WO2002051395A1 - Traitement de maladies neurodegeneratives - Google Patents

Traitement de maladies neurodegeneratives Download PDF

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Publication number
WO2002051395A1
WO2002051395A1 PCT/US1999/011840 US9911840W WO02051395A1 WO 2002051395 A1 WO2002051395 A1 WO 2002051395A1 US 9911840 W US9911840 W US 9911840W WO 02051395 A1 WO02051395 A1 WO 02051395A1
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diol
cis
trans
exo
butanediol
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PCT/US1999/011840
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English (en)
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David A. Brown
Wu Yun Ren
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Codon Pharmaceuticals, Inc.
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Priority to AU42154/99A priority Critical patent/AU4215499A/en
Publication of WO2002051395A1 publication Critical patent/WO2002051395A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates

Definitions

  • the present invention relates to increasing the differentiation of mammalian neuronal cells for purposes of treating neurodegenerative diseases or nerve damage by- administration of various compounds, including alcohols, diols and/or triols and their analogues.
  • compositions which are the subject of the present invention have been found to increase the melanin content of mammalian melanocytes , increase pigmentation in the epidermis of a mammal, and treat or prevent various skin and proliferative disorders. See U.S. application Serial No. 60/026,577 filed September 18, 1996; application Serial No. 60/035,947 filed January 21, 1997; application Serial No. 60/036,863 filed February 4, 1997, and application Serial No. 60/048,597 filed June 4, 1997. It has now been found that the present compositions may be used for treating neurodegenerative diseases or nerve damage.
  • the present invention provides a method for increasing the differentiation of mammalian neuronal cells, which comprises administering to a mammal in need of such increase an effective amount of a C 3 -C 50 diol, which may be aliphatic or aromatic, linear, branched, mono-, bi- or polyclicic, saturated or unsaturated, unsubstituted, ono- or polysubstituted.
  • a C 3 -C 50 diol which may be aliphatic or aromatic, linear, branched, mono-, bi- or polyclicic, saturated or unsaturated, unsubstituted, ono- or polysubstituted.
  • the present invention provides a composition for increasing the differentiation of mammalian neuronal cells, which comprises: a) an effective amount of one or more compounds described above; and b) a suitable carrier.
  • the present invention provides a method for increasing the differentiation of mammalian neuronal cells, which comprises administering to a mammal in need of such increase an effective amount of one or more compounds having the following structure:
  • R 2 is a linear, branched or unbranched, cyclic, bicyclic or polycyclic group containing from one atom to fifty atoms, at least one of which is carbon, nitrogen, oxygen, or sulfur, and each R is independently selected from R-_; R 2 ; hydroxyl, methyl, hydroxymethyl, -(CH 2 ) n CH 3 -, -(CH 2 ) n OH,
  • n is independently an integer from 0-25; and pharmaceutically acceptable salts or prodrugs thereof .
  • the present invention provides a composition for increasing the differentiation of mammalian neuronal cells, which comprises: a) an effective amount of one or more compounds depicted above; and b) a suitable carrier.
  • Figures 1A-1B are printouts as described in Example 1.
  • Figures 2A-2D are printouts as described in Example 2
  • Figures 3A-3D are printouts as described in Example 3 DETAILED DESCRIPTION OF THE INVENTION
  • the compounds and compositions of the present invention effectively and efficiently increase differentiation of neuronal cells, including increased neuronal dendricity and neuronal tyrosine hydroxylase activity, which has several consequences.
  • increasing dendricity leads to increased neuronal communication, thereby increasing neuronal function and performance.
  • the present invention is useful for treating diseases or disorders marked by reduction of neuronal dendricity and function, including but not limited to Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, or any other neurodegenerative disease, or physical or toxic damage to brain, spinal or peripheral nerve cells. Further, the present invention is useful for restoring or optimizing neuronal communication, function or performance.
  • the present invention is particularly useful for treating Parkinson's disease which is specifically marked by depletion of dopamine synthesis.
  • the present invention is useful for treating neuronal proliferative, tumorous, or cancerous disorders, or said disorders in any other cell type that might be similarly affected.
