WO2018204689A1 - Méthodes de traitement de la toxicité ou d'une surdose de cannabinoïde synthétique avec du rimonabant - Google Patents

Méthodes de traitement de la toxicité ou d'une surdose de cannabinoïde synthétique avec du rimonabant Download PDF

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WO2018204689A1
WO2018204689A1 PCT/US2018/030944 US2018030944W WO2018204689A1 WO 2018204689 A1 WO2018204689 A1 WO 2018204689A1 US 2018030944 W US2018030944 W US 2018030944W WO 2018204689 A1 WO2018204689 A1 WO 2018204689A1
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rimonabant
jwh
overdose
toxicity
subject
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PCT/US2018/030944
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Lance R. MCMAHON
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The Board Of Regents Of The University Of Texas System
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Definitions

  • methods of ameliorating one or more symptoms of synthetic cannabinoid toxicity or overdose in a subject comprising: (a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective amount of rimonabant.
  • FIG. 1 shows the effects of AM-2201, JWH-122, CP-47,497, JWH-250 and A9-THC, as a function of dose (left) and time (right) in rhesus monkeys discriminating A9-THC.
  • Abscissae vehicle (VEH) or dose in milligram per kilogram of body weight (left) and time (right). Ordinates: mean ( ⁇ S.E.M.) percentage of responding on the A9-THC lever (top) and mean ( ⁇ S.E.M) response rate expressed as a percentage of the control rate (bottom).
  • FIG. 2 shows the effects of AM-2201, JWH-122, CP 47,497, and JWH-250 in rhesus monkeys discriminating ⁇ 9- THC: antagonism by rimonabant.
  • Abscissae dose in milligram per kilogram of body weight or vehicle (VEH).
  • the control dose-response functions for AM-2201, JWH-122, CP 47,497, and JWH-250 are re- plotted from Fig.l.
  • FIG. 3 shows the effects of AM-2201 , JWH-122, CP 47,497, and JWH-250 in ⁇ 9-
  • THC treated rhesus monkeys discriminating rimonabant.
  • Abscissae dose of rimonabant in milligram per kilogram of body weight or vehicle (VEH).
  • Ordinates mean ( ⁇ S.E.M.) percentage of responding on the rimonabant lever (left) and mean ( ⁇ S.E.M) response rate expressed as a percentage of the control rate (right).
  • FIG. 4 shows the magnitude of rightward shift in the rimonabant dose-response function expressed as a function of AM-2201, JWH-122, CP 47,497, and JWH-250 dose.
  • Abscissae dose in milligram per kilogram of body weight.
  • Ordinate mean ( ⁇ S.E.M.) rightward shift in the rimonabant dose- response function, calculated as the rimonabant ED50 value after pretreatment with a cannabinoid agonist divided by the control rimonabant ED50 value.
  • Ranges can be expressed herein as from “about” or “approximately” one particular value, and/or to "about” or “approximately” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” or “approximately,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as "about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10" is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • the terms "optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term "subject” refers to the target of administration, e.g., a human.
  • the subject of the disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • a subject is a mammal.
  • the subject is a human.
  • the term does not denote a particular age or sex. Thus, adult, child, adolescent and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the term "patient” refers to a subject afflicted with a disease, disorder or condition.
  • the term “patient” includes human and veterinary subjects.
  • the "patient” has been diagnosed with a need for treatment for preventing or treating synthetic cannabinoid toxicity or overdose, such as, for example, prior to the administering step.
  • side effect refers to adverse effects or toxic effects produced by a drug including but not limited to on a tissue or organ system.
  • Such conditions can include altered mental status (e.g., hallucinations), tachycardia, agitation, loss of consciousness, seizures, kidney damage, nausea, vomiting, hypokalemia, hypothermia and death.
  • synthetic cannabinoid toxicity or “synthetic cannabinoid overdose” refers to the effects of synthetic cannabinoids that are toxic to a subject, resulting in effects that may be mild, moderate or severe including but not limited to mental status (e.g., hallucinations), tachycardia, agitation, loss of consciousness, seizures, kidney damage, nausea, vomiting, hypokalemia, hypothermia and death. Synthetic cannabinoid toxicity can be assessed by any appropriate method known to a clinical physician or skilled artisan.
