EP1363605A1 - Modulateurs du recepteur gaba pour le traitement de maladies neurodegeneratives de l'oeil - Google Patents
Modulateurs du recepteur gaba pour le traitement de maladies neurodegeneratives de l'oeilInfo
- Publication number
- EP1363605A1 EP1363605A1 EP02700233A EP02700233A EP1363605A1 EP 1363605 A1 EP1363605 A1 EP 1363605A1 EP 02700233 A EP02700233 A EP 02700233A EP 02700233 A EP02700233 A EP 02700233A EP 1363605 A1 EP1363605 A1 EP 1363605A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gaba receptor
- glaucoma
- gaba
- receptor modulator
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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Definitions
- the present invention relates to the use of a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases of the eye and suitable pharmaceutical compositions therefor.
- Increased intraocular glutamate levels are mainly responsible for a number of eye diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma and ocular ischemia syndrome.
- the pathologically most important glutamate receptor is the NMDA receptor.
- the NMDA receptor acts simultaneously depending on the voltage and ligand.
- the ion channel of the receptor is closed by Mg ions and a ligand cannot activate the receptor.
- Mg 2+ leaves the ion channel and the receptor 25 can then be activated by a ligand, which leads to the influx of Ca 2+ and Na + and an outflow of K + .
- Ca plays a central role in intracellular cascade triggers, although it is cell-toxic in high concentrations. In this context, one usually speaks of an excitotoxic effect. Excessive activation of the NMDA receptor, which is the glutamate receptor that is responsible for a large part of the neurodegenerative diseases, causes an increased Ca 2+ influx, which, as already explained above, cell-toxic. This Ca 2+ influx triggers apotosis and later necrosis processes in the cell, which ultimately lead to cell death.
- NMDA receptor antagonists In the advanced stage of a neurodegenerative disease, the cells occupied with NMDA receptors preferentially die. These cells are then no longer accessible for treatment with NMDA receptor antagonists, which leads to the fact that with increasing neurodegeneration, NMDA receptor antagonists lose their effectiveness more and more.
- NMDA receptor antagonists would be desirable for neuroprotective purposes, but it has been found in clinical trials that serious side effects occur which have made clinical introduction impossible. In addition, almost all NMDA receptor antagonists trigger moderate to severe psychiatric side effects.
- GABA agonists It is known in the art to use GABA agonists to lower pressure in the eye. GABA agonists have the major disadvantage that they are also found in Absence of a neurotransmitter work. Thus, agonists have a higher toxic potential, since an increase in the dose of agonists can lead to a linear increase in inhibition up to anesthesia and respiratory arrest. The increase in effectiveness with modulators is limited by the amount of transmitter present and cannot be increased arbitrarily.
- GABA receptor modulators in ophthalmology for the prevention and / or treatment of neurodegenerative diseases of the eye
- the GABA receptor modulators being selected from the group comprising benzodiazepines
- the object of the present invention is therefore to achieve glutamate protection by modulating the opposite transmitter system, namely the GABA-ergen system.
- neuroprotective therapy refers to those forms of treatment which lead to a reduction or prevention of the damage or destruction of neuronal cells.
- GABA is gamma-amino butyric acid. GABA arises within the glutamate metabolism and is the most important inhibitory transmitter in the mammalian nervous system. A lack of GABA or a suppression of the GABA-energetic system leads in most cases to spasms and epileptic cramps up to cell death.
- GABA is the physiological antagonist of glutamate. Activation of the GABA receptor causes an inflow of Cl " ions, which changes the membrane potential in the negative direction and reduces the probability of an action potential. GABA is therefore referred to as an inhibitory transmitter.
- GABA is therefore referred to as an inhibitory transmitter.
- enhancement of the GABA-energetic system leads to hyperpolarization of the cell. This makes depolarization or the spread of an action potential more difficult.
- the NMDA receptor only becomes permeable to Ca 2+ when the cell membrane is depolarized. In other words, application of GABA-enhancing agents leads to inhibition of the NMDA receptor in this way.
- the hyperpolarization of the cell membrane prevents glutamate receptor-independent voltage-dependent Ca 2+ channels from being activated. These channels are not detected by an NMDA receptor antagonist.
- GABA on the receptor In the absence of GABA, GABA receptor modulators are ineffective.
- the administration of GABA receptor modulators is therefore harmless in comparison to the administration of agonists, since agonists, regardless of the amount of the neurotransmitter present, have an increasing effect with increasing concentration and thus cause cell damage until cell death.
- the administration of GABA receptor modulators therefore has a significantly lower toxic risk compared to GABA agonists.
- GABA receptor modulators in the sense of this invention are substances which modulate the affinity / effectiveness of existing GABA on the synaptic GABA receptor.
- the GABA receptor modulators used according to the invention are so-called positive modulators, ie they increase the synaptic affinity / effectiveness of GABA.
- Pharmaceutically acceptable salts of the claimed GABA receptor modulators include, in particular, salts of benzodiazepines, beta-carbolines, barbiturates, barbituric acid derivatives and / or neurosteroids.
- benzodiazepine derivatives selected from the group comprising alprazolam, bentazepam, bromazepam, breadizolam, carmazepam, chlordiazepoxide, clobazam, clonazepam, cinolazepam, clotiazepam, cloxazolam, clozapine, delorazepam, diazepam, ethazolamate, ethazolam, dazzepam, dazzepam, dibenzene, dibazole, dibazole, diazole, diazole, diazole, diazole, diazole, diazole, diazole, diazole, diazole, diazole -Loflazepate, Etizolam, Fludiazepam, Flumazenil, Flunitrazepam, Flurazepam-lHCl, Flutoprazepam, Halazepam, Haloxazolam, Ketazol
- Particularly suitable according to the invention is the use of benzodiazepine receptor ligands of different chemical structure, selected from the group comprising RWJ-46771 (a pyrido- [1,2-a] -benzimidazole), SX-3228 (a 1,6-naphthydrin- 2 (lH) -one derivative), Y-23684 (a pyridazinone), bretazenil, imidazenil, nabazenil, sarmazenil, zaleplon, zolpidem and zopiclone.
- RWJ-46771 a pyrido- [1,2-a] -benzimidazole
- SX-3228 a 1,6-naphthydrin- 2 (lH) -one derivative
- Y-23684 a pyridazinone
- bretazenil imidazenil, nabazenil, sarmazenil, zaleplon, zol
- THBC tetrahydro-beta-carbolines
- Barbiturates or barbituric acid derivatives particularly suitable for use according to the invention are selected from the group comprising barbexaclone, dipropyl barbituric acid, Eunarcon, hexobarbital, mephobarbital, methohexital, Na methohexital, pentobarbital, phenobarbital, primidone, 2,4,6 (1H, 3H, 5H) - pyrimidine trione, secbutabarbital and / or thiopental and pharmaceutically acceptable salts thereof.
- Neurosteroids which are particularly suitable according to the invention are selected from the group comprising allopregnenolone, 3beta-hydroxyandrost-5-en-17-one-3 sulfate, dehydroepiandrosterone, eltanolone, ethinyl estradiol, 5-pregnen-3beta-ol-20-one sulfate , Pregnenolone and / or progesterone and pharmaceutically acceptable salts thereof.
- GABA receptor modulators which can be used according to the invention are flunitrazepam, midazolam, phenobarbital, abecarnil and / or dehydroepiandrosterone and pharmaceutically acceptable salts thereof.
- compositions for the purposes of this invention are understood to mean all salts known in the prior art, the pharmacological activity of which does not adversely affect the effectiveness of the active compounds, i.e. impaired to health.
- salts which can be used according to the invention can be a mono-, di- and / or polyvalent ion.
- Alkali and alkaline earth metal salts such as Na + , Ca 2+ , K + and / or Mg 2+ are particularly preferred.
- Salts of organic amines such as mono-, di- and triamines and ethanolamines can also be used.
- Salts can also be formed with caffeine, tromethamine and / or the like. In cases where a nitro group forms a salt is necessary, this can be formed with any organic and / or inorganic substance such as methyl iodite.
- Even more preferred are salts formed with inorganic acids such as chloric acid, sulfuric acid and / or phosphoric acid. 1-, 2- and 3-valent acids can be formed.
- the GABA receptor modulators can be used in ophthalmology for the prevention and / or treatment of neurodegenerative diseases.
- GABA receptor modulators for diseases of the retina is particularly preferred.
- GABA receptor modulators in premature retinopathy such as retinopathy prematurorum and / or in retrolental fibroplasia is suitable.
- the GABA receptor modulators can be used according to the invention.
- retinal vascular diseases such as retinopathy angiospastica, arteriosclerotic retinopathy, eclamptic retinopathy, diseases caused by carotid artery occlusion, periphlebitis retinae, diabetic retinopathy, non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, and diabetic retinopathy, diabetic macinopathy, diabetic macular disease.
- the GABA receptor modulators can also be used according to the invention for diseases caused by venous and / or arterial vascular occlusions, such as diseases caused by branch vein occlusions, central vein occlusion, Artery occlusion, amaurosis fugax, retinal vein occlusion, chronic ocular ischemia, sickle cell retinopathy, ocular ischemia syndrome and / or exudative retinitis.
- diseases caused by venous and / or arterial vascular occlusions such as diseases caused by branch vein occlusions, central vein occlusion, Artery occlusion, amaurosis fugax, retinal vein occlusion, chronic ocular ischemia, sickle cell retinopathy, ocular ischemia syndrome and / or exudative retinitis.
- the GABA receptor modulators can also be used to prevent and / or treat macular degeneration, such as wet and dry macular degeneration, acquired macular degeneration, age-related macular degeneration, retinopathy central serosa, myopic macular changes, and cystoid macular edema , vascular-like stripes, toxic macular diseases, macular foramen, exudative maculopathies due to other causes,
- macular degeneration such as wet and dry macular degeneration, acquired macular degeneration, age-related macular degeneration, retinopathy central serosa, myopic macular changes, and cystoid macular edema , vascular-like stripes, toxic macular diseases, macular foramen, exudative maculopathies due to other causes,
- the GABA receptor modulators can also be used according to the invention for the prevention and / or for the treatment of traumatic retinal changes, such as for bruising the eye, perforating eye injuries,
- GABA receptor modulators also be used according to the invention in retinoschisis.
- the use of GABA receptor modulators is suitable for the prevention and / or treatment of diseases of the choroid, such as hyaline deposits and / or chorioideremic.
- the GABA receptor modulators can also be used for diseases of the optic nerve. These include optic nerve damage from intoxications such as tobacco alcohol damage, methyl alcohol damage, ethambutol damage, quinine, arsenic, lead and / or bromine damage.
- the GABA receptor modulators can also be used for anterior ischemic optic neuropathy, such as apoplexia papillae and / or giant cell arteritis.
- the GABA receptor modulators may also be used to prevent and / or therapy of a optic nerve atrophy, such as traumatic optic atrophy, optic atrophy by tumor pressure, Hereditary optic atrophy, hepatic optic atrophy, secondary optic atrophy, Optrikusatrophie according Papillitis / retrobulbar neuritis, optic atrophy of unknown origin, glaucomatous optic atrophy and / or Changes in the optic nerve head can be used.
- a optic nerve atrophy such as traumatic optic atrophy, optic atrophy by tumor pressure, Hereditary optic atrophy, hepatic optic atrophy, secondary optic atrophy, Optrikusatrophie according Papillitis / retrobulbar neuritis, optic atrophy of unknown origin, glaucomatous optic atrophy and / or Changes in the optic nerve head can be used.
- GABA receptor modulators are used according to the invention for the treatment of glaucoma, such as primary glaucoma, open-angle glaucoma, primary open-angle glaucoma, normal-pressure glaucoma, angle-block glaucoma, acute angle-block glaucoma, intermittent angle-block glaucoma, subacute angle-block glaucoma and / or angle-block glaucoma, and / or angle-block glaucoma, chronic, and angle-block glaucoma.
