US 20100168030A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0168030 A1 Zoltani et al. (43) Pub. Date: Jul. 1, 2010 (54) METHODS AND COMPOSITIONS FOR (52) U.S. c1. ........................................................ .. 514/13 TREATMENT OF ORGANOPHOSPHATE-CAUSED (57) ABSTRACT PATHOLOGY A method of treating an organophosphate toxin-caused car (76) Inventors: Csaba K. Zoltani, Lutherville, MD diac abnormality is described Which includes administering a (US); Gennady E. Platoff, pharmaceutical composition including a therapeutically Millersville, MD (US); Steven I. effective amount of a chloride current modulator to an indi Baskin, Bel Air, MD (US) vidual subject having a cardiac abnormality caused by intoxi cation With an organophosphate toxin. The chloride current Correspondence Address: modulator is effective to modulate a chloride conductance U S ARMY RESEARCH LABORATORY and thereby reduce a symptom or sign of an organophosphate ATTN: RDRL-LOC-I toxin-caused cardiac abnormality, thus treating the toxin 2800 POWDER MILL RD caused cardiac abnormality. Optionally, included is adminis ADELPHI, MD 20783-1197 (US) tering a therapeutic agent to inhibit an organophosphate toxin-caused distortion of the action potential of myocytes, (21) App1.No.: 11/288,269 support restoration of usual intracellular ionic concentra tions, and support an increase in cardiac contractility. A com (22) Filed: Nov. 29, 2005 position according to the invention is described Which includes a chloride current modulator; and a therapeutic agent Publication Classi?cation to inhibit an organophosphate toxin-induced distortion of the (51) Int. Cl. action potential of myocytes, support restoration of usual A61K 38/16 (2006.01) intracellular ionic concentrations, and support an increase in A61P 9/06 (2006.01) cardiac contractility. 1.2 ' 1 __ C 0.8 - Voltage (mV) 2 0.6 — 0.4 ' 0.2 l 0 .. llllll 0 150 200 250 300 Time (ms) Patent Application Publication Jul. 1, 2010 Sheet 1 0f 2 US 2010/0168030 Al F | 9 LL 0 --o _oo u - “o —o N 150l (ms)Time Illlllllllllllllllllllllllo c‘! '_' 0°. Lo. "'1 N. O '—l O Q O O Voltage(mV) Patent Application Publication US 2010/0168030 A1 I I N12" l I l l l l l l l l l I A? l l l l l l l l I l l l l l l I I I lllllllllllLlilLllllllll‘i \ ow om 3. ow ow $5¢m~=o>a. US 2010/0168030 A1 Jul. 1,2010 METHODS AND COMPOSITIONS FOR a simulated electrocardiogram (ECG or EKG) illustrating a TREATMENT OF control trace, A, representative of normal cardiac activity, and ORGANOPHOSPHATE-CAUSED a trace B illustrating differences due to organophosphate. A PATHOLOGY normal T-Wave is shoWn in the simulated control trace, A, at (a). Notable changes include a decrease in amplitude of the GOVERNMENT INTEREST QRS and the modulation of the T-Wave, the repolariZation of the ventricle. In particular, a T-Wave as a separate entity is no [0001] The invention described herein may be manufac tured, used, and licensed by or for the United States Govem longer in evidence, the shape of the QRS portion has been altered and the peak has been shortened. ment. [0009] Treatment of organophosphate intoxication has FIELD OF THE INVENTION focused predominantly on treatment of symptoms and clear ance of organophosphate compounds from the body. Particu [0002] This invention relates to compositions and methods lar treatments include administration of atropine and ani for treatment of organopho sphate poisoning. In particular, the sodamine for treatment of symptoms such as gastrointestinal invention relates to compositions and methods for treatment and/or respiratory distress. Side effects may include arrhyth of cardiac arrhythmias and/or repolariZation abnormalities mia at higher doses. Further, particular oximes including resulting from organophosphate poisoning. obidoxime, pralidoxime and asoxime may be used in orga nophosphate-intoxicated patients to help restore acetylcho BACKGROUND OF THE INVENTION linesterase activity. [0003] Organophosphates are Widely used as insecticides [0010] Thus, there is a continuing need for neW treatments and as cholinergic threat agents. Accidents in their use are for organophosphate poisoning and for treating conditions common in agriculture and treatment is still rudimentary. relating to organophosphate exposure. In particular, treat Organophosphate-caused ventricular ?brillation results in ments addressing cardiac sequelae of organophosphate expo heart failure and is recogniZed as the most common cause of sure and other types of toxin intoxication are especially mortality in cases of organophosphate intoxication. sought after. [0004] The ?rst organophosphate toxins Were developed early in the 20th century, primarily as pesticides. In the course SUMMARY OF THE INVENTION of research on their pesticidal properties, the