WO2018094470A1 - Méthode et agents permettant de réduire une neuro-excitation induite par un anesthésique général - Google Patents

Méthode et agents permettant de réduire une neuro-excitation induite par un anesthésique général Download PDF

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Publication number
WO2018094470A1
WO2018094470A1 PCT/AU2017/051299 AU2017051299W WO2018094470A1 WO 2018094470 A1 WO2018094470 A1 WO 2018094470A1 AU 2017051299 W AU2017051299 W AU 2017051299W WO 2018094470 A1 WO2018094470 A1 WO 2018094470A1
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Prior art keywords
compound
inhibits
general anaesthetic
mediated responses
receptor mediated
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PCT/AU2017/051299
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English (en)
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Mark Bellingham
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The University Of Queensland
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Priority claimed from AU2016904858A external-priority patent/AU2016904858A0/en
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Publication of WO2018094470A1 publication Critical patent/WO2018094470A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • the present invention relates generally to anaesthesia, and in particular to the side effects of neuroexcitation associated with general anaesthetic agents.
  • the invention also relates to methods and compositions for reducing such side effects and to methods, compositions and combined products for inducing and maintaining general anaesthesia with reduced side effects associated with neuroexcitation.
  • Neuromotor excitation induced by the administration of such agents.
  • Neuromotor excitation resulting in involuntary myoclonic movement such as muscle twitching, limb movement and/or vocalisation during anaesthesia or recovery from anaesthesia is unpleasant and inconvenient in patients and, when used for veterinary purposes with large animals, poses a significant risk for injury to attending personnel.
  • Neuromotor excitation may be provoked by sensory stimuli during recovery from anaesthesia, such as by light or sound.
  • neurosteroidal general anaesthetics In a number of cases, the side effect of neuroexcitation has prevented general anaesthetic agents with otherwise large therapeutic windows from being used as an anaesthetic agent for humans. Other compounds have been restricted to specific veterinary use only.
  • One such class of general anaesthetic agent is the neurosteroidal general anaesthetics.
  • Neurosteroids used as general anaesthetic agents for medicinal and veterinary applications possess a number of desirable properties.
  • Neurosteroidal general anaesthetics have modest hemodynamic effects such that they generally demonstrate little or no depression of the cardiovascular or respiratory system. Neurosteroids are removed rapidly from the body by hepatic metabolism and elimination. Neurosteroids have a wide margin for safety and can reliably produce a good level of surgical anaesthesia lasting 30 to 60 minutes.
  • neurosteroids provide the option of administration via a number of routes including intravenous and intramuscular and can be safely readministered in top-up doses.
  • a common side effect of several known neurosteroid general anaesthetic agents is the occurrence of excitation with extraneous muscle movements affecting all parts of the body.
  • CB 1 cannabinoid type 1
  • the present invention provides a method of reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent, said method comprising the administration of an effective amount of a compound that inhibits CB 1 receptor mediated responses leading to said neuroexcitation.
  • the present invention provides a method of reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent, said method comprising the administration of an effective amount of a CB 1 receptor inhibitor.
  • the present invention provides the use of a compound that inhibits CB 1 receptor mediated responses in the manufacture of a medicament for reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent.
  • the present invention provides the use of a CB 1 receptor inhibitor in the manufacture of a medicament for reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent.
  • the present invention provides a pharmaceutical composition comprising a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent.
  • the present invention provides a combination comprising an effective amount of a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent.
  • the present invention provides a compound that inhibits CB 1 receptor mediated responses for use in reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent.
  • the present invention also provides a method for producing anaesthesia in a subject comprising administering a general anaesthetic agent to the subject and controlling, reducing or eliminating neuroexcitation by administering before, during or after administration of the general anaesthetic agent a compound that inhibits CB 1 receptor mediated responses.
  • Figure 1 Graphical representation of the response of evoked IPSCs recorded from single motor neurons to alfaxalone alone and in combination with CB 1 receptor inhibitor AM251.