- glaucoma such as primary glaucoma, open-angle glaucoma, primary open-angle glaucoma, normal-pressure glaucoma, angle-block glaucoma, acute angle-block glaucoma, intermittent angle-block glaucoma, subacute angle-block glaucoma and / or angle-block glaucoma, and / or angle-block glaucoma, chronic, and angle-block gla
- the GABA receptor modulators can also be used in congenital glaucoma and early childhood glaucoma, such as corneal chamber angle iris dysgenesis, Lowe syndrome, Sturge-Weber syndrome, neurofibromatosis, Rubinstein-Taybi syndrome, Pierre Robin syndrome, OtaNevus , Trisomy, Marfan's syndrome, Turner syndrome, aniridia, homocystinuria, intraocular tumors, orbital lymphangioma, retinopathia prematurorum, persistent hyperplastic primary vitreous, ectopia lensis, intraocular inflammation, cortisone therapy, Myopia with pigment glaucoma, rubella embryopathy, cataract extraction and / or in the treatment of blunt or acute trauma.
- congenital glaucoma and early childhood glaucoma such as corneal chamber angle iris dysgenesis, Lowe syndrome, Sturge-Weber syndrome, neurofibromatosis, Rubinstein-Taybi syndrome, Pierre Robin syndrome
- GABA receptor modulators is also suitable according to the invention for the treatment of glaucoma simplex, such as glaucoma for aphakia and pseudoaphakia, glaucoma for diabetes mellitus, glaucoma and endothelial dystrophy, hypersecretion glaucoma, glaucoma in pregnancy, higher myopia and / or juvenile glaucoma.
- GABA receptor modulators can also be used for the treatment of secondary glaucoma, such as traumatic and postoperative glaucoma, secondary open-angle glaucoma, secondary angle-block glaucoma, steroid-induced glaucoma, glaucoma after inflammation, phacolytic glaucoma, Posner-Schlossman syndrome, glaucoma syndrome, heterochromoma, heterochromoma, heterochromoma haemolytic glaucoma, neurofibromatosis, siderosis, glaucoma due to neovascularization, glaucoma by cortisone administration, pigment glaucoma, pseudoexfoliation glaucoma, glaucoma in anterior uveitis, glaucoma in Fuchs heterochromia, Grant syndrome, glaucoma angioma complications after glaucoma complications after genomic abnormality , Silicone glaucoma, lens-related gla
- Lens material pseudoexfoliation glaucoma, phacogenic uveitis, glaucoma in anterior uveitis, ciliary block glaucoma and / or in glaucoma due to increased episcleral venous pressure can be used.
- the GABA receptor modulators are suitable for the treatment of ocular hypertension, for example for the primary and secondary form.
- the pharmaceutical compositions containing GABA receptor modulators can be in liquid, gel and / or solid form be administered.
- the pharmaceutical composition containing GABA receptor modulator if it is in flowable form, is preferably administered as drops, topically or systemically in solid form.
- the GABA receptor modulators are preferably present in pharmaceutical compositions suitable for use in a concentration of 0.0001 to 5% by weight, based on the total composition.
- topical applications are preferred over systemic applications, since in the case of topical application a significantly higher concentration of active substance is effective directly on the eye.
- the ophthalmic compositions comprising GABA receptor modulator which can be used according to the invention can have preservatives, agents for adjusting the tonicity, buffers for adjusting the pH, antioxidants, viscosity regulating substances and / or further auxiliaries which can be used conventionally.
- Preferred preservatives are selected from the group comprising benzalkonium chloride, chlorobutanol, thiomersal, phenyl mercury acetate, cetrimide, EDTA and / or phenyl mercury nitrate.
- Carriers suitable according to the invention are selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, cyclodextrins and / or water.
- Tonicity adjusting agents are selected from the group consisting of salts, preferably sodium chloride and / or potassium chloride, mannitol, glycerin and the like.
- Acetate, citrate, phosphate and borate buffers can be used to adjust the pH.
- acids and / or bases can also be used as required.
- Ophthalmologically acceptable antioxidants are selected from the group comprising sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisoles and / or butylated hydroxytoluenes.
- Carbomers in particular can be used as viscosity regulators.
- the pharmaceutical compositions containing the GABA receptor modulator are used according to the invention, they are applied topically and / or systemically in neuroprotective prevention and / or treatment of mammalian eyes, in particular in humans.
- these pharmaceutical compositions containing GABA receptor modulator are in an ophthalmologically compatible preparation, e.g. used as eye drops, eye gel or eye ointment.
- a suitable pharmaceutical composition is particularly suitable if it has no harmful or endangering influence on the eye, neither in acute nor in chronic use. Pharmaceutical compositions which do not cause eye irritation such as reddening, itching or the like are particularly preferred.
- compositions having a GABA receptor modulator to the eye in the form of a solution or a gel.
- 1 shows the reduction in the number of dying cells in cell cultures of cultured cortical cells of the rat after 10, 30 and 60 minutes compared to the control group after administration of flunitrazepam.
- FIG. 3 to 5 show the number of dead cells in rat retinal preparations after injection of phenobarbital (FIG. 3), dehydroepiandrosterone (DHEA; FIG. 4) and midazolam (FIG. 5) after injection of a 100 nanomolar NMDA solution into the Anesthetized rat eyeball.
- compositions suitable for use according to the invention have 0.0001-5% by weight, preferably 0.001-3% by weight, more preferably 0.01-2% by weight, even more preferably 0.05-1.5% by weight. % and most preferably 0.1-1% by weight of active ingredient, based on the overall pharmaceutical composition.
- the proportion of preservative makes up 0-0.5% by weight, preferably> 0-0.1% by weight, preferably 0.001-0.3% by weight and more preferably 0.01-0.05% by weight. %, based on the overall pharmaceutical composition.
- the proportion of carrier substance makes up 0 to 99% by weight, preferably> 0 to 80% by weight, preferably 1 to 50% by weight, more preferably 5 to 40% by weight and most preferably 10 to 30% by weight. -%, based on the total pharmaceutical composition.
- the proportion of substances for adjusting the isotonicity is 1-10% by weight, preferably
- the proportion of buffer substances makes up 0.01-10% by weight, preferably 0.05-5% by weight, preferably 0.01-3% by weight and more preferably 0.1-2% by weight on the overall pharmaceutical composition.
- the pH of the pharmaceutical composition containing the GABA receptor modulator is preferably in the range between pH 4.5-7.5, preferably between pH 5-7.3, preferably between pH 6-7.1 and more preferably between 6. 5 - 7.0.
- the proportion of antioxidants is preferably 0-10% by weight, preferably> 0-8
- % By weight, preferably 0.005-5% by weight, more preferably 0.05-2% by weight and more preferably
- compositions containing GABA receptor modulator are listed in the following examples:
- Benzodiazepines are lipophilic. Midazolam is water-soluble. Beta-carbolines are lipophilic
- Phenobarbital-Na and Pentobarbital-Na are hydrophilic steroids are lipophilic example 1
- Aqueous eye drops :
- Example 8 effervescent tablet
- Example 9 tablet Sodium dihydrogen citrate, anhydrous 1200 mg ascorbic acid 240 mg citric acid, anhydrous 240 mg sodium hydrogen carbonate 920 mg sodium carbonate, anhydrous 200 mg
- Example 9 tablet Sodium dihydrogen citrate, anhydrous 1200 mg ascorbic acid 240 mg citric acid, anhydrous 240 mg sodium hydrogen carbonate 920 mg sodium carbonate, anhydrous 200 mg
- Example 9 tablet
- Dissociated cortical cells from 16-18 day old fetal rats were grown in 35 mm dishes.