potential of these agents for use in chemical Warfare and/or as threat [0011] A method of treating an organophosphate toxin agents Was discovered. induced cardiac abnormality in an individual subject is [0005] Organophosphate toxins bind to acetylcholinest described Which includes administering a pharmaceutical erase, preventing the hydrolysis of acetylcholine and leading composition including a therapeutically effective amount of a to its accumulation and consequent prolongation of its effects chloride current modulator to an individual subject having a at synapses. Symptoms of organophosphate toxin intoxica cardiac abnormality caused by intoxication With an organo tion include rhinorrhea, dyspnea, sWeating, miosis, bradycar phosphate toxin. The chloride current modulator is effective dia, tachycardia, loss of consciousness, convulsions, ?accid to modulate a chloride conductance and thereby reduce a paralysis, and apnea. Histological examination of organo symptom or sign of an organophosphate toxin-induced car phosphate-affected heart tissue shoWs cell sWelling, hemor diac abnormality, thus treating the toxin-induced cardiac rhaging and necrosis. abnormality. [0006] One of the most serious consequences of organo [0012] In a preferred option, the chloride current modulator phosphate intoxication is due to effects on the cardiovascular is a modulator of ICZ, We”. Modulators of chloride currents system. Organophosphate-caused heart failure is a syndrome include: a disulfonic stilbene; an arylaminobenZoate; a characterized primarily by left ventricular dysfunction, fenamate; an anthracene carboxylate; an indanylalkanoic reduced exercise tolerance, impaired quality of life and dra acid; a clo?bric acid; a clo?bric acid derivative; a sulfony matically shortened life expectancy. Decreased contractility lurea; a calixarene; suramin; and tamoxifen. Further pre of the left ventricle leads to reduced cardiac output With the ferred are modulators of ICZ, We” such as 4,4'-diisothiocyanos consequent systemic arterial and venous constriction. tilbene-2,2'-disulfonic acid (DIDS); 4,4'-dinitrostilbene-2,2' [0007] Cardiovascular effects of organophosphate intoxi disulfonic acid (DNDS); 4-acetamindo-4' cation are apparent When analyZed by electrocardiogram. The isothiocyanostilbene-2,2'-disulfonic acid (SITS); tamoxifen; electrocardiogram of an affected individual shoWs changes in 5-nitro-2-(3-phenylpropylamino)benZoic acid (NPPB); the P-Wave, the depolarization of the atria, and also prominent ni?umic acid (N FA); ?ufenamic acid; anthracene-9-carboxy modulation of the T-Wave, the repolariZation of the ventricles. late (9AC); diphenylaminecarboxylate (DPC); 2-(p-chlo After an initial bradycardia, Torsade de Pointes and tachycar rophenoxy)propionic acid (CPP); and indanyloxyacetic acid dia develop and the electrophysiology of the heart loses its (IAA-94). Mixtures of these modulators may also be admin predictability. In addition to these changes, the fast outWard istered. rectifying potassium current is blocked. The ensuing over [0013] Optionally, an inventive method further includes stimulation results in ion concentration imbalance and mem administering a therapeutic agent to inhibit organopho sphate brane current derangement. On the electrocardiogram, this is induced distortion of the action potential of myocytes, sup expressed by QT prolongation, ST and T Wave abnormalities. port restoration of usual intracellular ionic concentrations, Organophosphate-caused ventricular ?brillation culminates and support an increase in cardiac contractility. Such thera in heart failure and is recogniZed as the most common cause peutic agents include a second current modulator; an antiar of mortality in cases of organophosphate intoxication. rhythmic drug; a modulator of a mitochondrial membrane ion [0008] An example of effects of organophosphate com channel, ion pump and/or ion exchanger; inhibitor of protein pounds on cardiac tissue is shoWn in FIG. 1 Which illustrates kinase C; an anticonvulsant; an organophosphate clearing US 2010/0168030 A1 Jul. 1,2010 agent; an inhibitor of a muscarinic potassium channel; and an rophenyl)ethenyl diethyl phosphate), chlorfenvinphos acetylcholine receptor antagonist; and combinations thereof. (2-chloro- l -(2,4-dichlorophenyl)ethenyl diethyl phosphate), [0014] A composition according to the invention is crotoxyphos (l -phenylethyl3 -(dimethoxypho sphinoyloxy) described Which includes a chloride current modulator; and a isocrotonate), dichlorvos(2,2-dichlorovinyl dimethyl phos therapeutic agent to inhibit organopho sphate-induced distor phate), dicrotophos ((E)-2-dimethylcarbamoyl-l-methylvi tion of the action potential of myocytes, support restoration of nyl dimethyl phosphate or 3-dimethoxyphosphinoyloxy-N,