  • Figure 2. Graphical representation of the effect of alfaxalone on spontaneous IPSC frequency of hypoglossal motor neurons, when administered alone or in combination with the CB 1 receptor inhibitor AM251.
  • Figure 3. Graphical representation of the effect of alfaxalone on evoked or spontaneous IPSC frequency of hypoglossal motor neurons, when administered alone or in combination with a CB 1 receptor inhibitor NESS0327.
  • FIG. 1 Graphical representation of the effects of pre-treatment of Wistar rats with CB 1 receptor inhibitor NESS0327 prior to alfaxalone anaesthesia.
  • the present invention is based on the identification that neuroexcitation caused by the administration of general anaesthetic agents occurs through the suppression of the inhibitory pathway targeting motor neurons.
  • the present invention thereby advantageously provides safe methods for administering general anaesthetic agents without the unwanted neuroexcitation side effect associated with neuro steroidal general anaesthetic agents.
  • the compound that inhibits CB l receptor mediated responses leading to the said neuroexcitation may act at any site or at multiple sites in the pathway between the up-regulation of native agonists, for example, endogenous endocannabinoids, and downstream signal transduction pathways and cellular responses resulting from the activation of the CB l receptor.
  • the inhibition of CB l receptor mediated responses may be achieved by administering to a subject a compound that prevents the up-regulation of native CB 1 agonist, for example, a compound that inhibits the motor neurons activated by general anaesthetic agents. It is also envisaged that the compound that inhibits CB l receptor mediated responses may act by removing an excess of native CB l agonist, for example, by binding to the native ligand preventing it from acting on the CB 1 receptor. In other embodiments it is envisaged that the compound that inhibits CB l receptor mediated responses will act by binding directly to the CB l receptor and inhibiting the native agonist from activating the receptor.
  • CB l receptor mediated responses may be inhibited by administering to a subject a compound that selectively inhibits the downstream signal transduction pathway that results in neuroexcitation, for example, the signal transduction pathway that down-regulates glycine release.
  • the compound that inhibits CB l receptor mediated responses leading to neuroexcitation will be a CB l receptor inhibitor.
  • Cannabinoid type 1 receptor inhibitors or "CB l receptor inhibitors” of the present invention are compounds that bind to and inhibit the activation of the CB l receptor by native agonists such as endogenous endocannabinoids and include compounds that act as antagonists of the CB l receptor as well as reverse agonists of the receptor.
  • Certain compounds e.g. SR 141716
  • SR 141716 that were originally classified as selective antagonists are now considered to act as inverse agonists rather than pure antagonists. Whereas antagonists act by blocking the activation induced by agonist binding at the receptor, inverse agonists also occupy the receptor and function by decreasing the constitutive level of receptor activation in the absence of an agonist.
  • CB 1 receptor inhibitors include, but are not limited to Rimonabant (SR 141716 or SR 141716A), AM251, AM281, SR144528, NESS0327, AM4113, AM6527, 0-2654, LY320135, taranabant, CP272871.
  • Examples of publications disclosing such compounds include WO/2009/053553; Reggio, P. H., Curr. Pharm. Des., 2003, 9, 1607-33; Muccioli, G. G. and Lambert, D. M., Curr. Med. Chem., 2005, 12, 1361- 94.
  • a compound that inhibits CB 1 receptor mediated responses may be administered in combination with any general anaesthetic agent known in the art that has as a side effect the induction of neuroexcitation in a subject being anaesthetised.
  • general anaesthetic agent known in the art that has as a side effect the induction of neuroexcitation in a subject being anaesthetised.
  • agents include but not limited to, barbiturate general anaesthetics, benzodiazepine general anaesthetics, hypnotic agents and neurosteroidal general anaesthetics.
  • the general anaesthetic agent is a neurosteroidal general anaesthetic agent.
  • Neurosteroidal general anaesthetic agents are neuroactive steroid compounds that are believed to elicit their effects by interacting with neurotransmitter-gated ion channels such as the GABAA receptor.
