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(12) Patent Application Publication (10) Pub. No.: US 2009/0023706 A1 Albuquerque Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0023706 A1 Albuquerque Et Al US 20090023706A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0023706 A1 Albuquerque et al. (43) Pub. Date: Jan. 22, 2009 (54) METHOD OF TREATING Related U.S. Application Data ORGANOPHOSPHOROUS POISONING (63) Continuation-in-part of application No. 1 1/575.945, filed on May 23, 2007, filed as application No. PCT/ (75) Inventors: Edson X. Albuquerque, Baltimore, US05/33789 on Sep. 23, 2005. MD (US); Michael Adler, Bel Air, (60) Provisional application No. 60/613,121, filed on Sep. MD (US); Edna F.R. Pereira, 24, 2004. Baltimore, MD (US) Publication Classification (51) Int. Cl. Correspondence Address: A6II 3/55 2006.O1 EVANS & MOLINELLI, PLLC (52) U.S. Cl ( .01) S14/215 U.S. POST OFFICE BOX 7024 Oa - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - FAIRFAX STATION, VA 22039 (US) (57) ABSTRACT The present invention is directed to various methods for treat (73) Assignee: University of Maryland ing organophosphorus poisoning in an animal that is at risk of Baltimore, Baltimore, MD (US) exposure to an organophosphorus compound or preventing organophosphorus poisoning in an animal that has been exposed to an organophosphorus compound, by administer (21) Appl. No.: 12/199,250 ingatherapeutically effective amount of galantamine or a salt thereof, or a biologically active analog, derivative, fragment (22) Filed: Aug. 27, 2008 or variant thereof. A Soman, 1.5xLD50 B. Sarin, 1.5xLD50 C Soman, 1.5xLD50 25 Atropine, 10 mg/kg Atropine, 10 mg/kg Galantamine, 5 mg/kg O Galantamine, 8 mg/kg Y. P. ... First O. 1 10 O. 1 10 1 10 100 Galantamine, mg/kg Galantamine, mg/kg Atropine, mg/kg Patent Application Publication Jan. 22, 2009 Sheet 1 of 28 US 2009/0023706 A1 OGGITXG"|‘ueUuOS<D‘u?JeS8 0010|||0||||"00||- | 6x/6uu‘au?uequele?) ?eudonyº.Sók WAunSJO % Patent Application Publication Jan. 22, 2009 Sheet 3 of 28 US 2009/0023706 A1 S. S- O E : " : to E SH Crs is -- ar y ry m s r f . i 3 s eAnsg0% Patent Application Publication Jan. 22, 2009 Sheet 4 of 28 US 2009/0023706 A1 gefull 6. s togeq 0%) J???ES?BIT Life M pod d s ful Bloyed go 96) e M. podp. Patent Application Publication Jan. 22, 2009 Sheet 5 of 28 US 2009/0023706 A1 ||£|||No. Bu???S ov-GEGE-0801-G9-0 (Lo) 6.0L espeo Patent Application Publication Jan. 22, 2009 Sheet 6 of 28 US 2009/0023706 A1 Patent Application Publication Jan. 22, 2009 Sheet 7 of 28 US 2009/0023706 A1 FIG. 4A Post-treatment with galantamine alone effectively counteracts the acute toxicity and 24-h-survival Gallantamire m Saline 50 25 5 10 15 5 Time of treatment after soman challenge (min) No need for atropine or any additional supportive therapy Patent Application Publication Jan. 22, 2009 Sheet 8 of 28 US 2009/0023706 A1 FIG. 4B Animals challenged with 0.6 or 0.7xLD50 soman and post-treated with galantamine survived with no immediate signs of toxicit . Galantamine xh (8 mg/kg, im) H- 24-h survival or saline (im) SOman 0.6XD50 SOman 0.7xD50 (16.8 ug/kg, Sc) (19.6 ug/kg, SC) 100 75 Galantamine 50 Saline f SS 25 O 1 1 3 1 1 3 Time of treatment after soman callenge (h) Patent Application Publication Jan. 22, 2009 Sheet 9 of 28 US 2009/0023706 A1 FIG. 5 t Patent Application Publication Jan. 22, 2009 Sheet 10 of 28 US 2009/0023706 A1 FIG. 6 AN ACUTE EXPOSURE TO SOMAN LEADS TO BRAIN ATROPHY PRE-SOMAN EXPOSURE POST-SOMAN EXPOSURE Patent Application Publication Jan. 22, 2009 Sheet 11 of 28 US 2009/0023706 A1 FIG. 7 HISTOLOGICAL CONFIRMATION OF THE BRAIN DAMAGE OBSERVED IN THE MR OF SOMAN-EXPOSED GUINEA PIG BRAIN 7 HOURS POST-SOMAN EXPOSURE Patent Application Publication Jan. 22, 2009 Sheet 12 of 28 US 2009/0023706 A1 FIG. 8 HISTOLOGICAL CONFIRMATION OF THE BRAIN DAMAGE OBSERVED IN THE MR OF SOMAN-EXPOSED GUINEA PG BRAIN Patent Application Publication Jan. 22, 2009 Sheet 13 of 28 US 2009/0023706 A1 FIG. 9 EFFICACY OF GALANTAMINE IN PREVENTING BRAIN DAMAGE INDUCED BY ACUTE EXPOSURE TO 125X LD50 SOMAN. A VOXL-BASED MORPHOMETRICANALYSIS Patent Application Publication US 2009/0023706 A1 Patent Application Publication Jan. 22, 2009 Sheet 15 of 28 US 2009/0023706 A1 FIG. 11 A-B f o i o O), O iOO. 200 300 400. to also sco 450 Time (min) Tirre (fir) . after Brigg galaritainine. after 8 mg/kg galanta Tine Patent Application Publication Jan. 22, 2009 Sheet 16 of 28 US 2009/0023706 A1 FIG. 11 C-D C 1. O o do 200 360 400 10-108,064 to 2. after 8 mg/kg galantamine (Gallantantinel M. Patent Application Publication Jan. 22, 2009 Sheet 17 of 28 US 2009/0023706 A1 ¿? o o ed c 8 v (ueuos euogeq go 6) few Apo O 92 (u, va) en Ains 96 Patent Application Publication Jan. 22, 2009 Sheet 18 of 28 US 2009/0023706 A1 se ueueen ejoyed Jo 96) few