  • the present invention is useful for treating additional neurodegenerative disorders or neuropathies including but not limited to diffuse cerebral cortical atrophy, Lewy-body dementia, Pick disease, mesolimbocortical dementia, thalamic degeneration, Huntington chorea, cortical-striatal-spinal degeneration, cortical-basal ganglionic degeneration, cerebrocerebellar degeneration, familial dementia with spastic paraparesis, polyglucosan body disease, Shy-Drager syndrome, olivopontocerebellar atrophy, progressive supranuclear palsy, dystonia usculorum defor ans, Hallervorden-Spatz disease, Meige syndrome, familial tremors, Gilles de la Tourette syndrome, acanthocytic chorea, Friedreich ataxia, Holmes familial cortical cerebellar atrophy, Gerstmann-
  • the active compounds according to the present invention are the C 3 -C 50 diols described above (by "diol” is meant a compound which has at least two, but permissibly more, -OH groups) .
  • the active Preferably, the active have one of the six structures depicted above. More preferably, X is independently selected from a single bond; or C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene, each of which may contain one or more different heteroatoms or heteroatoms of the same type.
  • each R is independently selected from hydrogen; fluoro; chloro; or C; L -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 7 -C 20 aralkyl,
  • C 8 -C 20 aralkenyl, C 8 -C 20 aralkinyl, or C 6 -C 20 aryl each of which may contain one or more different heteroatoms or heteroatoms of the same type, or carboxyl, carboxamido, carbalkoxy, sulfamido, sulfona ido; hydroxyl, or amino . More preferably R 2 contains from two to twenty carbon atoms, each may contain one or more different heteroatoms or heteroatoms of the same type.
  • Particularly preferred compounds of this invention are 2, 3-cis/exo-pinanediol ( [1R,2R, 3S, 5R] - [-] -pinanediol and
  • Other preferred compounds are (IS, 2S, 5S, ) -2-hydroxy-3-pinanone;
  • the methods and compositions of the present invention contemplate the use of one or more of the above-mentioned compounds as an active ingredient for various uses.
  • the active ingredient (s) is given orally, intravenously, or transdermally in an acceptable formulation.
  • a particularly preferred carrier for some formulations is 1, 2-propylene glycol since it is an excellent solvent for certain compounds in this invention including but not limited to 5-norbornene-2 , 2-dimethanol, 5-norbornane-2 , 2-dimethanol and 3 , 3-dimethyl-l, 2- butanediol.
  • 1, 2-propylene glycol as carrier has itself, as described in this invention, similar but lesser activity than the preferred active ingredient (s) .
  • compositions of the present invention may also include other active ingredients, as well as inert or inactive ingredients.
  • the dose regimen will depend on a number of factors which may readily be determined, such as severity and responsiveness of the condition to be treated, but will normally be one or more doses per day, with a course of treatment lasting from several days to several months, or until a cure is effected or a diminution of disease state is achieved.
  • One of ordinary skill may readily determine optimum dosages, dosing methodologies and repetition rates.
  • unit dosage form compositions according to the present invention will contain from about 0.01 g to about 100 g of active ingredient, preferably about 0.1 mg to about 10 mg of active ingredient.
  • Topical formulations (such as creams, lotions, solutions, etc.) may have a concentration of active ingredient of from about 0.01% to about 50%, preferably from about 0.1% to about 10%.
  • Example 1 The PC12 rat pheochromocytoma cell line was obtained from American Type Culture Collection (ATCC) . Cells were cultured in 85% RPM 1640 medium, 10% horse serum (heat inactivated at 56°C for 30 minutes, 5% fetal bovine serum, 25 U/ml penicillin, and 25 ug/ml streptomycin (Greene, efc al . , 1991, "Methodologies for the culture and experimental use of the rat PC12 rat pheochromocytoma cells line", pp. 207-225, In: Culturing Nerve Cells, The MIT Press,
  • PC12 rat pheochromocytoma cells are considered to be an excellent model for neuronal cells because they respond to treatment with nerve growth factor (NGF) by acquisition of a number of properties of neurons including cessation of proliferation, extension of neurons, acquisition of electrical ' excitability, and increased neurotransmitter synthesis (Greene, et al . , 1991 and references therein).