  • the term “overdose” refers to a subject that takes a dose larger than originally intended that results in one or more adverse effects.
  • treating refers to partially or completely alleviating, ameliorating, relieving, delaying onset of, inhibiting or slowing progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular disease, disorder, and/or condition.
  • Treatment can be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • the disease, disorder, and/or condition can be toxicity or an overdose relating to the administration of one or more synthetic cannabinoids.
  • non-dependent refers to a subject that has taken any cannabinoid or synthetic cannabinoid at least once without becoming dependent prior to the instance for which treatment is sought.
  • Synthetic cannabinoid CB 1 and CB2 receptor agonists marketed under various brand names have been sold and abused worldwide since 2008. These products typically contain at least one synthetic cannabinoid and do not contain cannabis or its primary psychoactive drug A9-tetrahydrocannabinol (A9-THC).
  • a rise in synthetic cannabinoid abuse has been due to several factors, e.g., prior to regulation by the Drug Enforcement Agency synthetic cannabinoids provided legal alternatives to cannabis (Auwarter, 2009; Vardakou et al., 2010).
  • AM-2201 (l-(5-fluoropentyl)-3-(l-naphthoyl)indole), JWH-122 (4-methyl-l- naphthyl)- (l-pentylindol-3-yl)methanone, JWH-250 (2-(2-methoxyphenyl)- 1-( 1-pentylindol- 3- yl)ethanone), and CP-47,497 ([2-(lR,3S)-3-hydroxy-cyclohex>'l]-5-(2-methyloctan-2- yl)phenol) are divided into three distinct chemical groups.
  • AM-2201 and JWH-122 are naphthoylindoles (Makriyannis and Deng, 2001; 2007; Huffman et al., 2003) and JWH-250 is a phenylacetylindole (Huffman et al., 2005).
  • CP-47,497 is a cyclohexylphenol and lacks the pyran ring of A9-THC and other tricyclic terpenoid derivatives (Palmer et al., 2002).
  • CP- 47,497 is a cannabinoid CB1 and CB2 receptor agonist that produces effects typical of cannabinoid agonists such as hypolocomotion, analgesia, hypothermia, catalepsy, and discriminative stimulus effects in rodents (Weissman et al. 1982).
  • JWH-250 does not have the naphthalene ring present in JWH-122 and AM-2201, but instead has a 2 -methoxy- phenylacetyl group in that position (Huffman et al., 2005).
  • AM-2201, JWH-122, and JWH- 250 were demonstrated to produce A9-THC like discriminative stimulus effects in rodents (Gatch and Forster, 2014; 2016), suggesting that they produce cannabis-like subjective in humans.
  • rimonabant (1 mg/kg) antagonized the discriminative stimulus and rate-decreasing effects of the agonists. Quantitative analysis of the magnitude of antagonism of discriminative stimulus effects by rimonabant was similar for all cannabinoid agonists tested. AM-2201, JWH-122, CP-47,497, and JWH-250 dose-dependently attenuated the discriminative stimulus effects of rimonabant in monkeys receiving 1 mg/kg/ 12 h of ⁇ 9- THC.
  • JWH-018 and JWH-073 were the primary ingredients in Spice/K2 and related herbal blend products (Huffman et al., 1994; Atwood et al, 2009; Huffman, 2009). JWH-018 and JWH-073 were demonstrated to share
  • rimonabant can be useful for preventing or treating toxicity or overdose due to the administration of one or more synthetic cannabinoids.
  • Rimonabant is a selective CB1 receptor blocker or antagonist.
  • Rimonabant is also known as SR141716, AcompliaTM and ZimultiTM.
  • Rimonabant can be useful in the treatment of synthetic cannabinoids toxicity or overdose resulting from synthetic cannabinoids including but not limited to
  • cannabicyclohexanol JWH-018, JWH-073, JWH-398, JWH-250, CP-47,497 and HU-210, homologous thereof and any mixtures thereof.
  • Rimonabant can also be useful for the treatment of subjects that are non-dependent subjects suffering from synthetic cannabinoid toxicity or overdose. For example, those subjects who have used any cannabinoid or synthetic cannabinoid in the past and have not developed tolerance or dependence to any of the synthetic cannabinoids can be treated for synthetic cannabinoid toxicity or overdose.