Apo ||ZedaUOC] ('u') CS OO!. N (utra) emiAins % Patent Application Publication Jan. 22, 2009 Sheet 19 of 28 US 2009/0023706 A1 (sAep) eat Ains & |0|||83?12||?.99||9G c G2, utva) emains a Patent Application Publication Jan. 22, 2009 Sheet 21 of 28 US 2009/0023706 A1 d O (u va) en NunS 6 Patent Application Publication Jan. 22, 2009 Sheet 23 of 28 US 2009/0023706 A1 s6ideeuinôuiueudos £G|G| o 0 (uva) peANunS 6 Patent Application Publication Jan. 22, 2009 Sheet 25 of 28 US 2009/0023706 A1 Patent Application Publication Jan. 22, 2009 Sheet 26 of 28 US 2009/0023706 A1 Patent Application Publication Jan. 22, 2009 Sheet 28 of 28 US 2009/0023706 A1 areaE - 5 c. arE. CY) e- sK C en 9 C ls 5 ! CD E e - Fer C do El C. 5 E. ; &: t d E O O Og N D an N y (va) enl/uns 6 US 2009/0023706 A1 Jan. 22, 2009 METHOD OF TREATING erase (AChE), the enzyme that catalyzes the inactivation of ORGANOPHOSPHOROUS POSONING the neurotransmitter acetylcholine (Bajgar, J. (2004) Adv. Clin. Chem. 38, 151-216). In the periphery, acetylcholine CROSS-REFERENCE TO RELATED accumulation leads to persistent muscarinic receptor stimu APPLICATIONS lation that triggers a syndrome whose symptoms include mio 0001. This application is a continuation-in-part of U.S. sis, profuse secretions, bradycardia, bronchoconstriction, application Ser. No. 1 1/575,945, filedon Mar. 23, 2007, under hypotension, and diarrhea. OP poisoning also leads to over 35 U.S.C. S 120, which claims the benefit of U.S. Provisional stimulation followed by desensitization of nicotinic recep Patent Application No. 60/613,121 filed Sep. 24, 2004, under tors, causing severe skeletal muscle fasciculations and Sub 35 U.S.C. S 119(e). The entire contents of these applications sequent weakness. Central nervous system-related effects are hereby incorporated by reference as if fully set forth include anxiety, restlessness, confusion, ataxia, tremors, sei herein. Zures, cardiorespiratory paralysis, and coma. 0007 OPs are also known to cause an Intermediate Syn STATEMENT OF GOVERNMENT SUPPORT drome (IMS), which results in muscle weakness in the limbs, neck, and throat that develops in Some patients 24-96 hours 0002. The invention described herein was made, at least in after poisoning; long-term nerve damage sometimes devel part, with funding from the U.S. Army under Grant No. ops 2-3 weeks after poisoning. Researchers from Sri Lanka, DAAD19-02-D-001, NINDS/NIH U01NS059344-02, ARO Australia, and the UK recently showed that changes in neu contract W911NF-06-1-0098. Therefore, the government has romuscular transmission patterns often occur before a physi certain rights in the invention. cian can make an IMS diagnosis from clinical signs. About 38% of patients studied presented with muscle weakness that TECHNICAL FIELD OF THE INVENTION was not severe enough for an IMS diagnosis. Thus, IMS is a 0003. The present invention relates to a method of treating spectrum disorder. At one end of the spectrum the patients organophosphorus poisoning. demonstrate only the electrophysiological abnormalities without clinically detectable muscle weakness and at the BACKGROUND OF THE INVENTION other end, patients progress to severe muscular weakness with deterioration of electrophysiological measurements and 0004 Organophosphorus compound is (OP) are a com the risk of respiratory failure. mon class of chemicals used as pesticides, herbicides, and 0008. None of the current therapies for treating or prevent nerve agents. The nerve agents soman (3-(Fluoro-methyl ing OP poisoning and IMS have been ideal. Therefore, there phosphoryl)oxy-2,2-dimethyl-butane), Sarin (2-(Fluoro-me is still a critical need for an effective and safe method of thylphosphoryl)oxypropane), VX (S-2-diisopropylamino treating or preventing OP poisoning. This and other objects O— ethyl methylphosphonothioate), tabun (ethyl N,N- and advantages, as well as additional inventive features, will dimethylphosphoramidocyanidate) and Novichok agents are become apparent from the detailed description provided among the most lethal weapons of mass destruction ever herein. developed. Some of these nerve agents were used with cata strophic results in wars and also in terrorist attacks in Japan in DEFINITIONS the 1990s. The majority of pesticides are also OPs (such as parathion, fenthion, malathion, diazinon, dursban, chlorpyri 0009. Unless otherwise indicated, a “therapeutically fos, terbufos, acephate, phorate, methyl parathion, phosmet, effective amount of galantamine is an amount that provides azinphos-methyl, and dimethoate), and intoxication with a therapeutic benefit in the prevention, treatment or manage these compounds represents a major public-health concern ment of OP poisoning (organophosphorus poisoning), delays worldwide.
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