  • NGF nerve growth factor
  • PC12 cells are used as a model for studies of prevention or cure of neurodegenerative diseases since they provide a robust screen for agents that maintain neuron survival and prevent neuron cell death in serum-free media (Rukenstein, et al . , 1991, J. Neurosci . 11:255-2563).
  • Agents are considered to be potentially useful for treatment of neurodegenerative disorders if they not only promote PC12 cell survival, but also increase neurite outgrowth (Rukenstein, et al . , 1991). Agents are considered to be particularly useful for treatment of neurodegenerative disorders if they promote PC12 cell survival and neurite outgrowth in the absence of "priming" with NGF (Rukenstein, et al . , 1991).
  • PC12 cells are considered to be an especially good model for studies of Parkinson's disease (Michel, et al . , 1994, Europ. J. Neurosci . Assoc. 6:577-586 and references therein) .
  • PC12 cells have been used as a model to study aspects of Alzheimer's disease (Shen, et al . , 1995, Brain Res . 671:282-292), amyotrophic lateral sclerosis (Durham, et al . , 1995, Clin . Exp. Pharmacol . Physiol . 22:366-67) , Down's syndrome (Groner, et al . , 1994, Biomed. Pharmacother . 48:231-240), and age-related neurodegeneration (Taglialatela, et al . , 1996, J. Neurochem. 66:1826-1835).
  • cells were plated at 15,000 cells/35 mm dish. Two days following plating, cell culture media was replaced with that containing treatments. One week later, media and treatments were replaced with fresh media and treatments. Two weeks following the initial treatments, cells were examined microscopically, and the portion of cells exhibiting dendricity was estimated. Cells were harvested by trypsinization and counted by Coulter Counter.
  • Cells were pelleted by centrifugation at 200 X g, and cell pellets were lysed in 600 ul 50 mM Tris/Acetate pH 6.0/0.2% Triton X-100 by vortexing, sonicating 5 seconds, incubating on ice for 30 minutes, followed by revortexing. Protein was determined on aliquots of cell lysate by the Bradford Coomassie Blue method (Bradford, 1967, Anal . Biochem. 72:248-254) using Bio-Rad Protein Assay Kit I.
  • Tyrosine hydroxylase activity was determined by incubating 100 ul of PC12 cell lysate with 100 ul of the following reaction mixture at 37°C for 15 min: 200 mM sodium acetate pH 6.0, 50 uM tyrosine, 2000 U Cat/ml, 50 mU dihydropteridine reductase/ml, 0.1 mM NADH final, 200,000 cpm 3H tyrosine/100 ul, 0.1 mM NSD1015 (3-hydroxybenzylhydrazine) , and 100 uM tetrahydrobiopterin (BH4) (Nagatsu, et al . , 1969, Anal. Biochem. 9:122-126; Ribeiro, et al .
  • BH4 tetrahydrobiopterin
  • Ethanol used as a solvent for 3, 3-M-l, 2-BD and 5-NBene-2, 2-DM, and IBMX (3-isobutly-l-methylxanthine) , which increases cellular cAMP levels, resulted in only minor effects relative to the agents of this invention.
  • the reduced cell numbers resulting from treatment with 1,2-PG, 3, 3-M-l, 2-BD or 5-NBene-2 , 2-DM are in part indicative of the differentiation process induced by treatments.
  • some cells detached concomitantly with the acquisition of dendricity that occurred earlier than for other treatments .
  • This detachment phenomenon has been noticed previously for PC12 cells induced to differentiate with NGF, and can be avoided by coating treatment dishes with collagen (reviewed in Greene, et al . , 1991).
  • the compounds of this invention induced dendricity and tyrosine hydroxylase activity in the absence of priming with NGF, a prerequisite for induction of neurite extension by many other agents tested on PC12 cells (Steiner, et al . 1997 , Nature Medicine 3:421-428; Rukenstein, et al . 1991, J " . Neurosci . 11:2552-2563).
  • agents under consideration as treatments for neurodegenerative diseases do not promote neurite extension even in NGF-primed PC12 cells (e.g., IGF-I and IGF-II; Rukenstein, et al . , 1991 and references therein) .
  • GDNF glial cell-derived neurotrophic factor
  • Parkinson's disease many agents under consideration for treatment of neurodegenerative diseases including GDNF (glial cell-derived neurotrophic factor) being developed for treatment of Parkinson ' s disease are neurotrophic peptides that cannot cross the blood-brain barrier and therefore require gene therapy implantation at the site of action (Haase, et al. 1997, Nature Medicine 3 -.429-436) .
  • L-Dopa which is presently used for treatment of Parkinson's disease is toxic (Yahr, M. D. 1993, Adv.
  • Neurol . 60:11-17 in part, by generation of peripherally formed dopamine (Riederer, et al . 1993, Adv. Neurol . 60:626-635), and in part, by virtue of its ability to form highly reactive semiquinone and quinones via autooxidation (Karg, et al . 1989, Acta Derm. Venereol . 69:521-524).
  • the agents of the present invention (i) act directly without a requirement for NGF; (ii) induce neuronal differentiation thereby setting into motion cellular reprogramming to the desired phenotype; (iii) induce tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis; (iv) are small molecule drugs that are likely to cross the blood brain barrier; and (v) have no known ability to form semiquinone, quinone or other toxic intermediates, it is contemplated that the agents of this invention will be particularly advantageous for treatment of neurodegenerative diseases including but not limited to Parkinson's disease.
  • Example 2 Previous studies have shown that both induction of tyrosine hydroxylase activity and neurite outgrowth in PC12 cells are mediated by the nitric oxide (NO) /guanosine 3 ' , 5 ' -cyclic monophosphate (cGMP) signal transduction pathway (Roskoski and Roskoski, 1987, J " . Neuochem. 48:236- 242; Hindley, et al . , 1997, J. Neurosci . Res . 47 :427-439) .
  • NO nitric oxide
  • cGMP 5 ' -cyclic monophosphate
  • PC12 cells were grown and treated with 5-norbornene- 2, 2-dimethanol as described in Example 1, except that cells were analyzed one week after treatments, rather than two weeks after treatments. Furthermore, in addition to the analysis described in Example 1, the media of cells was also collected for analysis of nitric oxide (NO) . For measurement of NO, media was centrifuged at 200 X g for 5 min to remove cells and debris. Nitric oxide was measured using a CalBiochem (San Diego, CA) Colorimetric Nitric Oxide Assay Kit.
  • NO nitric oxide
  • nitric oxide is converted into nitrite and nitrate with seconds of production in biological fluids
  • nitric oxide is measured by first converting nitrate to nitrite using nitrate reductase, followed by addition of Greiss reagent to detect nitrite as optical density at 550 nm (Moshage, et al . , 1995, Clin . Chem. 41:892-896; Schmidt, et al . , 1995, Biochemica 2:22)).
  • Results show that the degree of neurite outgrowth (% with neurites of length exceeding cell body diameter) , the amount of nitric oxide (NO) released into the media, the amount of NO generated per cell, and tyrosine hydroxylase (Tyr Hydrox) activity all increased following treatment with 5-norbornene-2,2-dimethanl (5-NBene-2, 2-DM) (Table 2). Induction of NO and tyrosine hydroxylase were apparent at 1 mM 5-NBene-2, 2-DM, and appeared to reach a maximum at 2.5 M 5-NBene-2, 2-DM, since no further increases were observed at 5 mM 5-NBene-2 , 2-DM (Table 2).
  • FIG. 2 shows photographs of cultured unstained PC12 cells.
  • PC12 cells are untreated.
  • PC12 cells in Figure 2B were treated for one week with 2.5 mM 5-NBene-2, 2-DM, while cells in Figures 2C and 2D were treated with 5 mM 5-NBene- 2, 2-DM.
  • PC12 cells treated with 5 mM 5-NBene-2 , 2-DM exhibited both longer and more branched neurites than those treated with 2.5 mM 5-NBene-2 , 2-DM.