  • the time period of therapeutic effectiveness of rimonabant from a single (or multiple) dose(s) administration can last from about 15 minutes to over 4 hours. In an aspect, a time period of therapeutic effectiveness of rimonabant can be between 15 minutes to 30 minutes or 30 minutes to 1 hour. In an aspect, the time period of therapeutic effectiveness of rimonabant can be at least 1 hour, at least 2 hours, at least 3 hours or at least 4 hours or any time period in between.
  • the rimonabant can be used in combination with other therapeutic drugs used to treats subjects suffering from cannabinoid toxicity, synthetic cannabinoid toxicity or overdose.
  • rimonabant can be administered with one or more synthetic cannabinoid receptor agonists.
  • methods of treating or preventing synthetic cannabinoid toxicity or overdose in a subject comprising: (a) identifying a subject in need of treatment; and (b) administering to the subject a therapeutically effective amount of rimonabant.
  • methods of ameliorating one or more symptoms of synthetic cannabinoid toxicity or overdose in a subject comprising: (a) identifying a subject in need of treatment; and (b) administering to the subject a
  • a therapeutically effective amount of a pharmaceutical composition comprising rimonabant and a pharmaceutically acceptable carrier can be administered to the subject.
  • the synthetic cannabinoid toxicity or overdose results from synthetic cannabinoid administration to a non-dependent subject.
  • the subject can be a synthetic cannabinoid user.
  • the administration of rimonabant can reduce one or more symptoms of drug toxicity or overdose.
  • one or more of the symptoms of drug toxicity or overdose can be reduced over a period of at least 15 to about 30 minutes.
  • one or more of the symptoms of drug toxicity or overdose can be reduced over a period of at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours or more.
  • the one or more symptoms of synthetic cannabinoid toxicity or overdose can be selected from seizures, tachycardia, hypokalemia, nausea and vomiting.
  • compositions described herein can be formulated to include a therapeutically effective amount of a rimonabant.
  • rimonabant can be contained within a pharmaceutical formulation.
  • the pharmaceutical formulation can be a unit dosage formulation.
  • rimonabant can administered on an as-needed basis.
  • Therapeutic administration encompasses prophylactic applications. Based on genetic testing and other prognostic methods, a physician in consultation with their patient can choose a prophylactic administration where the patient has a clinically determined predisposition or increased susceptibility (in some cases, a greatly increased susceptibility) to one or more side effects associated with synthetic cannabinoid use.
  • compositions described herein can be administered to the subject.
  • compositions are administered to a subject (e.g., a human patient) already expressing or diagnosed with one or more synthetic cannabinoid toxic symptoms in an amount sufficient to at least partially improve a sign or symptom or to inhibit the progression of (and preferably arrest) the symptoms of the condition, its complications, and consequences.
  • An amount adequate to accomplish this is defined as a therapeutically effective amount.
  • a therapeutically effective amount of a pharmaceutical composition can be an amount that achieves a cure or reverses one or more symptoms of synthetic cannabinoid toxicity, but that outcome is only one among several that can be achieved.
  • a therapeutically effect amount includes amounts that provide a treatment in which the onset, progression or expression of one or more of the side effects associated with synthetic cannabinoid use or toxicity or overdose is delayed, hindered, or prevented, or the one or more symptoms associated with synthetic cannabinoid use or toxicity or overdose is reduced, ameliorated or reversed.
  • One or more of the symptoms can be less severe. Recovery can be accelerated in an individual who has been treated.
  • Amounts effective for this use can depend on the severity of the symptoms of drug toxicity or overdose and the weight and general state and health of the subject, but generally range from about 0.05 ⁇ g to about 1000 ⁇ ig (e.g., 0.5-100 mg) of an equivalent amount of the rimonabant per dose per subject.
  • the total effective amount of a rimonabant as disclosed herein can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol in which multiple doses are administered over a more prolonged period of time.
  • continuous intravenous infusions sufficient to maintain therapeutically effective concentrations in the blood are also within the scope of the present disclosure.
  • the therapeutically effective amount or dosage of the rimonabant used in the methods as disclosed herein applied to mammals can be determined by one of ordinary skill in the art with consideration of individual differences in age, weight, sex, other drugs administered and the judgment of the attending clinician. Variations in the needed dosage may be expected. Variations in dosage levels can be adjusted using standard empirical routes for optimization.