- the nutrient medium contained L-glutamine (4 mM), glucose (6 g / l), penicillin (100 U / ml), streptomycin (100 ⁇ g / ml) and 10% hormone-enriched medium, which transferrin (1 mg / ml), insulin (250 ⁇ g / ml), putrescin (600 ⁇ M), sodium selenite (0.3 ⁇ M), progesterone (0.2 ⁇ M) and estradio (0.1 pM).
- the dishes were stored in an atmosphere tempered to 37 degrees Celsius (5% CO 2 and 95% O).
- the hormone-containing nutrient medium was suctioned off and exchanged for another one which was without the hormonal addition but otherwise had the same composition.
- the other half of the dishes with the nutrient medium flunitrazepam 500 nm and 10 nm L-glutamate were added (row 2) and also incubated under normoxic conditions.
- the number of surviving or dead cells was determined by determining the amount of lactate dehydrogenase (LDH) expelled into the cell medium.
- LDH activity was determined by spectrometry by measuring the NADH metabolism at 340 nm.
- the measured values were entered in the diagram in FIGS. 1 and 2 as follows: The measured value describes the number of dead cells after the test in relation to the total number of cells before the test in percent. Larger values indicate a higher proportion of dead cells, 100% describes complete cell loss.
- control measurements were carried out on the right eye and the substance measurements (row 2) on the left eye.
- Row 1 In the control series (right eye), the same dosing scheme was used as in row 2, except that instead of the drug solution with the active ingredient phenobarbital 500 nanomoles, the same drug solution without active ingredient was dripped.
- 100 nM NMDA in 5 ⁇ l of a sodium phosphate buffer solution without drug was injected into the control eye.
- Row 2 One day before the NMDA injection, 50% of the rats (siblings) weighing 200-250 g received 5 ⁇ l drops of the drug solution in two administrations, once in the morning and once in the late afternoon in the left eye. Each administration consisted of one drop of drug solution and a second drop 30 minutes later.
- the rats On the morning of the glutamate injection, the rats received a 5 ul injection of the drug solution and were then anesthetized with 0.3 ml kg "1 Hyponorm (Janssen, Grove, UK). After 30 minutes, 5 ul of the 15 minutes later, 100 nM NMDA in 5 ⁇ l of a sodium phosphate buffer solution was injected into the vitreous body, and 2 drops of the drug solution were administered to each eye in the afternoon of the same day, followed by morning and evening for the following 4 days 2 drops of the drug solution injected into the eye.
- the animals were anesthetized again (0.3 ml kg "1 Hyponorm, Janssen, Grove, UK) and the retinae were removed for further immunohistochemical examination.
- the retinae were fixed in 2% paraformaldehyde solution for 45 minutes and then frozen in 30% sucrose solution. Frozen sections (10 ⁇ m) were cut approximately 5 mm from the optic nerve and observed on a gelatin-coated slide. The sections were then processed to locate the Thy-1.
- the measured values were entered in the diagram in FIGS. 3, 4 and 5 as follows:
- the measured value describes the number of dead cells after the test in relation to the total number of cells before the test in percent. Larger values indicate a higher proportion of dead cells, 100% describes complete cell loss.