  • ⁇ • Values are estimates wherein neurites were counted as extended if their length exceeded the cell body's diameter. Evaluations include single cells and cells on periphery of clumps, but exclude cells in middle of clumps.
  • Example 3 To further elucidate and substantiate the role of NO in differentiation of PC12 cells, additional studies were done using the guanylyl cyclase inhibitor LY83583. This inhibitor blocks differentiation of PC12 cells otherwise induced by NO donors, indicating they act via cGMP. Similarly it was contemplated that if 5-NBene-2 , 2-DM was inducing NO within PC12 cells, and if this endogenously generated NO was responsible for inducing differentiation of PC12 cells by the cGMP pathway, then LY83583 should block the effects of 5-NBene-2 ,2-DM. All PC12 culture and treatment methods were the same .as in Examples 1 and 2.
  • Co-treatment of PC12 cells with 5-NBene-2, 2-DM and the guanylyl cyclase inhibitor LY83583 shows that blockage of the NO/cGMP/PKG pathway completely blocks neurite outgrowth otherwise induced by 5-NBene-2 , 2-DM.
  • Figure 3A shows photographs of unstained cultured PC12 cells.
  • Figure 3B shows induction of extensive neurite outgrowth in PC12 cells treated with 5 mM 5-NBene-2 , 2-DM for two weeks.
  • Figure 3D shows that PC12 cells cotreated with both 5 mM 5- NBene-2, 2-DM and 0.1 uM LY83583 for two weeks exhibit no neurite outgrowth, similar to untreated PC12 cells (Figure 3A) or PC12 cells treated with 0.1 uM LY83583 alone for two weeks ( Figure 3C) .
  • Results shown here and in Example 2 show that 5-NBene- 2, 2-DM induces nitric oxide activity, that induction of nitric oxide activity is associated with induction of neurite outgrowth and tyrosine hydroxylase activity, and that LY83583 can block neurite outgrowth induced by 5- NBene-2,2-DM.
  • 5-NBene-2 2-DM stimulates PC12 cell differentiation by stimulating the NO/cGMP/PKC signal transduction pathway. Since, 5-NBene- 2, 2-DM cannot be a source of NO, 5-NBene-2 , 2-DM must stimulate NO production within PC12 cells.
  • the compounds of the present invention are distinguished from NO donors not only by the fact that they induce synthesis of NO within treated cells, but also because in contrast to NO donors (Hindley et al . , supra) , the compounds of the present invention induce neurite outgrowth from PC12 cells in the absence of co- reatment with NGF. Thus, unlike NO donors which induce no neurite outgrowth in the absence of NGF (Hindley et al . , supra) , the compounds of the present invention induce neurite outgrowth in the complete absence of added NGF. In fact, as shown below in Example 4, addition of NGF has little or no effect on neurite outgrowth induced by compounds of the present invention.
  • Both 5-NBene-2,2-DM and 2 , 3-cis/exo-pinanediol have been shown to stimulate NO production and differentiation of a melanoma cell line.
  • Many other diols including those shown in Example 1, Table 1, have been shown to induce differentiation of melanoma cells and melanocytes . Since melanocytes are considered to be a good model for elucidating biological modulators of neuronal cells, it is contemplated that other diols including but not limited to 5-NBene-2, 2-DM and 2, 3-cis/exo-pinanediol will induce NO production and differentiation of PC12 cells.
  • Example 4 As discussed in Example 1, the compounds of the present invention appear to be particularly efficacious relative to other compounds proposed for treatment of neurodegenerative diseases (Steiner, et al . , 1997, Nature Med. 3:421-428; Rukenstein, et al . , 1991, J. Neurosci . 11:2552-2563) in that they act without co-treatment with nerve growth factor (NGF) . Furthermore, as discussed in Example 3, although the compounds of the present invention induce PC12 differentiation at least in part via the
  • NO/cGMP/PKG pathway NO donors are ineffective without the presence of NGF.
  • the purpose of this study was to determine if addition of NGF would markedly improve the ability of the compounds of this invention to stimulate PC12 differentiation.