  • the particular dosage of a pharmaceutical composition to be administered to the patient will depend on a variety of considerations (e.g., the severity of side effects of the synthetic cannabinoids), the age and physical characteristics of the subject and other considerations known to those of ordinary skill in the art. Dosages of rimonabant can be in the range of 0.1 mg to 100 mg per kilogram of the subject's body weight.
  • the dosage of rimonabant can be 100, 200, 300 or 400 mg total. In an aspect, the dosage of rimonabant can be 0.1 to 25 mg/kg. It is presently believed that 0.2 mg/kg rimonabant administered intravenously occupies about 50% of cannabinoid receptors in rhesus monkeys. In an aspect, rimonabant can be administered intravenously.
  • the side effects (e.g., behaviorally disruptive effects) of synthetic cannabinoids can be reversed by 0.1-0.32 mg/kg rimonabant i.v. in rhesus monkeys that, for example, also received daily treatment with 2 mg/kg A 9 -tetrahydrocannabinol.
  • rimonabant doses in humans assuming a body weight of 70 kg is about 7-25 mg/kg total.
  • the therapeutically effective amount of rimonabant can be between 7 to 25 mg/kg of body weight or any amount in between.
  • smaller therapeutically effective doses may retain the ability to reverse one or more side effects (e.g., behaviorally disruptive effects) of synthetic cannabinoids.
  • compositions comprising rimonabant and a pharmaceutical acceptable carrier described herein.
  • rimonabant can be formulated for intravenous administration.
  • the compositions can be formulated for administration by any of a variety of routes of administration, and can include one or more physiologically acceptable excipients, which can vary depending on the route of
  • excipient means any compound or substance, including those that can also be referred to as “carriers” or “diluents.”
  • compositions is considered routine in the art, and thus, one of ordinary skill in the art can consult numerous authorities for guidance if needed.
  • compositions can be administered directly to a subject.
  • the compositions can be suspended in a pharmaceutically acceptable carrier (e.g., physiological saline or a buffered saline solution) to facilitate their delivery.
  • a pharmaceutically acceptable carrier e.g., physiological saline or a buffered saline solution
  • Encapsulation of the compositions in a suitable delivery vehicle may increase the efficiency of delivery.
  • compositions can be formulated in various ways for parenteral or nonparenteral administration.
  • oral formulations can take the form of tablets, pills, capsules, or powders, which may be enterically coated or otherwise protected.
  • Sustained release formulations, suspensions, elixirs, aerosols, and the like can also be used.
  • Pharmaceutically acceptable carriers and excipients can be incorporated (e.g., water, saline, aqueous dextrose, and glycols, oils (including those of petroleum, animal, vegetable or synthetic origin), starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monosterate, sodium chloride, dried skim milk, glycerol, propylene glycol, ethanol, and the like).
  • oils including those of petroleum, animal, vegetable or synthetic origin
  • starch cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monosterate, sodium chloride, dried skim milk, glycerol, propylene glycol, ethanol, and the like.
  • compositions may be subjected to conventional pharmaceutical expedients such as sterilization and may contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.
  • conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.
  • Suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, which is herein incorporated by reference.
  • Such compositions will, in any event, contain an effective amount of the compositions together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the patient.
  • compositions as disclosed herein can be prepared for oral or parenteral administration.
  • Pharmaceutical compositions prepared for parenteral administration can be prepared for parenteral administration.
  • compositions can be prepared for parenteral administration that includes rimonabant dissolved or suspended in an acceptable carrier, including but not limited to an aqueous carrier, such as water, buffered water, saline, buffered saline (e.g., PBS), and the like.
  • an aqueous carrier such as water, buffered water, saline, buffered saline (e.g., PBS), and the like.
  • an aqueous carrier such as water, buffered water, saline, buffered saline (e.g., PBS), and the like.
  • PBS buffered saline
  • the excipients included can help approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like.
  • the compositions include a solid component (as they may for oral
  • one or more of the excipients can act as a binder or filler (e.g., for the formulation of a tablet, a capsule, and the like).
  • a binder or filler e.g., for the formulation of a tablet, a capsule, and the like.
  • one or more of the excipients can be a solvent or emulsifier for the formulation of a cream, an ointment, and the like.
