Lipid emulsion therapy for treating acute cannabinoid intoxication

Abstract

A lipid emulsion composition including soybean oil, egg lecithin, glycerol and, or osmolality and method for treating acute cannabinoid intoxication or intoxication from other substances, such as alcohol or other drugs, by orally or intravenously administering this composition according to a predetermine protocol to treat patients experiencing acute cannabinoid intoxication or intoxication from other substances. The lipid emulsion composition could be administered to the intoxicated patient orally or intravenously. In some embodiments, the lipid emulsion composition includes soybean oil, egg yolk phospholipids, and glycerin.

Claims

1. A lipid emulsion composition and method for treating a patient having acute tetrahydrocannabinol intoxication with the lipid emulsion composition, comprising: assessing the patient for tetrahydrocannabinol intoxication; performing a mental status examination on the patient; administering a lipid emulsion composition to the patient, said lipid emulsion composition including soybean oil, lecithin, and glycerol; and repeating the mental status examination on the patient; wherein administration of the lipid emulsion composition results in an improvement in the patient's behavior, speech, thought process, or cognition as assessed by the patient's repeat mental status examination.

2. The method of claim 1, wherein the lipid emulsion composition further comprises: egg lecithin.

3. The method of claim 1, wherein the lipid emulsion composition having: osmolality.

4. The method of claim 1, wherein the lipid emulsion composition having: osmolality.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) This instant invention is a lipid emulsion composition 10 and method for administering the composition 100 to treat patients experiencing acute cannabinoid intoxication. Cannabinoids are a diverse class of chemical compounds that act on cannabinoid receptors in cells that alter neurotransmitter release in the brain. Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially). The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is another major constituent of the cannabis plant. The liquid emulsion therapy composition and method for administering same may be modified to treat patients with overdose incidents involving fentanyl, prescription pain relievers, heroin, cocaine, antidepressants, methamphetamine, acetaminophen, alcohol, diphenhydramine, sedatives, dextromethorphan, benzodiazepines and new diagnosis cannabinoid-hyperemesis-syndrome-marijuana.

(2) Pharmacokinetics. THC is a lipid soluble, highly protein-bound (95-99%) drug that has a volume of distribution of 2.5-3.5 L/kg. The pharmacokinetics of THC vary by route of administration. For inhaled marijuana, onset of psychoactive effects occurs rapidly with peak effects felt at 15-30 minutes and lasting up to four hours. These effects mirror plasma THC concentrations. Approximately 2-3 mg of inhaled THC is sufficient to produce drug effects in naïve user. Pulmonary bioavailability varies from 10-35% percent of an inhaled dose and is determined by the depth of inhalation, along with the duration of puffing and breath-holding.

(3) Ingested marijuana has a delayed onset of effect that ranges from 30 minutes to three hours, with clinical effects lasting up to 12 hours. Orally administered cannabis has low bioavailability (5-20%) because of chemical degradation in gastric acid and substantial first-pass metabolism in the liver. In naive users, psychotropic effects occur with 5-20 mg of ingested THC.

(4) Cannabis Toxicity. In recreational cannabis use, there is no clear demarcation between the dose that achieves effects desired by the user and the dose that produces noxious effects. Because of this lack of clarity in dosing, recreational cannabis use can often result in adverse effects. In adolescents and adults, inhaled doses of 2-3 mg of THC and ingested doses of 5-20 mg of THC impairs attention, concentration, short-term memory, and executive functioning. More severe adverse effects may occur at higher doses, such as nausea, postural hypotension, delirium, panic attacks, anxiety, and myoclonic jerking. Psychosis has also been associated with use of higher potency/concentrated cannabis products.

(5) Toxicity in children most often occurs with ingestion of a highly concentrated cannabis food product. Estimated oral doses from 5-300 mg in children have caused a range of symptoms such as mild sleepiness, ataxia, behavior changes, excessive and purposeless motor activity of the extremities (hyperkinesis), coma, and respiratory depression with more severe intoxication correlated with higher estimated doses.

(6) Clinical Manifestations. The clinical manifestations of acute cannabis intoxication vary according to age. In children, neurologic abnormalities are more prominent. At smaller doses, children may display sleepiness, euphoria, irritability, lethargy, and excessive and purposeless motor activity of the extremities (hyperkinesis). Vital signs may show sympathomimetic effects (e.g. tachycardia and hypertension), or bradycardia in patients with depressed mental status. Nausea, vomiting, conjunctival injection (red eye), nystagmus, ataxia, and slurred speech may also be present. Large overdoses may cause coma with apnea or depressed respirations.

(7) In adolescents and adults, acute marijuana intoxication is often not the primary complaint. Patients who come to medical attention are more likely to complain of hyperemesis or behavioral problems (e.g. dysphoria or agitation) caused by adverse cannabis effects or medical emergencies (e.g. bronchospasm or pneumothorax) associated with cannabis inhalation. The physiologic signs of cannabis intoxication in adolescents and adults include: tachycardia; increased blood pressure; in the elderly, orthostatic hypotension; increased respiratory rate; conjunctival injection (red eye); dry mouth; increased appetite; nystagmus; ataxia; or slurred speech. In asthmatic patients, inhalation may induce acute asthma exacerbations or poor chronic symptom control.

