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United States Patent (10) Patent No.: US 8,003,632 B2 Tracey Et Al

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United States Patent (10) Patent No.: US 8,003,632 B2 Tracey Et Al US008.003632B2 (12) United States Patent (10) Patent No.: US 8,003,632 B2 Tracey et al. (45) Date of Patent: Aug. 23, 2011 (54) CHOLINESTERASE INHIBITORS FOR Sg: A t 3. Ryaninomiya et et alal. TREATING INFLAMMATION 5,536,728 A 7/1996 Ninomiya et al. 5,554,780 A 9, 1996 Wolf (75) Inventors: Kevin J. Tracey, Old Greenwich, CT 5,693,668 A 12, 1997 Sain et al. (US); Valentin A. Pavlov, Ridgewood, 5,760,267 A 6/1998 Gandolfi et al. NY (US) 5,861.411 A 1/1999 Ninomiya et al. 5,929,084 A 7, 1999 Zhu et al. 5,981,549 A 11, 1999 V (73) Assignee: The Feinstein Institute for Medical 6, 194403 B1 2, 2001 E. al. Research, Manhasset, NY (US) 6,433,173 B1 8, 2002 Omori 6,610,713 B2 * 8/2003 Tracey .......................... 514,343 (*) Notice: Subject to any disclaimer, the term of this 6,838,471 B2 ck 1/2005 Tracey ded or adiusted under 35 2003. O139391 A1 7/2003 Parys et al. .............. 514,214.03 patent 1s extende 2004/0214.863 A1 10, 2004 Pratt U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/893,116 EP O 633 251 A1 1/1995 JP 571 14512 7, 1982 (22) Filed: Aug. 14, 2007 WO WO98/OO119 A 1, 1998 9 WO WO99,08672 2, 1999 O O WO WOO1,89526 A 11, 2001 (65) Prior Publication Data WO WO 2004/034963 A 4, 2004 US 2008/OO70901 A1 Mar. 20, 2008 OTHER PUBLICATIONS Rees et al., Cardiovascular Research (1993)27:453-458.* Related U.S. Application Data Rees et al. (Cardiovascular Research (1993) 27:453-458).* Leone et, al. (Expert Opinion on Emerging Drugs (2010) 15:41-52).* (63) Continuation of application No. 11/044,649, filed on Aboab (Expert Opinion on Emerging Drugs (2006) 11:7-22).* Jan. 27, 2005, now abandoned. Greenlee, W., et al., “Muscarinic Agonists and Antagonists in the Treatment of Alzheimer's Disease.” IL Farmaco, 56:247-250 (2001). (60) Provisional application No. 60/539,557, filed on Jan. Bruhwyler, J., et al., “Multicentric Open-Label Study of the Efficacy 27, 2004, provisional application No. 60/548,461, and Tolerability of Citicoline in the Treatment of Acute Cerebral filed on Feb. 27, 2004. Infarction.” Current Therapeutic Research, 55: 5, pp. 309-316 (May 1997). Int. C. Freeman, S., et al., “Tacrine: A Pharmacological Review.” Progress (51) in Neurobiology, 36: pp. 257-277, (1991). AOIN 43/00 (2006.01) Rees, S., et al., “Tacrine Inhibits Ventricular Fibrillation Induced by AOIN 43/46 (2006.01) Ischaemia and Reperfusion and Widens QT Interval in Rat.” Cardio AOIN 43/58 (2006.01) vascular Research, pp. 453-458 (1993). AOIN 43/42 (2006.01) Zemlan, F.P. et al., “Double-Blind Placebo-Controlled Study of A6 IK3I/55 (2006.01) Velnacrine in Alzheimer's Disease.” Life Sciences, 58:21, pp. 1823 A6 IK3I/50 (2006.01) 1832 (1996). Pavlov, V., et al., “The Cholinergic Anti-Inflammatory Pathway: A A6 IK3I/435 (2006.01) Missing Link in Neuroimmunomodulation.” Molecular Medicine, 9: (52) U.S. C. ........ 514/183; 514/215; 514/247; 514/278: 5-8, pp. 125-134 (May-Aug. 2003). Buerkle, H., et al., “Central and 514/297 Peripheral Analgesia Mediated by the Acetylcholinesterase-Inhibitor Field of Classification Search .................. 514/183, Neostigmine in the Rat Inflamed Knee Joint Model.” Anesthesia and (58) Analgesia, 86:1027-1032 (1998). 514/215, 247, 278, 297 Patocka, J., et al., "Huperzine A. An Interesting Anticholinesterase See application file for complete search history. Compound From the Chinese Herbal Medicine.” ACTA Medica, 41(4): 155-157 (1998). (56) References Cited Behling, A., et al., “Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in U.S. PATENT DOCUMENTS heart failure.” American Heart Journal, 146(3): 494-500 (2003). 4.550,113 A 10/1985 Lavretskaya et al. Cozanitis, D.A., et al., “A Cinebronchographic Study Demonstrating 4,562,196 A 12/1985 Hornet al. the Effect of Galanthamine Hydrobromide on Conscious Asthmatic 4,631,286 A 12/1986 Shutske et al. Volunteers.” der Anaesthesist, 21(1): 63-66 (1972). 4,754,050 A 6, 1988 ShutSkeet al. Ponce, R.J., et al., “Neostigmine for the Treatment of Acute Colonic 4,816,456 A 3, 1989 Summers Pseudo-Obstruction.” The New England Journal of Medicine, 4,831,155 A 5, 1989 Brufani et al. 341(3): 137-141 (1999). 4,835,275 A 5, 1989 ShutSkeet al. 4,839,364 A 6, 1989 ShutSkeet al. (Continued) 4,868,177 A 9, 1989 ShutSkeet al. Primary Examiner — Marcos SZnaidman 4,895,841 A 1/1990 Sugimoto et al. 4.914,102 A 4, 1990 Glamkowski (74) Attorney, Agent, or Firm — Riverside Law LLP 4.948,807 A 8, 1990 Rosin et al. (57) ABSTRACT 4,950,653 A 8, 1990 Jauw 4,950,658 A 8, 1990 Becker et al. A method of treating a subject with a cytokine-mediated 4,978,155 A 12/1990 Kobayashi inflammatory disorder comprising administering to the Sub 5,081,117 A 1/1992 Glamkowski et al. ject an effective amount of a pharmaceutically acceptable 5,100,901 A 3/1992 Sugimoto et al. cholinesterase inhibitor, provided that the inhibitor is not 5,104,880 A 4, 1992 Kozikowski galantamine. 5,185,350 A 2f1993 Effland et al. 5,254,548 A * 10/1993 Wermuth et al. ............. 514,242 9 Claims, 14 Drawing Sheets US 8,003,632 B2 Page 2 OTHER PUBLICATIONS Nakayama, et al., “Sepsis attenuates the intensity of the neuromuscular blocking effect of d-tubocurarine and the antagonistic Breccia, M., et al., “Ogilvie’s syndrome in acute myeloid leukemia: actions of neostigmine and edrophonium accompanying depression pharmacological approach with neostigmine.” Annals of Hematol of muscle contractility of the diaphragm. Acta Anaesthesiol Scand. ogy, 80:614-616 (2001). 43(2): 196-201(1999). Vesentini, S., et al., Effects of Choline-Esterase Inhibitor in Experi Yoshiyama Y. et al., “Anti-inflammatory action of donepezilamelio mental Acute Pancreatitis in Rats, International Journal of Pancreatology, 13(3): 217-220 (1993). ratestau pathology, synaptic loss, and neurodegeneration in a tauopat Debord, J., et al., Cholinesterase Inhibition by Derivatives of mouse model”, JAlzheimers Dis. 2010; 22 (1): 295-306 (Abstract). 2-Amino-4,6-Dimethylpyridine, J. Enzyme Inhibition, 12:13-26 (1997). * cited by examiner U.S. Patent Aug. 23, 2011 Sheet 1 of 14 US 8,003,632 B2 s U.S. Patent Aug. 23, 2011 Sheet 2 of 14 US 8,003,632 B2 U.S. Patent US 8,003,632 B2 U.S. Patent Aug. 23, 2011 Sheet 4 of 14 US 8,003,632 B2 0?I. I|}!————————— [u]]Kuafiunsuængeeur?I. -00|| G/. f Ao eAA in S U.S. Patent Aug. 23, 2011 Sheet 5 of 14 US 8,003,632 B2 U.S. Patent Aug. 23, 2011 Sheet 6 of 14 US 8,003,632 B2 U.S. Patent Aug. 23, 2011 Sheet 7 of 14 US 8,003,632 B2 (sÁep)aut? (~~~~+0 00?. 06 08 02 09 09 07 09 02 0\, (%) emiAunS (%) lealAuns U.S. Patent Aug. 23, 2011 Sheet 8 of 14 US 8,003,632 B2 ---;|, s! 08 te S. (9) enlarS U.S. Patent Aug. 23, 2011 Sheet 9 of 14 US 8,003,632 B2 .. U.S. Patent Aug. 23, 2011 Sheet 10 of 14 US 8,003,632 B2 U.S. Patent Aug. 23, 2011 Sheet 11 of 14 US 8,003,632 B2 | wn O O O O O O O CO CO w N w (%) emi Auns U.S. Patent US 8,003,632 B2 VIelz?|06819Gºz (sÁep)auu?i (%) emmunS U.S. Patent Aug. 23, 2011 Sheet 13 of 14 US 8,003,632 B2 00|| (%) emiAins U.S. Patent Aug. 23, 2011 Sheet 14 of 14 US 8,003,632 B2 | US 8,003,632 B2 1. 2 CHOLINESTERASE INHIBITORS FOR before endotoxin injection. Four groups of mice are shown: 1) TREATING INFLAMMATION mice treated with vehicle (O); 2) mice treated with 4 mg/kg galantamine (O); 3) mice treated with 2 mg/kg galantamine RELATED APPLICATIONS (A); and 4) mice treated with 1 mg/kg galantamine (D). FIG. 7A shows results for two groups of 10 mice; FIG. 7B shows This application is a Continuation of U.S. application Ser. results for four groups of 20 mice each; FIG.7C shows results No. 11/044,649, filed on Jan. 27, 2005 now abandoned, which for four groups of mice, either 10 or 20 animals as indicated. claims the benefit of U.S. Provisional Application No. FIG. 8A show survival percentage of mice with sepsis 60/539,557, filed on Jan. 27, 2004 and U.S. Provisional induced by cecalligation and puncture that were treated with Application No. 60/548.461, filed on Feb. 27, 2004. The 10 tacrine post-operatively. Results from three groups of mice entire teachings of the above applications are incorporated are shown: 1) Mice treated with the saline vehicle (()); 2) herein by reference. mice treated with 0.25ug/kg tacrine (O); and 3) mice treated with 2.5 lug/kg tacrine (O). BACKGROUND OF THE INVENTION FIG.8B is a bar plot showing the effect of administration of 15 tacrine at 0.25 ug/kg and 2.5 g/kg on serum TNF (pg/ml) in There is a continuing need for new medications for treating septic mice. inflammatory disorders. FIG. 8C is a bar plot showing the effect of administration of tacrine at 0.25ug/kg and 2.5 g/kg on serum HMGB1 (ng/ml) SUMMARY OF THE INVENTION in Septic mice.
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