  • PC12 cells were treated with the bicyclic diol 5-norbornene-2 , 2-dimethanol (5-NBene-2, 2-DM) , the bicyclic diol 2 , 3-cis/exo-pinanediol (2, 3-cs/ex-PD) , or the bicyclic alcohol (S) -cis-verbenol (S-cs-VBol) .
  • concentration of NGF used for co- treatments (0.5 ng/ l) was identical to that shown to be essential for induction of PC12 cell differentiation by immunophilins (Steiner, et al . , supra) . 50 ng/ml NGF was used as a positive control (Steiner, et al . , supra) .
  • Cells were plated, treated and neurite outgrowth evaluated as described in Example 2, Table 1 except that cells were evaluated 7 and 21 days after initiation of treatments.
  • Results showed that supplementary NGF resulted in a slight stimulation of neurite outgrowth when PC12 cells were examined 7 days after the initiation of treatments, but mixed results were obtained when cells were examined 21 days after the initiation of treatments (Table 3) .
  • the highest levels of neurite outgrowth were seen following 7 days treatment with 50 ng/ml NGF, following 7 days treatment with 5 mM 2 , 3-cs/ex-PD, and following 21 days treatment with 5 mM 5-NBene-2 , 2-DM (Table 3); highest levels of neurite outgrowth were apparently unaffected by inclusion of 0.5 ng/ml NGF.
  • Results show that the compounds of this invention can induce significant levels of neurite outgrowth (similar to the 50 ng/ml NGF positive control) without inclusion of supplementary NGF.

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Abstract

L'invention concerne des méthodes et des compositions permettant d'augmenter la différenciation des cellules neuronales mammifères dans le but de traiter les maladies neurodégénératives ou les lésions nerveuses par administration de divers composés, y compris des alcools, des diols et/ou des triols et leurs analogues.
PCT/US1999/011840 1998-05-28 1999-05-28 Traitement de maladies neurodegeneratives WO2002051395A1 (fr)

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Cited By (9)

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WO2005047492A1 (fr) * 2003-11-14 2005-05-26 Olsson Mats J Melanocytes utilises dans le traitement de maladies neurodegeneratives
EP1796658A2 (fr) * 2004-09-21 2007-06-20 Ketocytonyx Inc. Mimetiques dopaminergiques
WO2010015965A2 (fr) * 2008-08-04 2010-02-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions de traitement d'un dommage neuronal et de modulation de canaux potentiels de récepteurs transitoires
WO2013181084A1 (fr) * 2012-05-31 2013-12-05 Prima Innovations Llc 1,2-diols et 1,2,3-triols antispasmodiques
US9566261B2 (en) 2013-03-12 2017-02-14 Bio-Pharm Solutions Co., Ltd. Phenyl carbamate compound and a composition for preventing or treating a memory loss-related disease comprising the same
US9682059B2 (en) 2013-03-12 2017-06-20 Bio-Pharm Solutions Co., Ltd. Phenyl carbamate compounds for use in preventing or treating epilepsy or epilepsy-related syndrome
US20180243235A1 (en) * 2015-09-09 2018-08-30 Korea Research Institute Of Bioscience And Biotech Nology Composition for preventing or treating muscle weakness-related diseases comprising sobrerol
US10206905B2 (en) * 2015-06-10 2019-02-19 Jiangsu Simcere Pharmaceutical Co., Ltd Use of composition for preparing a medicament for treatment of amyotrophic lateral sclerosis
WO2021038253A1 (fr) * 2019-08-30 2021-03-04 University Of Greenwich Traitement de l'obésité et d'états apparentés

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US5352440A (en) * 1988-03-30 1994-10-04 Trustees Of Boston University Methods for increasing melanin content in melanocytes using diacylglycerols and uses thereof