(8) Cannabis intoxication in adolescents and adults also results in neuropsychiatric effects that affect mood, perception, and thought content. There is typically a “high” feeling marked by euphoria and a decrease in anxiety, alertness, depression, and tension. However, first-time cannabis users, as well as anxious or psychologically vulnerable persons, may experience anxiety, dysphoria, and panic. Increased sociability usually occurs during intoxication, although dysphoric reactions may be accompanied by social withdrawal. Inexperienced users who ingest cannabis products may not be aware of the delayed onset of effect (up to three hours), which may induce them to continue to consume high potency products with an increased likelihood of dysphoria.

(9) Lipid Emulsion Therapy. For this invention, a lipid emulsion composition is administered to the patients experiencing acute cannabinoid intoxication. Intravenous lipid emulsions have had a role in toxicology as an antidote to medication overdose or accidental exposure, in particular, as rescue from systemic toxicity brought on by local anesthetics. The lipid emulsion may work by a “lipid sink” mechanism of action. This “lipid sink” mechanism proposes that lipid-soluble drugs, such as local anesthetics, are absorbed into the lipid emulsion of the plasma and removed from tissues affected by toxicity. That is, infusing a large amount of lipids to the blood could move the lipid-soluble drugs away from the site of toxicity and dissolve it in the plasma, which would alleviate the toxic effects of the lipid-soluble drug. THC is a highly lipophilic (fat-soluble) compound and is likely to be drawn into this “lipid sink” created by the administered lipid emulsion treatment.

(10) Lipid Emulsion Composition. Any suitable lipid emulsion composition may be used in this invention. One particular lipid emulsion product that could be used is Intralipid®. Intralipid is a fat emulsion containing soybean oil, egg yolk phospholipids, glycerin, and water. The emulsified fat particles are approximately 0.5 μm size. Because it is intended for intravenous infusion, Intralipid is sterile and buffered for pH range of 6.0 to 8.9. Soybean oil itself is a refined natural product that is a mixture of neutral triglycerides of predominantly unsaturated fatty acids. The neutral triglycerides have the following general structure:

(11) ##STR00001##

(12) where R1, R2, and R3 are saturated and unsaturated fatty chains. The major constituent fatty acids are linoleic acid (44-62%), oleic acid (19-30%), palmitic acid (7-14%), a-linolenic acid (4-11%), and stearic acid (1.4-5.5%).

(13) ##STR00002##

(14) The purified egg phosphatides are a mixture of naturally occurring phospholipids isolated from egg yolk. These phospholipids have the following general structure:

(15) ##STR00003##

(16) where R1 and R2 are saturated or unsaturated fatty chains. R3 is primarily either the choline or the ethanolamine ester of phosphoric acid.

(17) ##STR00004##

(18) Intralipid is available in varying formulations. Intralipid 20% is a fat emulsion containing 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, and water. This 20% formulation has an osmolality of approximately 350 mOsmol/kg water (which represents 260 mOsmoL/L of emulsion). The composition of other formulations of Intralipid are provided in Table 1 below.

(19) TABLE-US-00001 Content per 1000 ml Intralipid 10% Intralipid 20% Intralipid 30% Soybean oil 100 g (10 wt %) 200 g (20 wt %) 300 g (30 wt %) Egg lecithin 12 g 12 g 12 g Glycerol 22.0 g 22.0 g 22.0 g Osmolality 300 350 310 (mOsmol/kg water)

(20) Dosing. The lipid emulsion composition may be administered via any suitable route. Most typically, the lipid emulsion composition is administered by intravenous (IV) administration. But oral administration of the lipid emulsion composition may also be possible. See Tuzcu et al, “Oral intralipid emulsion use: a novel therapeutic approach to pancreatic β-cell injury caused by malathion toxicity in rats” (2014) Drug Chem Toxicol, 37(3):261-267. A variety of dosing formats are possible. For example, one possible dosing regimen for Intralipid 20% is to give 1.5 mL/kg as an initial bolus (which is about 100 mL in a typical 70 kg adult). If necessary, this bolus may be followed by a continuous infusion of 0.25 mL/kg/min over 60 minutes time. Additional boluses may be given or the infusion rate could be adjusted upwards as needed.

(21) A clinical study that could be conducted to support the utility of the invention is as follows. For a patient presenting with possible cannabinoid intoxication, assess the patient for recent cannabinoid use or exposure, for example, by patient history, medical records, or witness reports. Take vital signs (blood pressure, pulse, body temperature, O2 saturation) and electrocardiography (ECG). Secure intravenous line access. Administer fluid resuscitation according to clinical judgment. Perform physical examination, with particular attention to signs of recreational drug use. Perform neurologic and mental status examination. Perform intubation if necessary. Perform rapid urine drug screen. Draw blood and order laboratory tests according to clinical judgement. Administer 20% Intralipid according to drug detoxification protocol. Continue monitoring vital signs. Perform repeat neurological and mental status examinations to assess for recovery from intoxication. The instant invention 10 may be used on or administered to adults, children and pets for reversal or treating of cannabinoid intoxication or other forms of intoxication mentioned herein.

(22) It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described herein above. In addition, unless mention was made above to the contrary, it should be noted that all of the accompanying drawings are not to scale. A variety of modifications and variations are possible in light of the above teachings without departing from the scope and spirit of the invention, which is limited only by the following claims.