  • Specific neurosteroidal general anaesthetics include, but are not limited to alfaxalone, alphadolone, eltanolone, hydroxydione, minaxolone, Org 20599 or Org 21465. Examples of publications disclosing such agents include Ramsay, A.E., et al. BMJ 1974, 2, 656-9; Sear, J. W., J. Clin. Anesth., 1996, 8, 91S-8S; McNeill, G. M., et al.
  • Another embodiment of the invention provides a method of co-administering a compound that inhibits CB 1 receptor mediated responses with general anaesthetic agents whereby neuroexcitation side effects associated with the general anaesthetic are reduced.
  • the effective amount of the compound that inhibits CB 1 receptor mediated responses and the general anaesthetic agent may, as appropriate, be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the method of reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent may comprise (i) administration of a CB l receptor inhibitor in free or pharmaceutically acceptable salt form and (ii) administration of the general anaesthetic agent in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order.
  • the individual components of the combination of the invention can be administered separately at different times during the course of anaesthesia or concurrently in divided or single combination forms.
  • the method and timing of administration of the compound that inhibits CB 1 receptor mediated responses and the general anaesthetic agent will depend on a number of factors including the length of the procedure, the nature of the subject and the properties of the compound that inhibits CB l receptor mediated responses and the anaesthetic agent, including the durations of action of the compound and the anaesthetic, and the time between administration and onset of action for each.
  • the inhibitor of CB 1 receptor mediated responses will be administered prior to the induction of anaesthesia as a premedicant. It is also envisaged that the inhibitor of CB l receptor mediated responses may be administered towards the end of the procedure or period of anaesthesia.
  • the inhibitor of CB l receptor mediated responses and the anaesthetic agent will be administered at the same time, as separate components or as a combination, when anaesthesia is initially induced.
  • anaesthesia After induction of anaesthesia with the anaesthetic agent it is also possible for anaesthesia to be maintained with a different anaesthetic agent, and the compound that inhibits CB l receptor mediated responses could be administered with, or combined with, either or both of those agents.
  • the compound that inhibits CB l receptor mediated responses will be administered between about 120 minutes and about 1 minute prior to the administration of the general anaesthetic. In a further embodiment the compound that inhibits CB 1 receptor mediated responses will be administered between about 60 minutes and about 2 minute prior to the administration of the general anaesthetic agent. In another embodiment the compound that inhibits CB l receptor mediated responses will be administered between about 30 minutes and about 5 minutes prior to the administration of the general anaesthetic agent.
  • the compound that inhibits CB l receptor mediated responses is administered to the subject in a treatment effective amount.
  • a treatment effective amount is intended to include at least partially attaining the desired effect, or reducing to an acceptable level the degree of observable myoclonus, or halting altogether the neuroexcitation induced by the administration to a subject of a general anaesthetic agent.
  • the compound is administered before, during or after initial administration of the anaesthetic agent such that it is capable of reducing the neuroexcitation induced by the anaesthetic.
  • the term "effective amount" refers to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur once, or at intervals of minutes or hours, or continuously over any one of these periods. Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. A typical dosage is in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • the compound that inhibits CB l receptor mediated responses may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition or pharmaceutical composition. Accordingly, in one embodiment the present invention provides a pharmaceutical composition comprising a compound that inhibits CB 1 receptor mediated responses with at - Si - least one pharmaceutically acceptable adjuvant, carrier or diluent. In a preferred embodiment, the compound that inhibits CB 1 receptor mediated responses will be a CB 1 receptor inhibitor.
  • the CB 1 receptor inhibitor may be in any suitable form, including the form of a pharmaceutically acceptable salt.
  • the phrase "pharmaceutically acceptable carrier” includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals, birds, reptiles and amphibians.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as colouring agents, release agents, coating agents, sweetening, flavouring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • a pharmaceutical composition is generally formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, intraperitoneal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, or liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of a dispersion or by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by incorporation of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, or sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally comprise an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, or orange flavouring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from a pressurised container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished with nasal sprays or suppositories.
  • the compounds can be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • Dosage unit form preferably refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the present invention provides a pharmaceutical composition comprising a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent together with at least one pharmaceutically acceptable adjuvant, carrier or diluent.
