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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application Ser. No. 61 / 738,782, filed Dec. 18, 2012, the disclosure of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention discloses the novel uses of cannabinoid system modulators and terpenes in treatment of the symptoms and signs of anticholinesterase toxicity associated with organophosphate (“OP”) and / or carbamate exposure. More particularly, the present invention relates to compositions containing cannabinoid receptor agonists and derivatives thereof, including partial agonists and modifiers of cannabinoid metabolism and terpenes for prevention and treatment of acute and chronic OP toxicity and acute and chronic carbamate toxicity.BACKGROUND OF THE INVENTION[0003]Organophosphates are compounds having the general chemical formula:wherein R1 and R2 are alkyl-, alkoxy-, alkylthio- or amido groups and X is an acyl residue or leaving group when t...

AI Technical Summary

Benefits of technology

[0008]AChE is a serine protease in the carboxylesterase family of enzymes with EC number 3.1.1.7. Mammals have a single AChE gene; however, AChE diversity in humans results from location, other molecular associations such as with membrane components, as well as from alternative mRNA splicing and posttranslational associations or structural and catalytic subunits. Inhibition of AChE prevents the breaking down of the neurotransmitter ACh thereby increasing both the level and duration of action of this neurotransmitter. ACh is a neurotransmitter that contributes to nerve conduction following its release in the central nervous system (CNS) as well as autonomic ganglia at sympathetic preganglionic synapses, at parasympathetic postganglionic synapses, and at neuromuscular junctions.

Problems solved by technology

OPs typically cause a more severe and difficult to treat cholinergic crisis because OPs are capable of irreversibly inhibiting AChE.

The use of Sarin more than once recently in the Syrian conflict lead to many casualties alarming the international community about the risks to the stability of the region.

They are estimated to cause around 300,000 fatalities a year.

In summary, OP and carbamate pesticides cause hundreds of thousands of deaths each year and many more injuries.

When OPs or carbamates are used as insecticides the prolonged exposure and inhalation of such compounds could lead to multiple ophthalmic and neuromuscular symptoms.

OPs are also used as warfare nerve agents, (“nerve gas”) and acute exposure to them by any route of exposure can be fatal.

Even if not fatal, exposure may lead to temporary incapacitation as well as permanent cognitive deficits, depression and other neuropsychiatric disorders.

Current treatment after acute injury does not seem to prevent the emergence of “Organophosphate induced delayed neuropathy,” an axonpathy.

G agents in liquid form may penetrate skin and as well as volatilize presenting significant respiratory hazards.

Since G agents and some OP pesticides are colorless, tasteless, and virtually odorless, they may also be accidently ingested into the GI tract or ingested via deliberate contamination of food and drinking liquids.

The V-agents, oily liquids at room temperature that very slowly release gas due to their low volatilities, are both more toxic, as well as longer persisting in the environment than the G-agents.

A single drop of VX the size of this dot (.) unless rapidly decontaminated or removed, may be fatal within 30 minutes if placed on intact thin moist skin, faster if on a wound, and within 120 minutes if on dry thick skin.

Toxicity associated with OP compounds mainly results from excessive cholinergic stimulation through inhibition of AChE.

The resulting hypercholinergic tone crisis may also cause other neuronal hyperexcitation, e.g. glutamate release and depletion of high energy phosphates leading to cellular damage and physiological exhaustion.

Phosphorylated AChE is not able to functionally hydrolyze ACh.

However, the binding or inhibition can eventually become permanent (irreversible or aged).

It is well documented that exposure to high concentrations of nerve agent vapor causes immediate loss of consciousness, followed shortly by convulsions, flaccid paralysis, and respiratory failure.

Percutaneous absorption of nerve agent typically results in localized sweating caused by direct nicotinic effect on the skin, followed by muscular fasciculations and weakness as the agent penetrates deeper and a nicotinic effect is exerted on underlying muscle.

Nerve agents cause death via respiratory failure, which in turn is caused by increased airway resistance (eg bronchospasm), excessive bronchopulmonary secretions, respiratory muscle paralysis, and most importantly, loss of central respiratory drive.

It has also been reported that prolonged exposure to OP leads to cognitive impairment of central information processing leading eventually to IQ loss.

In the absence of OP intoxication an atropine dose of 2 mg will cause severe poisoning and a dose of 100 mg will be fatal.

However, since pyridostigmine barely crosses the blood-brain barrier it provides no protection against nerve agent-induced central injury.

Pyridostigmine, as written in the FDA approved prescribing information, is ineffective when administered without post-exposure treatment of atropine / 2 PAM or similar drugs.

Also many of the prophylactic and treatment regimens cause cognitive impairment or excessive dryness (e.g. atropine and other antimuscarinics), certainly not desirable in combat situations or hot environments where perspiration also serves as a temperature regulator.

Excessive dryness increases the chances of heat exhaustion related disorders including heat stroke.

Atropine overdose or misuse risks heat stroke and temporary psychosis.

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