP for the TRH receptor. Conversely, TRH has relatively little effect on glutamate-mediated neurotoxicity, whereas EEP has neuroprotective properties.
  • TRH analog p-GLU-GLU-PRO-NH 2 is neuroprotective in cultured neurons derived from the forebrains and spinal cords of fetal rats (Soc. Neurosci. Abstr. 14, 459, 1998). Moreover, it is more neuroprotective than TRH.
  • the tripepide which differs from TRH only in the substitution of GLU for HIS as the middle amino acid, is found in the brain (principally in the hippocampus and brain stem).
  • EEP levels increase in specific brain regions in response to seizures (Pekary et al, Pep ⁇ des 20:107-119, 1999).
  • EEP may be an endogenous neuroprotectant. It has been found that the tripepide has neuroprotective effects in rabbit retinal neurons exposed to ischemic conditions. Neurons acutely isolated from adult rabbit retinas were treated with 5 mM KCN and 10 mM 2-deoxyglucose to simulate ischemic conditions. EEP at 30 ⁇ M and 100 ⁇ M was added to some of the neuronal preparations. The bathing medium was removed after a 1 h exposure, and neuronal viability was assessed using the colorimetric dye MTT as an indicator of succinate dehydrogenase activity in viable neurons.
  • EEP has potential for therapeutic use in ophthalmology against neurodegenerative diseases of the eye, such as diabetic neuropathy, age-related macular degeneration and glaucoma, as well as against laser-induced retinal damage,
  • the neuroprotective efficacy of the tripeptide which acts, at least in part, by reducing glutamate receptor-mediated calcium influx, is significantly enhanced by the addition of the free radical scavenger N-tert-butyl-(2-sulfophenyl)-nitrone (SPBN).
  • SPBN free radical scavenger N-tert-butyl-(2-sulfophenyl)-nitrone
  • TRH-Iike peptide Pglu-GLU-PR0-NH2 is present in the porcine pituitary but not in reproductive tissues. Biochem. Biophys. Res. Cornmun. 181(3):1557-1563, 1991.
  • Dynorphin A-induced rat spinal cord injury evidence for excitatory amino acid involvement in a pharmacological model of ischemic spinal cord injury. J. Pharm. Exp. Ther. 269(l):358-366, 1994.
  • ECS Electroconvulsive seizures
  • EEP Pglu- GLU-PRO-NH2
  • Electroconvulsive seizures increase levels of pGLU-GLU-PRO-NH2 (EEP) in rat brain, (in press, 1998).
  • EEP pGLU-GLU-PRO-NH2

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Abstract

L'invention concerne une composition neuroprotectrice dont l'ingrédient actif est pGLU-GLU-PRO-NH2 ou une combinaison de pGLU-GLU-PRO-NH2 (EEP) et de N-tert-Butyl-α-(2-sulfophényl)nitrone (SPBN) ou d'une autre nitrone. L'invention concerne également un procédé de traitement et de prévention de maladies et de lésions cérébrales, médullaires ou rétiniennes par administration de ce EEP tripeptidique endogène à un sujet en tant que neuroprotecteur, ou par administration de EEP en combinaison avec SPBN ou une autre nitrone.
PCT/US2000/029278 1999-10-22 2000-10-20 Composition pharmaceutique a base de pglu-glu-pro-nh2 et procede de traitement de maladies et de lesions cerebrales WO2001028578A2 (fr)

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US60/160,972 1999-10-22

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Cited By (5)

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WO2002062372A2 (fr) * 2001-02-05 2002-08-15 Neurotell Ag Derives de tripeptides pour le traitement de maladies post-lesionnelles du systeme nerveux
WO2002062373A2 (fr) * 2001-02-05 2002-08-15 Neurotell Ag Tripeptides et derives de tripeptides pour le traitement de maladies post-lesionnelles du systeme nerveux
US7129213B2 (en) 2001-02-05 2006-10-31 Neurotell Ag Tripeptides and tripeptide derivatives for the treatment of neurodegenerative diseases
EP2670403A1 (fr) * 2011-02-04 2013-12-11 Hough Ear Institute Méthodes de traitement de lésions cérébrales
EP4034147A4 (fr) * 2019-09-26 2023-10-18 S.I.S. Shulov Innovative Science Ltd. Compositions et procédés pour traiter des troubles dégénératifs, liés à l'âge et induits par un traumatisme

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US5508305A (en) * 1993-12-23 1996-04-16 Oklahoma Medical Research Foundation 2, 4-disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceuticals
WO2000064440A1 (fr) * 1999-04-22 2000-11-02 Department Of The Army, U.S. Government Traitement et/ou prevention des lesions cerebrales et medullaires

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Title
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062372A2 (fr) * 2001-02-05 2002-08-15 Neurotell Ag Derives de tripeptides pour le traitement de maladies post-lesionnelles du systeme nerveux
WO2002062373A2 (fr) * 2001-02-05 2002-08-15 Neurotell Ag Tripeptides et derives de tripeptides pour le traitement de maladies post-lesionnelles du systeme nerveux
WO2002062373A3 (fr) * 2001-02-05 2002-11-14 Tell Pharm Ag Tripeptides et derives de tripeptides pour le traitement de maladies post-lesionnelles du systeme nerveux
WO2002062372A3 (fr) * 2001-02-05 2004-01-08 Neurotell Ag Derives de tripeptides pour le traitement de maladies post-lesionnelles du systeme nerveux
US7122524B2 (en) 2001-02-05 2006-10-17 Neurotell Ag Tripeptides and tripeptide derivatives for the treatment of postlesional disease of the nervous system
US7129213B2 (en) 2001-02-05 2006-10-31 Neurotell Ag Tripeptides and tripeptide derivatives for the treatment of neurodegenerative diseases
US7163922B2 (en) 2001-02-05 2007-01-16 Neurotell Ag Tripeptide derivatives for the treatment of postlesional diseases of the nervous system
EP2670403A1 (fr) * 2011-02-04 2013-12-11 Hough Ear Institute Méthodes de traitement de lésions cérébrales
EP2670403A4 (fr) * 2011-02-04 2014-07-09 Hough Ear Inst Méthodes de traitement de lésions cérébrales
US9289404B2 (en) 2011-02-04 2016-03-22 Hough Ear Institute Methods for treating brain injury
US9642823B2 (en) 2011-02-04 2017-05-09 Hough Ear Institute Methods of treating tinnitus
US10022346B2 (en) 2011-02-04 2018-07-17 Hough Ear Institute Methods for treating brain injury
US10111843B2 (en) 2011-02-04 2018-10-30 Hough Ear Institute Methods for treating brain injury
EP4034147A4 (fr) * 2019-09-26 2023-10-18 S.I.S. Shulov Innovative Science Ltd. Compositions et procédés pour traiter des troubles dégénératifs, liés à l'âge et induits par un traumatisme

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