  • the pharmaceutical compositions can be sterile and sterilized by conventional sterilization techniques or sterile filtered.
  • Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation, which is encompassed by the present disclosure, can be combined with a sterile aqueous carrier prior to administration.
  • the pH of the pharmaceutical compositions typically will be between 3 and 11 (e.g., between about 5 and 9) or between 6 and 8 (e.g., between about 7 and 8).
  • the resulting compositions in solid form can be packaged in multiple single dose units, each containing a fixed amount of the above - mentioned agent or agents, such as in a sealed package of tablets or capsules.
  • composition described herein can be packaged in a suitable container labeled, for example, for use as a therapy to treat or prevent synthetic cannabinoid toxicity or overdose.
  • packaged products e.g., sterile containers containing the composition described herein and packaged for storage, shipment, or sale at concentrated or ready-to-use concentrations
  • kits including at least rimonabant as described herein and instructions for use, are also within the scope of the disclosure.
  • a product can include a container (e.g., a vial, jar, bottle, bag, or the like) containing the composition described herein.
  • an article of manufacture further may include, for example, packaging materials, instructions for use, syringes, buffers or other control reagents for treating or monitoring the condition for which prophylaxis or treatment is required.
  • the product may also include a legend (e.g., a printed label or insert or other medium describing the product's use (e.g., an audio- or videotape)).
  • the legend can be associated with the container (e.g., affixed to the container) and can describe the manner in which the compound therein should be administered (e.g., the frequency and route of administration), indications therefor, and other uses.
  • the compounds can be ready for administration (e.g., present in dose-appropriate units), and may include a pharmaceutically acceptable adjuvant, earner or other diluent.
  • the compounds can be provided in a concentrated form with a diluent and instructions for dilution.
  • Example 1 Effects of AM-2201, JWH-122, JWH-250 and CP-47,497 in Rhesus Monkeys Discriminating A9-THC.
  • Drug discrimination assays in non-human primates were used to assess the potency, time course, and CB1 receptor mediated effects of CP ⁇ 7,497, AM-2201, JWH-122, and JWH-250.
  • Two female and two male adult rhesus monkeys discriminated A9-THC from vehicle and one female and three male adult rhesus monkeys discriminated rimonabant while receiving chronic A9-THC (1 mg/kg/ 12 h, s.c).
  • the monkeys were housed individually in stainless-steel cages on a 14-h light/ 10-h dark schedule (lights on at 6:00 AM). They were maintained at 95% free-feeding weight (range 6.0-11.8 kg) with a diet consisting of primate chow (High Protein Monkey Diet; Harlan Teklad, Madison, WI), fresh fruit, and peanuts; water was provided in the home cage. Monkeys received cannabinoids in previous studies (Ginsburg et al., 2012; Hruba and McMahon, 2014).
  • Monkeys were seated in chairs (model R001; Primate Products, Miami, FL) and placed in ventilated, sound-attenuating chambers equipped with two levers and two lights, one positioned above each lever. Their feet were placed in shoes containing brass electrodes to which a brief electric stimulus (3 mA, 250 ms) could be delivered from an A/C generator (Coulboum Instruments, Allentown, PA).
  • the chambers were connected to a computer with an interface (MED Associates, St. Albans, VT); experimental events were controlled and recorded with Med-PC software (MED Associates).
  • A9-THC 0.1 mg/kg i.v.
  • vehicle 1 part absolute ethanol, 1 part Emulphor-620, and 18 parts saline
  • S fixed ratio S
  • monkeys received 1 mg/kg s.c. A9-THC at 6: 15 AM and again at 6: 15 PM and discriminated rimonabant (1 mg/kg i.v.) from vehicle at 12: 15 PM under an FR5 schedule of stimulus- shock termination.
  • the experimental sessions were divided into consecutive 10-min, multiple cycles; each cycle began with a 5-min timeout. Responses during the timeout had no programmed consequence. The timeout was followed by a 5-min schedule of stimulus-shock termination, the beginning of which was signaled by illumination of red lights. Five consecutive responses on the correct lever extinguished the red lights, prevented delivery of an electric stimulus, and initiated a 30-s timeout. Otherwise, an electric stimulus was scheduled for delivery every 40 s in monkeys discriminating A9-THC and 10 s in monkeys discriminating rimonabant.