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US5210076A (en) * 1988-09-13 1993-05-11 Berliner David L Methods of treating Parkinson's disease using melanin
US5554359A (en) * 1989-12-15 1996-09-10 The Board Of Regents Of The University Of Oklahoma Pigmentation enhancer and method
US5532001A (en) * 1993-07-07 1996-07-02 Trustees Of Boston University Stimulation of tanning by DNA fragments or single-stranded DNA

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005047492A1 (fr) * 2003-11-14 2005-05-26 Olsson Mats J Melanocytes utilises dans le traitement de maladies neurodegeneratives
EP1796658A2 (fr) * 2004-09-21 2007-06-20 Ketocytonyx Inc. Mimetiques dopaminergiques
EP1796658A4 (fr) * 2004-09-21 2007-12-12 Btg Int Ltd Mimetiques dopaminergiques
WO2010015965A2 (fr) * 2008-08-04 2010-02-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions de traitement d'un dommage neuronal et de modulation de canaux potentiels de récepteurs transitoires
WO2010015965A3 (fr) * 2008-08-04 2010-04-01 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Procédés et compositions de traitement d'un dommage neuronal et de modulation de canaux potentiels de récepteurs transitoires
WO2013181084A1 (fr) * 2012-05-31 2013-12-05 Prima Innovations Llc 1,2-diols et 1,2,3-triols antispasmodiques
US8853189B2 (en) 2012-05-31 2014-10-07 Prima Innovations, Llc Antispasmodic 1,2-Diols and 1,2,3-triols
JP2015518046A (ja) * 2012-05-31 2015-06-25 プリマ・イノベーションズ・エルエルシー 鎮痙性１，２−ジオール及び１，２，３−トリオール
RU2657556C2 (ru) * 2012-05-31 2018-06-14 ПРИМА ИННОВЕЙШНЗ ЭлЭлСи Антиспазматические 1,2-диолы и 1,2,3-триолы
US9682059B2 (en) 2013-03-12 2017-06-20 Bio-Pharm Solutions Co., Ltd. Phenyl carbamate compounds for use in preventing or treating epilepsy or epilepsy-related syndrome
KR20170058447A (ko) * 2013-03-12 2017-05-26 (주)바이오팜솔루션즈 페닐카바메이트 화합물 및 이를 포함하는 신경보호용 조성물
US9872847B2 (en) 2013-03-12 2018-01-23 Bio-Pharm Solutions Co., Ltd. Phenyl carbamate compounds for use in preventing or treating a movement disorder
US9907776B2 (en) 2013-03-12 2018-03-06 Bio-Pharm Solutions, Co., Ltd. Phenyl carbamate compound and a composition for preventing or treating a psychiatric disorder comprising the same
US9566261B2 (en) 2013-03-12 2017-02-14 Bio-Pharm Solutions Co., Ltd. Phenyl carbamate compound and a composition for preventing or treating a memory loss-related disease comprising the same
KR102014615B1 (ko) * 2013-03-12 2019-08-27 (주)바이오팜솔루션즈 페닐카바메이트 화합물 및 이를 포함하는 신경보호용 조성물
US10525030B2 (en) 2013-03-12 2020-01-07 Bio-Pharm Solutions Co., Ltd. Phenyl carbamate compound and a composition for neuroprotection comprising the same
US10206905B2 (en) * 2015-06-10 2019-02-19 Jiangsu Simcere Pharmaceutical Co., Ltd Use of composition for preparing a medicament for treatment of amyotrophic lateral sclerosis
US20180243235A1 (en) * 2015-09-09 2018-08-30 Korea Research Institute Of Bioscience And Biotech Nology Composition for preventing or treating muscle weakness-related diseases comprising sobrerol
CN108601755A (zh) * 2015-09-09 2018-09-28 韩国生命工学研究院 用于预防或治疗肌无力相关疾病的、包含水合蒎醇的组合物
US10765642B2 (en) * 2015-09-09 2020-09-08 Korea Research Institute Of Bioscience And Biotechnology Composition for preventing or treating muscle weakness-related diseases comprising sobrerol
CN108601755B (zh) * 2015-09-09 2021-08-10 韩国生命工学研究院 用于预防或治疗肌无力相关疾病的、包含水合蒎醇的组合物
WO2021038253A1 (fr) * 2019-08-30 2021-03-04 University Of Greenwich Traitement de l'obésité et d'états apparentés

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