  • a pharmaceutical composition comprising a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent together with at least one pharmaceutically acceptable adjuvant, carrier or diluent.
  • compositions of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.
  • the present invention provides that use of a compound that inhibits CB 1 receptor mediated responses in the manufacture of a medicament for reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent.
  • the compound that inhibits CB 1 receptor mediated responses is a CB 1 receptor inhibitor.
  • compositions comprising a compound that inhibits CB 1 receptor mediated responses in admixture with an anaesthetic agent and pharmaceutical compositions comprising the anaesthetic agent alone, will be formulated in manner that is suitable for the production of anaesthesia. It is envisaged that such compositions may be liquid compositions suitable for parenteral administration such as intravenous, intramuscular, intraperitoneal or subcutaneous administration. It is also envisaged that compositions comprising an anaesthetic agent may be in the form of a powder suitable for reconstitution into an injectable liquid solution. In other embodiments the pharmaceutical compositions will be formulated in manner that is suitable for inhalation, for example, as gaseous compositions or as volatile liquid compositions.
  • the composition will be formulated for parenteral administration.
  • the composition will comprise the anaesthetic agent alfaxalone and the pharmaceutically acceptable carrier hydroxypropyl- ⁇ - cyclodextrin in an aqueous liquid solution.
  • anaesthetic formulations are known in the art and are available to clinicians, for example, under the tradename Alfaxan ® .
  • the present invention also provides the use of an effective amount of a compound that inhibits CB 1 receptor mediated responses for reducing neuroexcitation induced by the administration to a subject of a general anaesthetic agent. It would be understood by those skilled in the art that the present invention is applicable to any mammalian species, including, but not limited to, human, canine, feline, equine, bovine, porcine, ovine, murine. The present invention is also applicable to non- mammalian species including, but not limited to birds, reptiles, and amphibians.
  • the compound that inhibits CB 1 receptor mediated responses and general anaesthetic agent will be administered separately. In other embodiments the compound that inhibits CB 1 receptor mediated responses will be administered prior to the neurosteroidal general anaesthetic, for example, as a premedicant.
  • the present invention provides a combination comprising an effective amount of a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent.
  • a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent.
  • Each of the components of the combination may be formulated separately, and may independently be in the form of a suitable compound in free or pharmaceutically acceptable salt form, or may be in the form of a pharmaceutical composition, or may be formulated for administration to a subject by any route including parenteral, e.g., intravenous, intradermal, subcutaneous, intraperitoneal; oral (e.g., inhalation); transdermal (topical), transmucosal, vaginal and rectal administration.
  • parenteral e.g., intravenous, intradermal, subcutaneous, intraperitoneal
  • oral e.g., inhalation
  • transdermal topical
  • transmucosal vaginal and rectal administration.
  • combination refers to a composition or kit of parts where the combination partners as defined above can be dosed dependency or independently or by use of different fixed combinations with distinguished amounts of the combination partners, i.e., simultaneously or at different time points.
  • the combination partners can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the ratio of the total amounts of the combination partners to be administered in the combination can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • the effective dosage of the general anaesthetic agent employed in compositions or combinations of the present invention will vary depending on the particular agent or pharmaceutical composition employed and the mode of administration, the species being anaesthetised, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion and any drug combination.
  • the dosage regimen for the general anaesthetic is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of the single active ingredients required to induce or maintain anaesthesia.
  • the effective amount of the general anaesthetic agent will be an amount effective to induce anaesthesia in a subject in need thereof.
  • the dosage required to effectively anaesthetise a subject including the general anaesthetic agent employed, the species of the subject being anaesthetised, the age, sex, weight and general physical condition of the subject, the mode of administration.
  • suitable dosages for inducing anaesthesia may be in the range of about 0.1 ⁇ g per kg of body weight to about 1 g per kg of body weight.
  • a typical dosage is in the range of 0.1 mg to 1 g per kg of body weight, such as is in the range of 0.2 mg to 1 g per kg of body weight.
  • the dosage may be in the range of 0.2 mg to 500 mg per kg of body weight.
  • the dosage may be in the range of 0.5 mg to 250 mg per kg of body weight.
  • the dosage may be in the range of 1 mg to 100 mg per kg of body weight, such as up to 50 mg per body weight.
  • the general anaesthetic agents will be in an amount effective to maintain anaesthesia in a subject in need thereof.
  • the appropriate dosage required to maintain anaesthesia in a subject will vary depending on, e.g. including the general anaesthetic agent employed, the species of the subject being anaesthetised, the age, sex, weight and general physical condition of the subject, the mode of administration. By balancing these features it is well within the general skill of a medical or veterinary practitioner to determine appropriate dosages.
  • anaesthesia will be maintained in a subject by supplemental administration of bolus doses of the one or more neurosteroidal general anaesthetic agents at dose rates, for example, in the range of about 0.1 ⁇ g per kg of body weight to about 1 g per kg of body weight.
  • a typical dosage is in the range of 0.1 mg to 1 g per kg of body weight per dosage, such as is in the range of 0.2 mg to 1 g per kg of body weight per dosage.
  • the dosage may be in the range of 0.2 mg to 500 mg per kg of body weight per dosage.
  • the dosage may be in the range of 0.5 mg to 250 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • anaesthesia will be maintained in a subject by as constant rate infusion of the general anaesthetic agent at a dose rate, for example, in the range of 0.1 mg to 1 g per kg of body weight per hour, such as is in the range of 0.2 mg to 1 g per kg of body weight per hour.
  • the dosage may be in the range of 0.2 mg to 500 mg per kg of body weight per dosage.
  • the dosage may be in the range of 0.5 mg to 250 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • kits comprising an effective amount of a compound that inhibits CB 1 receptor mediated responses and a general anaesthetic agent.
  • a “kit” or “kit of parts” refers to a combination of components which may include a container for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art that is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (for example, to hold a "refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil that is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a written memory aid where the written memory aid is of the type containing information and/or instructions for the physician, veterinarian, pharmacist or other health care.
  • a dose of one or more compositions of the kit can consist of one tablet, capsule, bottle, vial, or ampoule while a dose of another one or more compositions of the kit can consist of several tablets, capsules, bottles, vials or ampoules.
  • Electrophysiological recordings were made from transverse brainstem slices containing the hypoglossal motor nucleus, prepared from 10 to 16 day-old Wistar rats of either sex obtained from the University of Queensland institutional breeding colony. Animal care and handling was approved by the University of Queensland animal ethics committee, and was in accordance with university and national guidelines. In brief, animals were deeply anaesthetized with sodium pentobarbitone (100 mg/kg by intra-peritoneal injection) and then rapidly decapitated.
  • the brainstem was rapidly removed, glued onto a metal tray and support block of solid agar with cyanoacrylate glue (Supafix, Selleys) and 300 ⁇ thick transverse slices made on a vibratome (D.S.K Microslicer DTK- 1000, Ted Pella, USA) in sucrose-substituted, ice-cold Ringer solution containing (in mM): 260 Sucrose, 10 Glucose, 3 KC1, 1.25 NaH 2 P0 4 , 5 MgCl 2 , 1 CaCl 2 gassed with 95% 0 2 -5% C0 2 .
  • Patch electrodes (tip resistance of 3-5 ⁇ when filled with the intracellular solution below) were pulled from borosilicate glass capillaries (Vitrex, Modulohm AS, Denmark) and filled with an intracellular solution containing (in mM): 120 CsCl, 4 NaCl, 10 HEPES, 4 MgCl 2 , 0.001 CaCl 2 , 10 EGTA, 2 Mg 2 ATP, 0.3 Tris-GTP (pH 7.3). Patch electrodes were not Sylgard- coated or fire-polished; a high resistance seal (>1GQ) with the motor neuron membrane was always obtained before entering whole cell patch clamp mode. Motor neuron membrane potential was voltage clamped at -60mV or more negative.
  • Paired inhibitory synaptic currents with an inter- stimulus interval of 50 ms were evoked by electrical stimulation (single electrical pulse duration of 0.1 ms, intensity 5-100 V) of the reticular formation lateral to the border of the hypoglossal motor nucleus with a bipolar concentric wire electrode (FHC, Bowdoin, Maine USA) at a frequency of 0.1 Hz.
  • Inhibitory synaptic currents were recorded and measured using pCLAMP8.2 software (Axon Instruments, Foster City, CA, USA). Changes in evoked current amplitude were assessed by comparison of the mean amplitude of 8-12 consecutive synaptic currents immediately prior to drug application (control data block) with the same number of consecutive synaptic currents showing the largest mean amplitude change after drug application (test data block). When multiple drugs were applied, control measurements for each of the successively added drugs were taken from the period immediately before application of each individual drug, except where indicated in the results.
  • Paired pulse ratio was determined by averaging the evoked synaptic currents in the control block, and in the test block, then dividing the second averaged synaptic current amplitude by the first averaged synaptic current amplitude in each block; this method avoids spurious paired pulse facilitation which can be produced by calculating PPR as the average of individual synaptic current amplitude ratios (Kim, J. and Alger, B. E., 2001, 21, 1638-41). All data are given as mean + SEM and were compared statistically with a Students two-tailed paired t test except where noted, with statistical significance accepted at P ⁇ 0.05. All statistical tests were done with Prism 5.0 (Graphpad, CA, USA).
  • Miniature synaptic currents were recorded in continuous epochs of 2 minutes, with cadmium chloride (100 ⁇ ) added to block calcium-dependent neurotransmitter release (Scanziani, M. et al., Neuron, 1992, 9, 919-27). Miniature synaptic currents were detected and measured off-line with Clampfit 10 software (Axon Instruments) using a sliding template algorithm (Clements, J. D. and Bekkers, J. M., 1997, 73, 220-29).
  • Measured miniature synaptic current parameters were peak amplitude, 10-90% rise time (the time between 10% and 90% of peak amplitude during the synaptic current rising phase), half width (the time between 50% of peak amplitude during the synaptic currentrise and decay phases) and the time interval between successive synaptic currents. Cumulative frequency distributions of miniature synaptic current parameters recorded under different conditions in the same neuron were statistically compared with the Kolmogorov-Smirnov (K-S) test, using Clampfit 9 (Axon Instruments). The mean values of each parameter for each neuron recorded in different conditions were compared statistically with a Students two-tailed paired t test except where noted, with statistical significance accepted at ⁇ 0.05. Spontaneous synaptic currents were recorded without cadmium chloride present and analyzed in the same way.
  • IPC inhibitory synaptic currents
  • Figure 1 shows that co-application of AM251, a CB l receptor inverse agonist, completely blocked the effect of alfaxalone on inhibitory synaptic input size and PP ratio ( Figure 1C and D). This result indicates that alfaxalone causes activation of CB 1 receptors located on synaptic terminals releasing glycine, and the effect of CB 1 receptor activation is to decrease glycine release probability loss.
  • Example 2 In vitro electrophysiological analysis of the affects of alfaxalone on evoked or spontaneous IPSC frequency of hypoglossal motor neurons.
  • HM single hypoglossal motor neurons
  • Transverse slices at a thickness of 300 ⁇ were cut with a DSK Microslicer DTK- 1000 (TED Pella Inc) and incubated for 35-50 min in the same aCSF at 35°C. The slices were then maintained at room temperature (19-21°C) in a maintenance aCSF (see solutions), bubbled with carbogen.
  • the artificial cerebrospinal fluid (aCSF) solution used for cutting and initial incubation of slices contained (in mM) 130 NaCl, 26 NaHC0 3 , 3 KC1, 5 MgCl 2 , 1 CaCl 2 , 1.25 NaP0 4 , 10 Glucose.
  • the maintenance aCSF solution was a similar solution with the exception of 2 CaCl 2 and 1 MgCl 2 .
  • the patch pipette internal solution contained (in niM) 120 CsCl, 4 NaCl, 4 MgCl 2 , 0.001 CaCl 2 , 10 N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid (HEPES), 10 Caesium ethylene glycol-bis( -aminoethyl ether)-N,N,N,N-tetra-acetic acid (EGTA), pH adjusted to 7.2 with CsOH and osmolality was adjusted to 290-300 mOsM with sucrose. 3-adenosine 5 '-triphosphate (ATP-Mg) and 0.3 guanosine 5-triphosphate-tris (hydroxymethyl) aminomethane (GTP-Tris) was added to the internal solution before use.
  • ATP-Mg adenosine 5 '-triphosphate
  • GTP-Tris guanosine 5-triphosphate-tris (hydroxymethyl) aminomethan
  • DL-2-amino-5-phosphonopentanoic acid (APV, Sigma, 50 ⁇ ) and l,2,3,4-Tetrahydro-6- nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium salt hydrate (NBQX) disodium salt hydrate (Sigma, 10 ⁇ ) were added into the external bath solutions to block N-methyl-D-aspartate (NMD A) and non-NMDA glutamate receptor activity (both DL-a- amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) and kainate receptors).
  • AMPA DL-a- amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid
  • kainate receptors l(S),9(R)-(-)-Bicuculline methchloride (Sigma, 5 ⁇ ) was added to the external bath solution to block GABAA receptor activity.
  • 3-a-hydroxy-5-a-pregna-l l,20-dione (alfaxalone, Jurox Pty Ltd) was dissolved in hydroxypropyl substituted ⁇ -cyclodextrin (HPCD, Jurox Pty Ltd) to a ratio of 1:8 to make a stock concentration of 10 mM alfaxalone, then diluted to the required bath concentration of 100 nM, 1 ⁇ , and 10 ⁇ .
  • the stock solution solvent (DMSO, ethanol or HPCD) was always diluted by a factor of 1000 or greater in the external bathing solution, and had no effect when applied alone at these concentrations.
  • Application of drugs via the bathing fluid was always for >2 min; the time taken to completely exchange the recording chamber solution was typically ⁇ 40 s.
  • the alfaxalone dose response study was only applied to one HM per slice.
  • Brainstem slices were submerged in a mounted microscope chamber with a volume of ⁇ 0.5 mL and were continuously superfused with maintenance aCSF at a rate of 1.5-2 mL/min.
  • Patch electrodes were pulled from thin-walled borosilicate glass capillary tubes without a filament (Vitrex Medical) on a two-stage electrode puller (PP-83, Narishige); patch electrodes had a final DC resistance of 2-3 ⁇ when filled with the internal solution and a tip diameter of 1-2 ⁇ by visual inspection. Recordings were performed at room temperature (19-21°C) with the patch electrode connected to the headstage of an Axopatch ID patch-clamp amplifier (Axon instruments).
  • HMs were visually identified by their size, shape, location in the nXII, and whole cell capacitance (>20pF).
  • Whole cell recordings were obtained by the "blow and seal" method, where positive pressure (10-15kPa) was maintained in the pipette to allow surrounding neuropil to be cleaned away as the pipette tip is guided onto the surface of the target HM.
  • the program pCLAMP 8 (Axon Instruments) was used to apply voltage commands and record whole cell currents and measure responses.
  • Spontaneous and evoked inhibitory postsynaptic current (IPSC) activity was recorded with the motor neuron voltage clamped at a membrane potential of -60mV.
  • a bipolar concentric stimulation electrode (Frederick Haer Company) was placed in the reticular formation ventrolateral to the border of the hypoglossal motor nucleus, and a stimulus current of 0.5- 1.1mA and 0.1 ms duration was applied to reliably evoked an IPSC with consistent IPSC amplitudes.
  • the recorded signal was amplified (2-20x) and low pass filtered with a cut-off frequency of 2 kHz by the Axopatch ID amplifier before digitization with a 16-bit digitizer (Digidata 1320A, Axon Instruments) and recording on a PC hard disk (Dell Optiplex, running Windows XP Professional).
  • HM with a cannabinoid receptor inverse agonist or with a cannabinoid receptor competitive antagonist attenuates the reduction in amplitude of evoked or spontaneous inhibitory synaptic inputs observed after treating HM with alfaxalone.
  • Treatment of HM with alfaxalone was shown to produce a dose dependent reduction in amplitude of electrically evoked inhibitory synaptic inputs to the HM ( Figure 1A).
  • Alfaxalone was also demonstrated to produce a dose dependent decrease in the frequency of spontaneous inhibitory synaptic inputs to HM ( Figure 2A).
  • Example 3 Analysis of the effects of premedication of Wistar rats prior to alfaxalone anaesthesia.
  • the index to measure muscle twitching was scored as 0, 1, 2, or 3, with the criteria below:
  • NESS0327 as a premedication prior to alfaxalone anaesthesia significantly reduced muscle twitching during the induction and recovery phases of anaesthesia ( Figures 4A and 4B).
  • Pre-treatment with NESS0327 was also demonstrated to reduce the time taken from alfaxalone injection to dorsal recumbency ( Figure 4C).
  • Premedication with NESS0327 had no effect on the time from alfaxalone injection restoration of sternal recumbency or righting (Figure 4D), or the duration of immobilisation (Figure 4E).
  • Premedication with NESS0327 had no detrimental effect on arterial 0 2 saturation (Figure 4F) or respiration rate (Figure 4G) during alfaxalone anaesthesia.

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Abstract

La présente invention concerne d'une manière générale des méthodes et des compositions permettant de réduire les effets secondaires d'une neuro-excitation associée à des agents anesthésiques généraux à l'aide d'antagonistes du récepteur 1 de cannabinoïdes (CB1R) ou des agonistes inverses. L'invention concerne également des méthodes, des compositions et des produits combinés permettant d'induire et de maintenir une anesthésie générale avec des effets secondaires réduits associés à une neuro-excitation.
PCT/AU2017/051299 2016-11-25 2017-11-24 Méthode et agents permettant de réduire une neuro-excitation induite par un anesthésique général WO2018094470A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130616A2 (fr) * 2007-04-19 2008-10-30 Schering Corporation Diaryl morpholines comme modulateurs des récepteurs cb1

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130616A2 (fr) * 2007-04-19 2008-10-30 Schering Corporation Diaryl morpholines comme modulateurs des récepteurs cb1

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
DEAN, C: "Endocannabinoid modulation of sympathetic and cardiovascular responses to acute stress in the periaqueductal gray of the rat", AM J PHYSIOL REGUL INTEGR COMP PHYSIOL, vol. 300, no. 3, 2011, pages R771 - R779, XP055488332 *
DOUGALIS, A ET AL.: "The endocannabinoid signalling system: Implications for anaesthesia and the pain clinic", CURRENT ANAESTHESIA & CRITICAL CARE, vol. 16, no. 2, 2005, pages 71 - 80, XP005079390 *
ISLAND ER, G. ET AL.: "Severe neuroexcitatory symptoms after anaesthesia - with focus on propofol anaesthesia", ACTA ANAESTHESIOL SCAND, vol. 44, no. 2, February 2000 (2000-02-01), pages 144 - 149, XP055488346 *
LAU, C. ET AL.: "Plasma pharmacokinetics of alfaxalone after a single intraperitoneal or intravenous injection of Alfaxan (R) in rats", J. VET. PHARMACOL. THERAP., vol. 36, 2013, pages 516 - 520, XP055488349 *
LAU, C: "The Safety, Efficacy and Neuromotor Effects of the Neurosteroid Anaesthetic Alfaxalone in Rats", PHD THESIS. THE UNIVERSITY OF QUEENSLAND, 2013, Australia *
REN, Y. ET AL.: "Systemic or intra-amygdala infusion of an endocannabinoid CB1 receptor antagonist AM 251 blocked propofol-induced anterograde amnesia", NEUROSCIENCE LETTERS, vol. 584, 2015, pages 287 - 291, XP029114343 *
WALLACE, M. ET AL.: "The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 307, no. 1, 2003, pages 129 - 137, XP055360835 *

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