  • Training sessions consisted of a minimum of three and a maximum of six cycles.
  • Drug training consisted of administration of A9-THC (0.1 mg/kg i.v.) or rimonabant (1 mg/kg i.v.) within the first min of the first of three cycles; sham (dull pressure applied to the skin overlying the vascular access port) was administered within the first minute of the subsequent cycles.
  • Vehicle training involved administration of vehicle within the first min of the first cycle followed by vehicle or sham in subsequent cycles for a maximum of six cycles.
  • Zero to three vehicle-training cycles immediately preceded three A9-THC or rimonabant training cycles. Completion of the FR on the correct lever was required for reinforcement during each training cycle.
  • AM-2201, JWH-122, and JWH-250 had a relatively short duration of action. Therefore, the combined effects of rimonabant with a dose of AM-2201 (0.1 and 0.32 mg/kg), JWH-122 (0.32 and 1.0 mg/kg), and JWH-250 (0.32 and 1.0 mg/kg) were examined single-cycle test sessions conducted on different days.
  • Rimonabant was studied from ineffective doses up to doses that produced greater than 80% of responses on the rimonabant lever or up to a dose of 5.6 mg/kg, whichever occurred first. Due to limitations in the solubility of rimonabant in the vehicle and volume used for i.v. administration, 5.6 mg/kg was the largest dose studied.
  • the order of testing with the cannabinoid agonists (AM-2201, JWH-122, JWH-250 and CP-47,497) or rimonabant was non-systematic.
  • D9-tetrahydrocannabinol (A9-THC; 100 mg/ml in absolute ethanol) and rimonabant (The Research Technology Branch, National Institute on Drug Abuse, Rockville, MD); AM-2201 ([l-(5-fluoropentyl)-lH-indol-3-yl]-l-naphthalen-methanone; Cayman Chemical Company, Ann Arbor, MI); JWH-122 ((4-methyl-l-naphthalenyl)(l-pentyl-lH- indol-3-yl)-methanone; Cayman Chemical Company); CP-47,497 (rel-2[(lS,3R)-3- hydroxy cyclohexyl] -5 -(2-methyloctan-2- yl)phenoland; Cayman Chemical Company) and JWH-250 (2-(2-methoxyphenyl)-l-(l- pentylindol-3-yl)ethanone;
  • Discrimination data were expressed as a percentage of responses on the drug lever out of the total number of responses on both the drug and vehicle levers. Rate of responding on both levers (i.e., drug and vehicle) was calculated as responses per second excluding responses during timeouts. Rate of responding during a test was expressed as the percentage of the control response rate for individual animals. The control was defined as the average response rate for all cycles during the five previous vehicle training sessions excluding sessions during which the test criteria were not satisfied. Discrimination and rate data were averaged among subjects, separately per training drug, and were plotted as a function of dose and time.
  • pKB -log(B/dose ratio -1), with B expressed in moles per kilogram of body weight.
  • the potencies of AM-2201, JWH-122, JWH-250, and CP-47,497 were calculated by expressing the mean shift in the rimonabant dose-response function (i.e., ED50 value of rimonabant determined in the presence of agonist divided by the ED50 of rimonabant alone) as a function of dose for individual monkeys.
  • Linear regression of the individual data was used to estimate the dose of agonist producing a 2-fold rightward shift in the rimonabant dose-response function. Effects on response rate were examined with a one-way analysis of variance (ANOVA) separately per drug followed by post- hoc Tukey's multiple comparison test.
  • ANOVA analysis of variance
  • AM-2201, JWH-122, CP-47,497, and JWH-250 dose-dependently increased mean A9-THC lever responding (Fig. 1, top left).
  • mean responding on the A9-THC lever was 0% (Fig. 1, top left, leftmost symbols above VEH).
  • Potency ratios are the ED50 values of the agonist versus A9-THC (top) or the ED50 values of the agonist in combination with rimonabant (1 mg/kg) divided by the ED50 value of the agonist alone (bottom). * Significantly more potent than A 9 -THC; #Significantly different from the ED50 values of the drugs alone.
  • Rimonabant (1 mg/kg) alone produced 0% responding on the A9-THC lever and antagonized the discriminative stimulus effects of each cannabinoid agonist (Fig. 2, left panels). Rimonabant (1 mg/kg) increased the ED50 value 10.6-fold for AM-2201, 10.7-fold for JWH-122, 11.0-fold for CP-47,497, and 15.7-fold for JWH-250 (Table 1).
  • the single- dose apparent affinity estimates calculated for rimonabant were 6.61 in the presence of AM- 2201, 6.65 in the presence of JWH-122, 6.66 in the presence of CP-47,497, and 6.83 in the presence of JWH-250.
  • JWH-018 and JWH-073 had a duration of action of 1-2 h (Ginsburg et al., 2012).
  • Many cannabinoids from the JWH series including JWH-122 and JWH-250 contain an indole ring, and AM-2201 is a benzoylindole that differs from JWH-018 by the presence of a fluorine atom in the pentyl chain (Nakijama et al., 2011).
  • the bicyclic cannabinoid CP-47,497 has a longer duration of action (4-5 h).
  • rimonabant was administered prior to synthetic cannabinoids and pKB values were calculated in monkeys discriminating A9-THC. Reversal of the effects by rimonabant was examined in monkeys discriminating rimonabant while receiving A9-THC daily.
  • Rimonabant dose-dependently increased drug-lever responding with 0.1 mg/kg producing 0% responding on the drug lever and 1 mg/kg producing 100% responding on the drug lever (Fig. 3 left panels, circles).
  • the ED50 value was 0.2S mg/kg when rimonabant was administered in cumulative doses (i.e., the control function for experiments with CP-47,497) and 0.21 mg/kg when rimonabant was administered in a single dose per test session (Table 2). Rimonabant alone did not significantly modify rate of responding (Fig. 3, left panels, circles). Responding was 0% on the rimonabant lever when monkeys received i.v.
  • AM-2201 0.1 and 0.32 mg/kg
  • JWH-122 (0.32 and 1 mg/kg)
  • CP-47,497 0.2, 1, and 3.2 mg/kg
  • JWH-250 1 and 3.2 mg/kg 6 h after 1 mg/kg of A9-THC s.c.
  • the largest doses of AM-2201 (0.32 mg/kg) and JWH-122 ( 1 mg/kg) produced emesis and ataxia.
  • ED50 values and 95% CLs for rimonabant alone and in combination with AM-2201, JWH- 122, CP-47,497, and JWH-250, in ⁇ 9 -THC (1 mg/kg/12 h) treated rhesus monkeys discriminating rimonabant (1 mg/kg i.v ).
  • Potency ratios and 95% CLs are the ED50 values of rimonabant in combination with the agonist divided by the ED50 value of rimonabant alone. Indicates significantly different from rimonabant alone.
  • AM-2201, JWH-122, CP-47,497, and JWH-250 significantly and dose-dependently attenuated the discriminative stimulus effects of rimonabant in monkeys receiving 1 mg/kg/12 h A9-THC, CP-47497, at doses of 0.32, 1, and 3.2 mg/kg, increased the ED50 value of rimonabant by 2.0-, 4.1-, and 10.6-fold, respectively (Table 2).
  • AM-2201 (0.1 and 0.32 mg/kg) increased the ED50 value of rimonabant by 3.7 and 9.0-fold, respectively
  • JWH- 122 (0.32 and 1.0 mg/kg) increased the ED50 value of rimonabant by 2.3- and 8.6-fold, respectively
  • JWH-250 1.0 and 3.2 mg/kg increased the ED50 value of rimonabant by 2.7- and 10.5-fold, respectively (Table 2).
  • Rimonabant significantly antagonized the rate- decreasing effects of each cannabinoid agonist.
  • AM-2201 (0.32 mg/kg)
  • JWH-122 1.0 mg/kg
  • Fig 4 The relationship between magnitude of shift in the rimonabant dose-response function and dose of cannabinoid agonist is shown in Fig 4.
  • Linear regression was used to estimate the dose of each agonist producing a 2-fold rightward shift in the rimonabant dose-response function; the values were 0.06 for AM-2201, 0.24 for JWH-122, 0.44 for CP-47,497, and 0.64 for JWH-250.
  • the relative potencies of AM-2201, JWH-122, CP-47,497, and JWH-250 to attenuate the rimonabant discriminative stimulus and substitute for the A9-THC discriminative stimulus effect were similar.