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Abstract
Applications Claiming Priority (3)
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DE10106470 | 2001-02-13 | ||
DE10106470 | 2001-02-13 | ||
PCT/EP2002/001537 WO2002078680A1 (fr) | 2001-02-13 | 2002-02-13 | Modulateurs du recepteur gaba pour le traitement de maladies neurodegeneratives de l'oeil |
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EP02700233A Withdrawn EP1363605A1 (fr) | 2001-02-13 | 2002-02-13 | Modulateurs du recepteur gaba pour le traitement de maladies neurodegeneratives de l'oeil |
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US (1) | US20040102438A1 (fr) |
EP (1) | EP1363605A1 (fr) |
JP (1) | JP2004519511A (fr) |
KR (1) | KR20030084926A (fr) |
CN (2) | CN1813723A (fr) |
BR (1) | BR0207226A (fr) |
CA (1) | CA2439842A1 (fr) |
MX (1) | MXPA03007199A (fr) |
WO (1) | WO2002078680A1 (fr) |
ZA (1) | ZA200305817B (fr) |
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DE10136842A1 (de) * | 2001-07-23 | 2003-02-13 | Schering Ag | GABA¶A¶-Rezeptor-Modulatoren mit NMDA-antagonistischer Aktivität |
EP2305308A1 (fr) * | 2003-04-18 | 2011-04-06 | Advanced Medicine Research Institute | Remèdes à des affections, à usage ophtalmique |
WO2004093882A1 (fr) * | 2003-04-18 | 2004-11-04 | Advanced Medicine Research Institute | Remedes a appliquer sur l'oeil pour soigner differentes maladies |
WO2006002836A1 (fr) * | 2004-07-01 | 2006-01-12 | Losan Pharma Gmbh | Compositions effervescentes de somniferes |
GB2469339A (en) * | 2009-04-09 | 2010-10-13 | Bambour Omoyiola | Sleep-inducing ophthalmic compositions |
TWI671297B (zh) | 2009-05-27 | 2019-09-11 | Ptc治療公司 | 治療癌症及非腫瘤病症之方法 |
WO2010138695A1 (fr) * | 2009-05-27 | 2010-12-02 | Ptc Therapeutics, Inc. | Procédés pour traiter la neurofibromatose |
FR3016881B1 (fr) * | 2014-01-29 | 2016-03-04 | Biocodex | Traitement des degenerescences et des lesions photo-induites de la retine |
EP3664803A4 (fr) | 2017-08-01 | 2021-05-05 | PTC Therapeutics, Inc. | Inhibiteur de dhodh pour utilisation dans le traitement de cancers hématologiques |
US11020405B2 (en) | 2017-09-25 | 2021-06-01 | Kangwon National University University-Industry Cooperation Foundation | Method for prevention or treatment of diabetic complications |
KR101938991B1 (ko) | 2017-09-25 | 2019-01-15 | 강원대학교산학협력단 | 당뇨병성 합병증의 예방 또는 치료용 약제학적 조성물 |
CN115105512A (zh) * | 2022-08-29 | 2022-09-27 | 中山大学中山眼科中心 | 脱氢表雄酮在制备预防、治疗眼部近视的药物中的用途及其剂型和制备方法 |
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US6077839A (en) * | 1992-03-19 | 2000-06-20 | Allergan Sales, Inc. | Method for reducing intraocular pressure in the mammalian eye by administration of gamma aminobutyric acid (GABA) agonists |
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2002
- 2002-02-13 WO PCT/EP2002/001537 patent/WO2002078680A1/fr not_active Application Discontinuation
- 2002-02-13 JP JP2002576946A patent/JP2004519511A/ja not_active Withdrawn
- 2002-02-13 KR KR10-2003-7010632A patent/KR20030084926A/ko not_active Application Discontinuation
- 2002-02-13 CA CA002439842A patent/CA2439842A1/fr not_active Abandoned
- 2002-02-13 MX MXPA03007199A patent/MXPA03007199A/es unknown
- 2002-02-13 US US10/467,897 patent/US20040102438A1/en not_active Abandoned
- 2002-02-13 EP EP02700233A patent/EP1363605A1/fr not_active Withdrawn
- 2002-02-13 CN CNA200510130289XA patent/CN1813723A/zh active Pending
- 2002-02-13 BR BR0207226-2A patent/BR0207226A/pt not_active IP Right Cessation
- 2002-02-13 CN CNA028049012A patent/CN1501795A/zh active Pending
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JP2004519511A (ja) | 2004-07-02 |
KR20030084926A (ko) | 2003-11-01 |
CN1501795A (zh) | 2004-06-02 |
BR0207226A (pt) | 2004-03-09 |
ZA200305817B (en) | 2004-08-27 |
CN1813723A (zh) | 2006-08-09 |
CA2439842A1 (fr) | 2002-10-10 |
WO2002078680A1 (fr) | 2002-10-10 |
US20040102438A1 (en) | 2004-05-27 |
MXPA03007199A (es) | 2005-02-14 |
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