专利号:US-6187756-B1 优先权日:1996-09-05 标 题 :Composition and methods for treatment of neurological disorders and neurodegenerative diseases 发明人:LEE ROBERT K K; WURTMAN RICHARD J 权利人:MASSACHUSETTS INST TECHNOLOGY 摘要:It has been discovered that the stimulation of β-adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the in vitro or in vivo exposure of neuronal cells to certain compositions comprising β-adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP overproduction. These increases are blocked by β-adrenergic receptor antagonists, such as propranolol. The in vitro or in vivo treatment of these cells with 8Br-cAMP, prostaglandin E 2 (PG E 2 ), forskolin, and nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of β-adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E 2 , forskolin, or nicotine ditartrate is inhibited by immunosuppressants or anti-inflammatory agents, such as cyclosporin A, and FK-506 (tacrolimus), as well as ion-channel modulators, including ion chelating agents such as EGTA, or calcium/calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer's Disease.
专利号:US-6469055-B2 优先权日:1996-09-05 标题 :Compositions and methods for treatment of neurological disorders and neurodegenerative diseases 发明人:LEE ROBERT K K; WURTMAN RICHARD J 权利人:MASSACHUSETTS INST TECHNOLOGY 摘要:It has been discovered that the stimulation of β-adrenergic receptors, which activate cAMP formation, give rise to increased APP and GFAP synthesis in astrocytes. Hence, the in vitro or in vivo exposure of neuronal cells to certain compositions comprising β-adrenergic receptor ligands or agonists, including, e.g., norepinephrine, isoproterenol and the like, increases APP mRNA transcription and consequent APP overproduction. These increases are blocked by β-adrenergic receptor antagonists, such as propranolol. The in vitro or in vivo treatment of these cells with 8Br-cAMP, prostaglandin E 2 (PG E 2 ), forskolin, and nicotine ditartrate also increased APP synthesis, including an increase in mRNA and holoprotein levels, as well as an increase in the expression of glial fibrillary acidic protein (GFAP). Compositions and methods are disclosed of regulating APP overexpression and mediating reactive astrogliosis through cAMP signaling or the activation of β-adrenergic receptors. It has further been found that the increase in APP synthesis caused by 8Br-cAMP, PG E 2 , or forskolin is inhibited by immunosuppressants, immunophilin ligands, or anti-inflammatory agents, such as cyclosporin A, and FK-506 (tacrolimus), as well as ion-channel modulators, including ion chelating agents such as EGTA, or calcium/calmodulin kinase inhibitors, such as KN93. The present invention has broad implications in the alleviation, treatment, or prevention of neurological disorders and neurodegenerative diseases, including Alzheimer's Disease.
专利号:US-9265748-B2 优先权日:2011-08-11 标题 :Anhydrous and hemihydrate crystalline forms of an (R)-baclofen prodrug, methods of synthesis and methods of use 发明人:RAILLARD STEPHEN P; MANTHATI SURESH K; JOSHI SUDHIR 权利人:XENOPORT INC 摘要:Crystalline (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxyl)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid anhydrate and crystalline (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxyl)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid hemihydrate, pharmaceutical compositions comprising such compounds, methods of making and methods of using the same are disclosed.
专利号:US-2015313865-A1 优先权日:2011-08-11 标 题:Anhydrous and hemihydrate crystalline forms of an (r)-baclofen prodrug, methods of synthesis and methods of use
专利号:US-2014066501-A1 优先权日:2011-08-11 标 题:Anhydrous and Hemihydrate Crystalline Forms of an (R)-Baclofen Prodrug, Methods of Synthesis and Methods of Use
专利号:US-8580850-B2 优先权日:2011-08-11 标题 :Anhydrous and hemihydrate crystalline forms of an (R)-baclofen prodrug, methods of synthesis and methods of use
1. Kobayashi, S., Yano, M., Suetomi, T., et al. Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. J. Am. Coll. Cardiol. 53(21), 1993-2005 (2009). 2. Oo, Y.W., Gomez-Hurtado, N., Walweel, K., et al. Essential role of calmodulin in RyR inhibition by dantrolene. Mol. Pharmacol. 88(1), 57-63 (2015). 3. Kotsias, B.A., and Muchnik, S. Reversible effect of dantrolene sodium on twitch tension of rat skeletal muscle. Arch. Neurol. 35(4), 234-236 (1978). 4. Nelson, T.E., and Flewellen, E.H. Rationale for dantrolene vs. procainamide for treatment of malignant hyperthermia. Anesthesiology 50(2), 118-122 (1979).
合成参考文献
参考文献:10.1007/s004240050261 摘要:Buschman HPJ, Elzinga G, Woledge RC. The effects of the level of activation and shortening velocity on energy output in type 3 muscle fibres from Xenopus laevis. Pflgers Archiv European Journal of Physiology. 1996 Nov 18;433(1-2):153–9. doi: 10.1007/s004240050261.