  • Rimonabant pretreatment resulted in surmountable antagonism of the discriminative stimulus effects of AM-2201, JWH-122, JWH-250, and CP-47,497.
  • rimonabant produced dose-dependent rightwards shifts in the dose-response functions of other cannabinoid agonists (McMahon, 2009;
  • a quantitative analysis of the capacity of an antagonist to reverse the effects of synthetic cannabinoids not only provides insight into receptor mechanisms of action, but also could inform novel clinical applications.
  • pretreatment with AM- 2201, JWH-122, JWH-250, and CP-47,497 resulted in a decrease in the potency of rimonabant to produce discriminative stimulus effects. That is, rimonabant reversed the effects of each synthetic cannabinoid.
  • the capacity of rimonabant to reverse the effects of each synthetic cannabinoid was decreased as a function of increasing the dose of AM-2201, JWH-122, JWH-250, and CP- 47,497.
  • Figure 4 which shows the magnitude of rightward shift in the rimonabant dose-effect function as a function of synthetic cannabinoid agonist dose, demonstrates that the relative potencies of AM-2201, JWH-122, JWH-250, and CP- 47,497 are similar to their relative potencies in substituting for the discriminative stimulus effects of A9-THC (compare Fig. 4 to Fig. 1, top left).
  • cannabinoids cannabinoids. Although the use of rimonabant (AcompliaTM, ZimultiTM) for treatment of obesity-related illness was discontinued in 2009 due to concerns over adverse effects, its limited (i.e., acute) use to reverse synthetic cannabinoid overdose in emergency situations can be beneficial.
  • Synthetic cannabinoids were originally synthesized as research tools and for potential therapeutic applications such as pain control. However, several of them have become drugs of abuse and it is becoming increasingly clear that many synthetic cannabinoid agonists can produce undesired effects that pose a significant hazard to human health. As described herein, for example, intravenous administration of relatively large doses of AM-2201 and JWH-122 produced vomiting and ataxia in rhesus monkeys. These adverse effects were not observed in the presence of rimonabant or after intravenous administration of JWH-250 and CP ⁇ 7,497 alone.
  • McMahon LR (2009) Apparent affinity estimates of rimonabant in combination with

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Abstract

L'invention concerne des compositions et des méthodes de prévention ou de traitement d'un sujet souffrant d'une surdose de cannabinoïde synthétique. La méthode comprend l'administration à un patient ayant besoin d'un traitement d'une quantité efficace de rimonabant.
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KR20220109339A (ko) 2021-01-28 2022-08-04 주식회사 파미노젠 피라졸-카르복스아미드 유도체 화합물 및 이의 용도
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US11471437B2 (en) 2019-06-18 2022-10-18 Opiant Pharmaceuticals, Inc. Compositions and methods for treating cannabinoid hyperemesis syndrome with a cannabinoid receptor antagonist
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EP3890724A4 (fr) * 2018-12-07 2022-08-31 Opiant Pharmaceuticals, Inc. Compositions et procédés de traitement d'un surdosage aigu au cannabinoïde avec un antagoniste du récepteur cannabinoïde
US11471437B2 (en) 2019-06-18 2022-10-18 Opiant Pharmaceuticals, Inc. Compositions and methods for treating cannabinoid hyperemesis syndrome with a cannabinoid receptor antagonist
US11141404B1 (en) 2020-11-18 2021-10-12 Anebulo Pharmaceuticals, Inc. Formulations and methods for treating acute cannabinoid overdose
WO2022109043A1 (fr) * 2020-11-18 2022-05-27 Anebulo Pharmaceuticals, Inc. Formulations et méthodes de traitement d'une surdose aigüe de cannabioïdes
KR20220109339A (ko) 2021-01-28 2022-08-04 주식회사 파미노젠 피라졸-카르복스아미드 유도체 화합물 및 이의 용도
US11795146B2 (en) 2021-10-11 2023-10-24 Anebulo Pharmaceuticals, Inc. Crystalline forms of a cannabinoid receptor type 1 (CB1) modulator and methods of use and preparation thereof
US12180155B2 (en) 2021-10-11 2024-12-31 Anebulo Pharmaceuticals, Inc. Crystalline forms of a cannabinoid receptor type 1 (CB1) modulator and methods of use and preparation thereof

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