Use of cannabinoids and terpenes for treatment of organophosphate and carbamate toxicity

Abstract

Pharmaceutical compositions in which isolated cannabinoid receptor modulators are optionally combined with terpene blends in a pharmaceutically acceptable carrier. Methods for treating or preventing a disease, disorder, dysfunction or condition caused by exposure to an organophosphate or carbamate acetylcholineesterase inhibitor with the inventive compositions are also disclosed.

1 . A pharmaceutical composition comprising an isolated cannabinoid receptor modulator, and optionally containing a blend of terpenes in a pharmaceutically acceptable carrier. 
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising a blend of two or more terpenes selected from the group consisting of limonene, pinene, myrcene, linalool, beta caryophylene, terpineol and terpinolene. 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 2 , wherein the weight ratios of said terpenes is within the in range of about 1-10:about 1-10:about 1-6: and about 1-6:0.25-3, respectively. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein said cannabinoid receptor modulator agonist is a CB receptor agonist or a modifier selected from the group consisting of phytocannabinoids, tetrahydrocannabinol (THC) (−) trans delta 9 THC, dronabinol, (±)-trans-3-(1,1-dimethylheptyl)-6,6a, 7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one (nabilone), anandamide, 2-arachidonoyl-glycerol (2-AG), N-acyl-phosphatidylethanolamine-phospholipase D, diacyl glycerol lipase (DAGL), cannabidiol (CBD), abnormal cannabidiol (abn-CBD), nabiximols, EPIDIOLEX®, rimonabant, (−)-1,1 dimethylheptyl analogs of 11-hydroxy-8-tetrahydrocannabinol (HU 210), HU 211, HU 308, ajulemic acid, AM-411, L-759,633, AM-855, VCHSR, nonabine, JWH 133, JWH-171, BML-190, A-41988, O-806, O-2694 and 0-2545, JZL184, JWH-359, CB-13, GW-405,833, JTE-907, URB754, inhibitors of FAAH or fatty acid amide hydrolasel-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM-1241), WIN 55,212-2, other natural or endogenous endocannabinoid derivatives, and combinations thereof. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the composition is in oral, nasal, topical, ophthalmic, buccal, sublingual, rectal, vaporization-ready, nebulization-ready, nanoparticle formulations, liposomal formulations, vaginal and/or IV or other parenteral form. 
     
     
         9 . The pharmaceutical composition of  claim 1 , further comprising one or more non-cannabinoid active ingredients selected from the group consisting of a terpene, a benzodiazepine, a belladonna alkaloid, an anticholinesterase an oxime, and combinations thereof. 
     
     
         10 . (canceled) 
     
     
         11 . A method of treating or preventing a disease, disorder, dysfunction or syndrome caused by exposure to an organophosphate (OP) or carbamate acetylcholinesterase inhibitor, saqid method comprising administering to a subject exposed to or at risk of exposure to said OP or carbamate in an amount effective to moduolate the cannabinoid receptors of said subject. 
     
     
         12 . The method of  claim 11  wherein the mediated disease, disorder, dysfunction or syndrome is selected from the group consisting of muscle disorder, ophthalmic dysfunction, metabolic disorders, cardiac, rhythm and contractility dysfunctions, social related disorders, mood disorders, seizures, learning disorders, cognition disorders, memory disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth, pain or neurodegenerative related syndromes, drug abuse, alcohol abuse, bipolar disorder, cognitive impairment, post traumatic stress disorder (PTSD), Gulf War like syndrome and premature senile dementia. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 11 , wherein said cannabinoid receptor modulator is selected from the group consisting of phytocannabinoids, tetrahydrocannabinol (THC) (−) trans delta 9 THC, dronabinol, (±)-trans-3-(1,1-dimethylheptyl)-6,6a, 7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one (nabilone), anandamide, 2-arachidonoyl-glycerol (2-AG), N-acyl-phosphatidylethanolamine-phospholipase D, diacyl glycerol lipase (DAGL), cannabidiol (CBD), abnormal cannabidiol (abn-CBD), nabiximols, EPIDIOLEX®, rimonabant, (−)-1,1 dimethylheptyl analogs of 11-hydroxy-8-tetrahydrocannabinol (HU 210), HU 211, HU 308, ajulemic acid, AM-411, L-759,633, AM-855, VCHSR, nonabine, JWH 133, JWH-171, BML-190, A-41988, O-806, O-2694 and 0-2545, JZL184, JWH-359, CB-13, GW-405,833, JTE-907, URB754, inhibitors of FAAH or fatty acid amide hydrolasel-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole (AM-1241), WIN 55,212-2, other natural or endogenous endocannabinoid derivatives, and combinations thereof. 
     
     
         17 . The method of  claim 11 , further comprising administering a non-cannabinoid receptor modulator selected from the group consisting of opioids, gabapentins, pregabalins, a benzodiazepines, atropines, oximes, antioxidants, alkalizing agents, terpenes, and NSAIDs. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 11 , wherein said composition is administered prior to exposure to said organophosphate or carbamate and said composition comprises at least one terpene selected from the group consisting of limonene, mycrene, pinene, linalool, beta caryophyllene, and a cannabinoid selected from the group consisting of THC, CBD, and a ixture of THC, CBD. 
     
     
         20 . The method of  claim 19 , further comprising the step of exposing said subject to an OP or carbamate acetylcholinesterase inhibitor as a prophylactic treatment. 
     
     
         21 . The method of  claim 20 , further comprising administering to said subject atropine and an oxime in an amount effective to prevent adverse effects from said prophylactic exposure to OP or carbamate. 
     
     
         22 . The method of  claim 19 , further comprising co-administering pyridostigmine bromide to said subject. 
     
     
         23 . The method of  claim 11 , wherein said composition is administered to said subject after exposure to an OP or a carbamate acetylcholinesterase inhibitor and said composition comprises a blend of CBD and THC in a weight ratio of between about 3 and 400 mg to about 0.0001 and 10 mg, respectively. 
     
     
         24 . The method of  claim 23 , further comprising the step of administering a blend of two or more terpenes. 
     
     
         25 . The method of  claim 24 , wherein said terpine blend comprises two or more terpenes selected from the group consisting of limonene, pinene, myrcene, linalool, beta caryophylene, terpineol and terpinolene. 
     
     
         26 . A method of treating or preventing a disease, disorder, dysfunction or syndrome caused by exposure to an organophosphate or carbamate acetylcholinesterase inhibitor, said method comprising administering to a subject exposed to or at risk of exposure to said OP or carbamate, q composition comprising at least two terpines selected from the group consisting of limonene, myrcene, linalool, beta caryophylene, terpineol, terpinolene, and pinene, in an amount effective to treat or prevent said disease, disorder, dysfunction or syndrome. 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . A compound having the following structure: 
       
         
           
           
               
               
           
         
       
       wherein L is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       Z═O, S or NR7, R7=H, alkyl, aryl, —OH, —O, or lower alkoxy; A is aryl, heteroaryl, fused pyran or a fused tetrahydropyran; B is C(═O)—O—R6; R6 is an alkaloid azabicyclo ring substituent; C is H, F, lower alkoxy, CN, S(O) n CH 3  where n=0-2, and Z═O. 
     
     
         30 . The compound of  claim 29 , selected from the group consisting of: