Methods for inducing anesthesia

Abstract

A method of inducing and / or maintaining anesthesia in a subject, comprising co-administering to the subject an amount of propofol and an effective amount of a compound 2,4,5-trifluoro-2-(trifluoromethyl)-1,3-dioxolane (TTD) or a stereoisomer thereof. The method provides that the co-administered amounts of propofol and TTD are a fraction of the standalone effective amounts for propofol and TTD, respectively, based on one or more characteristics of the subject, where the sum of the co-administered fractions are less than 1.0. Also, a method of providing antinociceptive activity in a subject under general anesthesia, by administering TTD, whereby the subject experiences a reduction in fluctuation of one or more physical signs in response a noxious stimulus to the subject while under the general anesthesia. Also, a method of inducing and / or maintaining, analgesia in a subject, by administering to the subject an effective amount of TTD.

Description

Attorney Docket: XXP-005X-PCTMETHODS FOR INDUCING ANESTHESIAFIELD OF THE INVENTION

[0001] The present invention relates to methods of inducing and / or maintaining anesthesia using a fluorinated dioxolane compound.BACKGROUND OF THE INVENTION

[0002] Halogenated dioxolane compounds have previously been identified as candidates for anesthetic activity. See for example, U.S. Patent Nos. 3,314,850, 3,749,791 and 3,812,261, International Patent Publication WO / 2014 / 011235A1, German Patent Publication DE 2604350 (Stanford Research Institute), Eger et al., Anesth. Analg., Vol. 60, No. 4, April 1981, pp. 201-203, Burns et al., Anaesthesia, Vol. 19, No.. 2, April 1964, pp. 167-176, Bagnall et al., Journal of Fluorine Chemistry, 1977, Vol. 9, pp. 359-375, the disclosures of which are hereby incorporated by reference in their entireties. Each of the compounds identified in these references has previously been registered with the Chemical Abstracts Service (CAS), and generally have been previously synthesized and characterized for their chemical properties.

[0003] Induction and maintenance of general anesthesia in a subject undergoing certain procedures, e.g., abdominal surgery, may require administration of a pharmaceutical compound from two or more categories of: induction agents, anesthetic inhalation agents, muscle relaxants, a.k.a. paralytic agents, and optionally opioid analgesics.

[0004] The pharmaceutical compounds in the aforementioned categories are generally administered in subject-specific amounts. For example, for an indication of induction of anesthesia, propofol may be administered in an amount of about 2 to 2.5 mg / kg body weight (for adult human patients under age 55 and with American Society of Anesthesiology (ASA) status of I or II), or about 1 to 1.5 mg / kg body weight (for adult human patients over age 55, or with ASA status of III or IV, or with other debilitations).

[0005] Several pharmaceutical compounds used in the induction and maintenance of anesthesia are known to have potential side effects. For example, administration of propofol (e.g., Diprivan®) is known to elicit pain at and around the site of injection. Other side effects such as drug abuse and drug dependence are known, especially for compounds in the categories of induction agents and opioid analgesics. There is growing evidence that propofol may exhibit addictive properties, such as with repeated administration or in large amounts. See, e.g., Yang et al., Anesth Periop. Sci., Vol. 2, Art. 6, January 2024, the disclosure of which is incorporated by reference in its entirety. Some other studies appear to show that co-administering one compound provides an additive effect on the secondAttorney Docket: XXP-005X-PCT compound; see, e.g., Spelina et al., Br. J. Anaesth., Vol. 58, October 1986, pp. 1080-1084, and Singsank-Coats et al., Can. J. Vet. Res., Vol. 79, No. 2, April 2015, pp. 95-100, the disclosures of which are incorporated by reference in their entireties. Despite current efforts, little is known about the effects of co-administration of multiple anesthetic compounds used for inducing and / or maintaining general anesthesia.

[0006] Consequently, there exists a need to identify and quantify anesthetic effects of coadministering anesthetic compounds of different categories, and how the effective amounts of the anesthetic compounds may be different when co-administered as opposed to separately administered.SUMMARY OF THE INVENTION

[0007] The present invention provides a use of a composition comprising an anesthetic compound propofol, and a composition comprising an anesthetic compound 2,4,5-trifluoro-2-(trifluoromethyl)- 1,3 -di oxolane (TTD), for inducing anesthesia, maintaining anesthesia, or inducing and maintaining anesthesia (hereinafter, “inducing and / or maintaining anesthesia”).

[0008] The present invention also provides a method of inducing and / or maintaining anesthesia in a subject, comprising a step of co-administering a composition comprising propofol and a composition comprising TTD.

[0009] The present invention further provides a method of inducing and / or maintaining anesthesia in a subject, comprising the step of co-administering propofol and TTD, wherein the propofol is administered in an amount that is a fraction of a standalone effective amount of propofol, determined based on one or more characteristics of the subject, and TTD is administered in an amount that is a fraction of a standalone effective amount of TTD, determined based on one or more characteristics of the subject, and wherein the sum of the fractions of the administered amounts of propofol and TTD, relative to the respective standalone effective amounts of the propofol and TTD, also known as a combination index, is less than 1.0.

[0010] In some embodiments, the sum of the fractions of the administered amounts of propofol and TTD is less than 0.9, preferably less than 0.8.

[0011] In some embodiments, the sum of the fractions of the administered amounts of propofol and TTD is less than 0.7, or less than 0.6, or less than 0.5, or less than 0.4, or less than 0.3.

[0012] In various embodiments, the administered amount of propofol is a synergistically effective amount of propofol, and the administered amount of TTD is a synergistically effective amount of TTD.

[0013] In various embodiments, the one or more characteristics of the subject are selected from the group consisting of: an ED50 (effective median dose) of the compound in the subject; a minimumAttorney Docket: XXP-005X-PCT alveolar concentration (MAC) of the compound in the subject; one or more physical signs of the subject such as heart rate, blood pressure, mean arterial pressure, respiratory rate, tidal volume, other indicators known in the art, or a combination thereof; a cardiological sign of the subject such as activity measured by an electrocardiogram (EKG); a neurological sign of the subject such as activity measured by an electroencephalogram (EEG); or a combination thereof. In some embodiments, the subject characteristics upon which the standalone effective amount of propofol is determined can be common (overlap) with the subject characteristics upon which the effective amount of TTD is determined. In other embodiments, the subject characteristics upon which the effective amount of propofol is determined are different from the subject characteristics upon which the effective amount of TTD is determined.

[0014] In various embodiments, the subject is a mammal. In some embodiments, the subject is a human. Other non-limiting examples of a mammal can include, and be selected from the group consisting of, a non-human primate, a domesticated mammal, preferably a canine or a feline, an agricultural mammal, preferably selected from the group consisting of equine, bovine, ovine, and porcine, and a laboratory mammal selected from the group consisting of rattus, lagomorpha, and hamster.

[0015] In some embodiments, one or more additional compounds or compositions thereof are also co-administered.

[0016] In various embodiments, the step of co-administering comprises administering propofol by a first route of administration, to a subject, and administering TTD by a second route of administration different from the first route of administration, to a subject. In some embodiments, the step of coadministering includes administering propofol and administering TTD by the same selected route of administration, to the subject. In some embodiments, the first route of administration and the second route of administration can be independently selected from the group consisting of: intravenous, inhalational, subcutaneous, intramuscular, transdermal, sublingual, oral, nasal, topically, rectal, intrathoracic, or enteral, or any combination thereof. In some embodiments, the first administration route is intravenous. In some embodiments, the second administration route is inhalational, via the respiratory system.

[0017] The present invention also provides a pharmaceutical composition comprising propofol, and a pharmaceutical composition comprising TTD, for use in the method of inducing and / or maintaining anesthesia in the subject. In some embodiments, the use includes a step of administering the two pharmaceutical compositions to the subject.

[0018] In various embodiments, the pharmaceutical composition comprising propofol further comprises one or more active compounds and / or one or more excipients.Attorney Docket: XXP-005X-PCT

[0019] In various embodiments, the pharmaceutical compound comprising TTD further comprises one or more active compounds and / or one or more excipients.

[0020] The present invention also provides a system for induction and / or maintenance of anesthesia, comprising co-administering to a subject an amount of a composition comprising propofol and an amount of a composition comprising TTD.

[0021] In various embodiments, propofol and TTD are formulated to arrive at separate compositions, or a combined composition, that provide(s) a desired effect by administration of the composition(s) via a selected route(s). In some embodiments, propofol and TTD are formulated in separate compositions, or a combined composition, to minimize or eliminate interactions with other pharmaceutical compounds, excipients, or compositions thereof, previously administered, coadministered, and / or subsequently administered to the subject.

[0022] In various embodiments, the step of co-administering propofol and TTD, or compositions thereof, includes co-administering the compounds or compositions thereof in amounts to induce and / or maintain a desired endpoint. In some embodiments, the amounts are effective amounts or sufficient doses. The desired endpoint can be selected from the group consisting of induction and / or maintenance of general anesthesia, induction and / or maintenance of sedation, induction and / or maintenance of tranquilization, induction and / or maintenance of immobility, induction and / or maintenance of amnesia, induction and / or maintenance of analgesia, induction and / or maintenance of unconsciousness, induction and / or maintenance of autonomic quiescence, induction and / or maintenance of antinociception, and reduction of a subject’s risk of drug abuse and / or dependence on one, some, or all of the administered compounds.

[0023] An appropriate amount or dosage of the anesthetic compound(s) or composition(s) thereof can vary according to several factors, including: A) the chosen routes of administration; B) the formulation of the compositions; C) subject response; D) one or more characteristics of the subject comprising i) the severity of one or more conditions of the subject, ii) one or more physical signs of the subject such as weight, heart rate, blood pressure, mean arterial pressure, respiratory rate, tidal volume, other indicators known in the art, activity measured by an electrocardiogram (EKG), or activity measured by an electroencephalogram (EEG), or iii) one or more biological signs such as the presence or concentration of a biomarker in blood or bodily fluid collected from the subject, or a combination thereof; and E) the judgment of a person directing or controlling administration of the anesthetic compound(s) or composition(s) thereof, e.g., a prescribing physician. The amount can be administered at a rate that is increased or decreased over time, as required to achieve and / or maintain a desired anesthetic endpoint in an individual subject. In some embodiments, an appropriate amount of anesthetic compound(s) or composition(s) thereof is determined by measuring the subject’s bloodAttorney Docket: XXP-005X-PCT concentration of the anesthetic compound(s) or metabolite(s) thereof, and comparing the measurement(s) to known reference ranges of the compound(s).

[0024] In various embodiments, TTD can be a mixture of one or more stereoisomers, particularly as one or more enantiomers, one or more diastereomers, one or more epimers, one or more conformers, and any combination thereof, based on the stereocenters at the C2, C4, and C5 positions. In some embodiments, for example with TTD, the stereoisomer mixture can comprise isomers of TTD in which the C4 and C5 fluorine atoms are oriented in opposing directions (hereinafter, “trazz -isomer). In some embodiments, the stereoisomer mixture can comprise isomers of TTD in which the C4 and Cs fluorine atoms are oriented in the same direction (hereinafter, “cz -isomer”). In some embodiments, cz -isomers can further be identified by the orientation relative to the trifluoromethyl moiety at C2, as either cis- syn or cz -anti isomers.

[0025] In some embodiments, a mixture of isomers of TTD has a molar ratio of cis-i somers and trans-i somers of between 99: 1 and 1 :99, and any ratio therebetween.

[0026] In some embodiments, any one or a mixture of the isomers of TTD can exhibit anesthetic activity. In some embodiments, a / zz / zz.s-isomer has anesthetic activity. In some embodiments, a cisisomer has anesthetic activity. In some embodiments, a composition comprising a mixture of a cisisomer and a trcms-isomer has anesthetic activity.

[0027] The present invention also provides a packaging insert comprising a pharmaceutical composition comprising TTD. In various embodiments, the packaging insert comprises an amount of a pharmaceutical composition comprising propofol and an amount of the pharmaceutical composition comprising TTD. In some embodiments, the respective amount of each pharmaceutical composition is a subject-dependent amount.

[0028] In various embodiments, the packaging insert comprises one or more additional pharmaceutical compositions. In some embodiments, a use of one, some, or all of the additional pharmaceutical compositions in combination with the use of propofol and the use of TTD induces and / or maintains anesthesia.

[0029] The present invention also provides a method of providing antinociceptive activity in a subject under general anesthesia, comprising administering to the subject an effective amount of TTD to induce and / or maintain general anesthesia, wherein the subject experiences a reduction in fluctuation of one or more physical signs in response to a noxious stimulus while under general anesthesia.

[0030] The present invention also provides a use of a composition comprising TTD, for providing antinociceptive activity in a subject under general anesthesia, wherein the subject experiences a reduction in fluctuation of one or more physical signs in response to a noxious stimulus while underAttorney Docket: XXP-005X-PCT the general anesthesia. In some embodiments, the use includes a step of administering the pharmaceutical composition to the subject.

[0031] In various embodiments, a step of administering described herein can include administering the anesthetic compound or composition thereof via a route (an administration route) to the subject to achieve a desired or intended anesthetic effect. In some embodiments, the administration route can be intravenous, inhalational, subcutaneous, intramuscular, transdermal, subcutaneous, sublingual, oral, nasal, topical, rectal, intrathoracic, or enteral, or any combination thereof. In some embodiments, the administration route is inhalation, via the respiratory system.

[0032] In various embodiments, the one or more physical signs of the subject are selected from the group consisting of heart rate, blood pressure, mean arterial pressure, respiratory rate, tidal volume, other indicators known in the art, or a combination thereof; a cardiological sign of the subject such as activity measured by an electrocardiogram (EKG); a neurological sign of the subject such as activity measured by an electroencephalogram (EEG); or a combination thereof.

[0033] Without being limited by a particular theory, a fluctuation of the one or more physical signs, as described herein, may indicate that the body of the subject is experiencing a negative reaction to a noxious stimulus, and the negative reaction is expressed as the fluctuation. A compound that is administered to an unconscious subject that reduces this fluctuation, may modulate one or more of the pathways by which the subject’s body experiences, or expresses, the negative reaction to the noxious stimulus.

[0034] An appropriate amount or dosage of the anesthetic compound or composition thereof can vary according to several factors, including: the chosen route of administration; the formulation of the compositions; subject response; one or more characteristics of the subject comprising i) the severity of one or more conditions of the subject, ii) one or more physical signs as described herein, or iii) one or more biological signs such as the presence or concentration of a biomarker in blood or bodily fluid collected from the subject, or a combination thereof; and the judgment of a person directing or controlling administration of the anesthetic compound or composition thereof, e.g., a prescribing physician. The amount can be administered at a rate that is increased or decreased over time, as required to achieve and / or maintain a desired anesthetic endpoint in an individual subject. In some embodiments, an appropriate amount of anesthetic compound or composition thereof is determined by measuring the subject’s blood concentration of the anesthetic compound or a metabolite thereof, and comparing the measurement(s) to known reference ranges of the compound(s).

[0035] In some embodiments, the step of administering the anesthetic compound or composition thereof includes administering the anesthetic compound or composition thereof in an amount sufficient to induce and / or maintain a desired effect. In some embodiments, the amount sufficient is a sufficientAttorney Docket: XXP-005X-PCT dose. The desired effect can be selected from the group consisting of general anesthesia, sedation, tranquilization, immobility, amnesia, analgesia, antinociception, unconsciousness, autonomic quiescence, and any combination thereof.

[0036] In some embodiments, the anesthetic or pharmaceutical composition can comprise one or more additional anesthetic excipients or one or more other anesthetic compounds.

[0037] The present invention also provides a packaging insert comprising a pharmaceutical composition comprising TTD. In various embodiments, the packaging insert comprises an amount of a pharmaceutical composition comprising TTD, preferably a subject-dependent amount. In various embodiments, the packaging insert comprises one or more additional pharmaceutical compositions. In some embodiments, a use of one, some, or all of the additional pharmaceutical compositions in combination with the use of TTD induces and / or maintains anesthesia.

[0038] The present invention also provides a use of a composition comprising TTD, for inducing analgesia, maintaining analgesia, or inducing and maintaining analgesia (hereinafter, “inducing and / or maintaining analgesia”).

[0039] The present invention also provides a method of inducing and / or maintaining analgesia in a subject, comprising a step of administering to the subject an effective amount of TTD.

[0040] In another embodiment, the step of administering includes administering TTD, by any selected route of administration, to a subject. In a further embodiment, the step of administering includes co-administering TTD with one or more other analgesic compounds, by separate routes of administration or common routes of administration, to the subject.

[0041] The present invention also provides a pharmaceutical composition comprising TTD, for use in a method of inducing, producing, and / or maintaining analgesia in a subject.

[0042] The present invention also provides a pharmaceutical composition comprising TTD, for use in inducing and / or maintaining analgesia in a subject. In some embodiments, the use includes a step of administering the pharmaceutical composition to the subject, and preferably wherein the subject is a mammal.

[0043] In various embodiments, a step of administering described herein includes administering the analgesic compound or composition thereof via an administration route to the subject to achieve or maintain a desired analgesic effect. In some embodiments, the administration route is intravenous, inhalational, subcutaneous, intramuscular, transdermal, subcutaneous, sublingual, oral, nasal, topical, rectal, intrathoracic, or enteral, or any combination thereof.

[0044] In an embodiment, the step of administering the analgesic compound or composition thereof includes administering the analgesic compound or composition thereof in an effective amount toAttorney Docket: XXP-005X-PCT induce and / or maintain a desired analgesic effect or endpoint. In some embodiments, the effective amount is a sufficient dose. In an embodiment, the desired effect is selected from the group consisting of sedation, tranquilization, amnesia, and analgesia.

[0045] In some embodiments, the effective amount of the administered TTD delivers an effective blood concentration of TTD in the subject. In some embodiments, the effective amount of the administered TTD increases the pain threshold of a subject, relative to the subject’s baseline pain threshold. In an embodiment, the effective amount of the administered TTD increases the pain threshold of a subject in a dose-dependent manner. In an embodiment, the effective amount of the administered TTD increases the pain threshold of a subject to a pain threshold similar or equivalent to a control subject. In an embodiment, the effective amount of the administered TTD increases the pain threshold of a subject without increasing it beyond the pain threshold of a control subject.

[0046] An appropriate amount or dosage of TTD or composition(s) thereof can vary according to several factors, including: A) the chosen route(s) of administration; B) the formulation of the composition(s); C) subject response; D) one or more characteristics of the subject comprising i) the severity of one or more conditions of the subject, ii) one or more physical signs of the subject such as weight, heart rate, blood pressure, mean arterial pressure, respiratory rate, tidal volume, other indicators known in the art, activity measured by an electrocardiogram (EKG), or activity measured by an electroencephalogram (EEG), or iii) one or more biological signs such as the presence or concentration of a biomarker in blood or bodily fluid collected from the subject, or a combination thereof; and E) the judgment of a person directing or controlling administration of the compound(s) or composition(s) thereof, e.g., a prescribing physician. The amount can be administered at a rate that is increased or decreased over time, as required to achieve and / or maintain a desired effect in an individual subject. In some embodiments, an appropriate amount of compound(s) or composition(s) thereof is determined by measuring the subject’s blood concentration of the compound(s) or metabolite(s) thereof, and comparing the measurement s) to known reference ranges of the compound(s).

[0047] In various embodiments, TTD is useful and effective for chronic pain states. In various embodiments, TTD is also useful and effective for acute pain states.

[0048] In various embodiments, TTD is useful and effective to eliminate, ameliorate or modulate: post-operative and / or injury-associated pain; skin and wound pain, including resulting from bathing and / or dressing changes; upper and lower gastrointestinal tract pain; musculoskeletal pain, including joint pain, bone pain, back pain, arthritis, and eye pain; neuropathic pain; cancer pain; trigeminal neuralgia; stroke; other conditions where pain is a symptom; and combinations thereof.Attorney Docket: XXP-005X-PCT

[0049] In various embodiments, TTD is administered to a subject having existing pain, and in other embodiments, administered prophylactically when considered necessary by a person authorized to care for, or treat, the subject, for instance, in advance of a surgical procedure, bath, and / or dressing change.

[0050] In various embodiments, TTD is either administered alone, or co-administered with one or more conventional analgesics, to induce and / or maintain a desired effect. Without being limited by a particular theory, such administrations or co-administrations may be used to reduce, diminish, or limit, or avoid altogether, the common, familiar and sometimes undesirable side effects, for example chemical dependence or abuse, associated with the use of certain conventional analgesic compounds. In some embodiments, TTD is co-administered with one or more conventional non-opioid analgesic compounds. In some embodiments, TTD is co-administered to a subject with an opioid, in order to reduce the amount administered and / or frequency of the administration of an opioid, while inducing and / or maintaining the desired effect.

[0051] In an embodiment, TTD is formulated differently depending on the manner in which TTD is to be administered by a provider and / or tolerated by the subject. In a non-limiting embodiment, the composition comprises TTD in the form of a powder and incorporated in a tablet, capsule, liquid, gel, or any other suitable form. In another non-limiting embodiment, TTD is dissolved in a suitable solvent (which can include water) to form a liquid composition. In another non-limiting embodiment, TTD is incorporated within a slow or delayed release device or enteric coating.

[0052] In some embodiments, TTD or a pharmaceutical composition thereof can comprise one or more additional analgesic excipients or one or more other analgesic compounds.

[0053] The present invention also provides a packaging insert comprising a pharmaceutical composition comprising TTD. In various embodiments, the packaging insert comprises an amount of a pharmaceutical composition comprising TTD, preferably a subject-dependent amount. In various embodiments, the packaging insert comprises one or more additional pharmaceutical compositions. In some embodiments, a use of one, some, or all of the additional pharmaceutical compositions in combination with the use of TTD induces and / or maintains analgesia.BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG. 1 shows an isobologram depicting normalized fractional amounts of propofol and the / ra / s-isomer of TTD administered to maintain anesthesia.Attorney Docket: XXP-005X-PCT

[0055] FIG. 2 shows a bar graph depicting changes in heart rate to noxious stimuli, after induction of anesthesia with sevoflurane and separately after induction of anesthesia with the / ra / .s-isoiner of TTD.

[0056] FIG. 3 shows a line graph depicting changes in heart rate to noxious stimuli, after induction of anesthesia with propofol and subsequent additions of the / ra / .s-isomer of TTD.

[0057] FIG. 4 shows a line graph depicting changes in mean arterial pressure (MAP) to noxious stimuli, after induction of anesthesia with propofol and subsequent additions of the / ra / / .s-isomer of TTD.DETAILED DESCRIPTION OF THE INVENTIONDefinitions:

[0058] The term “comprising”, when used, is understood to also disclose that the elements or feature can be “consisting essentially of’ or “consisting of’. For example, where a composition A “comprises” a compound(s) B, it is understood that the description provides a disclosure of: “composition A comprises compound B”, “composition A consists essentially of compound B”, and / or “composition A consists of compound B”.

[0059] The term "effective amount" or "pharmaceutically effective amount" refer to an amount and / or dosage, and / or dosage regime of one or more compounds, necessary to bring about a desired effect, e.g., an amount sufficient to effect anesthesia, maintain anesthesia, render the subject unconscious and / or immobilize the subject, these effects being determined by a provider authorized to declare the subject as having such effect(s). For example, amounts may be defined as rates of amounts (e.g., amounts of compound(s) administered per unit of time) given to the subject effective to bring about the desired result(s). In another example, an amount is determined by multiplying the rate of amount being administered, by the time elapsed of administering at said rate (i.e., total amount).

[0060] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0061] As used herein, the phrase "pharmaceutically acceptable salt" refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.Attorney Docket: XXP-005X-PCT

[0062] As used herein, the term "composition" or phrase "pharmaceutical composition" refers to a mixture of at least one compound useful with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

[0063] The phrase "cause to be administered" refers to the actions taken by a person licensed to administer agents or compounds to a subject (e.g., a physician), or a person controlling medical care of the subject, who controls and / or permits the administration of the agent(s) / compound(s) at issue to the subject. Causing to be administered can involve diagnosis and / or determination of an appropriate therapeutic or prophylactic regimen, and / or prescribing particular agent(s) / compounds for a subject. Such prescribing can include, for example, drafting a prescription form, annotating a medical record, and the like. Further, the term “administration” generally refers to delivery of one or more agents or compounds, while the term “co-administration” generally refers to delivery of at least two agents or compounds.

[0064] The terms “patient” and “individual” can interchangeably refer to a subj ect such as a mammal or human as described herein.

[0065] “ Combination index” (CI) is a measure of potency shifting. The combination index is known in the art and is described, e.g., in U.S. Patent Publication No. 2013 / 0295102, the contents of which are incorporated herein by reference. A CI value of greater than 1 generally indicates antagonistic effect; a CI value of 1.0 generally indicates an additive effect; and a CI value of less than 1 generally indicates a synergistic effect resulting from the combination of co-admini st ering two or more pharmaceutical compounds. The CI value can be determined at various fractions of effect or noneffect.

[0066] The CI provides a fraction of the original (standalone administration) amounts of each of two pharmaceutical compounds that would be needed in combination relative to the separate amounts of the compounds required, if administered individually, to provide a desired effect. For example, when the combination index has a value of 0.1, only about one tenth of the sum of the fractional amounts of the individual compounds (expressed as a fraction of the amount of that compound when administered by itself to achieve a chosen effect) is needed for the combination to provide the same desired effect. In another example, if an amount of 100 mg / kg of drug A individually or an amount of 200 mg / kg of drug B individually is needed to provide a desired effect, and the combination index is 0. 1, then about 5 mg / kg of drug A co-administered with about 10 mg / kg of drug B would provide the desired effect (one twentieth of the original amounts of each of the single compounds adds up to a total of one tenth). The amounts of the single compounds need not be reduced by the same fractional value so long as the sum of their fractional values adds up to the combination index. In this example, an amount of 8Attorney Docket: XXP-005X-PCT mg / kg of drug A co-administered with an amount of 4 mg / kg of drug B would also achieve the chosen effect (this is 0.08 times the original amount of drug A and 0.02 times the original amount of drug B; the sum of the fractional amounts (0.08 + 0.02) would be equal to the combination index of 0.1.)

[0067] The phrase “standalone effective amount” refers to an amount of a single pharmaceutical compound that, when administered to a subject, induces and / or maintains a desired effect. That is, the single pharmaceutical compound alone contributes to the induction and / or maintenance of the desired effect. The standalone effective amount may be provided to the subject in a single administration, in two or more administrations (of which the standalone effective amount would be the sum of the separately administered amounts), or in a continuous administration (of which the standalone effective amount would be the average steady-state rate of administered compound, over time).

[0068] A “synergistic” or “synergizing” effect can be such that the one or more effects of the combination of administered compounds are greater than the one or more effects of each component alone, or they can be greater than the sum of the one or more effects of each component alone. In some embodiments, the synergistic effect is greater than the effect on a subject with one of the components alone, or the additive effects of each of the components when administered individually. The effect can be any of the effects or endpoints described herein.

[0069] The terms “antinociception” and “antinociceptive” generally refer to the lessening or calming of responses to noxious stimuli in a subject lacking consciousness, i.e., “nociceptive activity”. There are several known treatments to lessen or calm the responses to noxious stimuli in a conscious subject, e.g., analgesics; there are also treatments to lessen or calm the responses to noxious stimuli in an unconscious subject, e.g., antinociceptives. Importantly, compounds, compositions thereof, and therapies thereof involving analgesia can also involve antinociception, and vice versa. Since an unconscious subject is typically not able to communicate subjective feelings of pain, their experience of nociception is generally indicated by transient changes in physical signs or measurements, e.g., spikes in heart rate, blood pressure (e.g., mean arterial pressure), and / or respiratory rate, as well as changes from baseline measurements in electrocardiogram (EKG), CO2 / O2 inspired and expired gas monitoring, and / or electroencephalogram (EEG) monitoring. Treatments involving antinociceptives are generally directed to lessening or smoothing the changes in the physical signs or measurements.

[0070] The term “dose” or the phrase "unit dose" means a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active compound. The amount of the active compound is generally equal to the dosage of the active compound that would be administered to a subject or a convenient fraction thereof such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4Attorney Docket: XXP-005X-PCT or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0071] The term “analgesia” generally refers to reduction or elimination of a pain sensation in a subject. Typically, the subject is conscious when the analgesic effect is occurring, and is able to experience a change in levels, threshold, or other measure of the pain sensation. This change is typically observed and interpreted by the person administering, or controlling administration of, the active compound(s). A state of induced and / or maintained analgesia may accompany other states of anesthesia induced and / or maintained by administration of TTD, or additional co-administered analgesic or anesthetic compounds, which can include but is not limited to: tranquilization, sedation, amnesia, a hypnotic state, and / or a state of insensitivity to noxious stimulation.Embodiments of the Present Inventions

[0072] The present invention encompasses the use of a propofol compound, or a composition comprising propofol, with TTD or a composition thereof, which can include any of its isomers or combinations thereof.

[0073] Non-limiting examples of types of pharmaceutically acceptable carriers or additional compounds are a salt, liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, encapsulating material, coating, antibacterial agent, antifungal agent, or absorption delaying agent, another anesthetic compound, and any mixture or combination thereof.

[0074] In various embodiments, an amount of TTD, and any additional compound in a composition, can be selected to any desired concentration. By way of example, the composition may comprise between 0.01% and 100% by weight TTD.

[0075] In some embodiments, TTD including any of its stereoisomers may be isolated or present within a composition as, or converted into, a pharmaceutically acceptable salt, such as in combination with an acceptable cation or anion, as is well known in the art.

[0076] In various embodiments, non-limiting examples of an additional compound are a sugar, such as lactose, glucose and sucrose; a starch, such as corn starch or potato starch; a cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, or cellulose acetate, or a mixture thereof; a powdered tragacanth; a malt; a gelatin; a talc; an excipient, for example cocoa butter or suppository wax; an oil, for example peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,Attorney Docket: XXP-005X-PCT corn oil and soybean oil; a glycol, for example propylene glycol; a polyol, for example glycerin, sorbitol, mannitol, polyethylene glycol, or a mixture thereof; an esters, for example ethyl oleate and ethyl laurate; agar; a buffering agents, for example magnesium hydroxide or aluminum hydroxide; a surface active agent; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and a phosphate buffer solution; and any mixture thereof.

[0077] In various embodiments, the compounds are formulated for delivery via a respiratory pathway, .g, suitably developed for inhalational, pulmonary, and / or intranasal delivery. In various embodiments, the compound or mixture of compounds is vaporized into or directly mixed or diluted with a carrier gas, e.g., oxygen, air, or helium, or a mixture thereof A preservative may be further included in the vaporized formulations, as appropriate. Other contemplated formulations include projected nanoparticles, oil-in-water emulsions, and liposomal preparations.

[0078] The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors such as the type and severity of the disease being treated, the type and age of the subject receiving the administered compound(s), and other factors as described herein.

[0079] The formulations of anesthetic compositions can be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active compound into association with a carrier or one or more other accessory compounds, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

[0080] Administration of an amount of a compound can be adjusted individually to provide a level of the compound(s) in a subject that induces and / or maintains a desired effect. For example, an amount of a compound is determined by measuring a plasma or serum level of the compound or metabolite(s) thereof in the subject. In cases of local administration or selective uptake, the determined or measured amount of a compound may not be related to plasma or serum concentration thereof, or of its metabolite(s). One having skill in the art is able to optimize local administration of a compound, or administration of a compound having selective uptake, without undue experimentation.

[0081] In various embodiments, the co-administration of propofol and TTD, or compositions thereof, comprises: simultaneous administration of both propofol and TTD over one or more periods of time; sequential or alternating administration of propofol and then TTD, one or more times, over a period time.

[0082] In various embodiments, the co-administration of propofol and TTD, or compositions thereof, comprises a regime of two or more administrations of each of propofol and TTDAttorney Docket: XXP-005X-PCT independently over one or more periods of time, to induce and / or maintain the desired effect. In some embodiments, either or both propofol and TTD are administered continuously, at constant rates, until the desired effect is induced and / or maintained. In some embodiments, propofol and / or TTD are administered continuously at variable rates adjusted (titrated) by a provider, adjusted over a portion of, or the entire, duration of the administration, until the effect is induced and / or maintained. In an embodiment, the variability of the rate of continuous administration of propofol and / or TTD is itself adjusted by the provider. In some embodiments, amounts of propofol and / or TTD are administered two or more times with one or more intervals of time therebetween, until the effect is induced and / or maintained. The intervals may comprise between about 15 seconds to about 60 minutes, preferably between about one minute to about 10 minutes, more preferably between about 3 minutes to about 5 minutes. In an embodiment, propofol and / or TTD are administered in a single rapid administration, e.g., a bolus administration.

[0083] In an embodiment, the step of co-administering propofol and TTD comprises administering the pharmaceutical composition comprising propofol precedes the step of administering the pharmaceutical composition comprising TTD. In another embodiment, the step of co-administering the pharmaceutical composition comprising a step of administering TTD precedes the step of administering the pharmaceutical composition comprising propofol. In a further embodiment, the steps of administering the pharmaceutical composition comprising propofol and the pharmaceutical composition comprising TTD occur substantially simultaneously; that is, one of the two pharmaceutical compositions is administered less than about 15 seconds, less than about 30 seconds, less than about 60 seconds, less than about 90 seconds, or less than about 120 seconds after the other of the two pharmaceutical compositions is administered.

[0084] Detailed information about the delivery of TTD and compositions thereof, in the form of vapors or gases is available in the art. TTD is typically vaporized using a vaporizer using a carrier gas such as oxygen, air, or helium, or a mixture thereof, to achieve a desired concentration of TTD suitable for inhalation by use of a semi-open or semi-closed anesthetic circuit, as is known to individuals familiar with the art of anesthesia. The compound in a gaseous form can also be directly mixed with a carrier gas such as oxygen, air, or helium, or a mixture thereof, to achieve a desired amount of TTD suitable for inhalation by use of a semi-open or semi-closed anesthetic circuit, as is known to persons skilled in the art of anesthesia.

[0085] TTD or composition thereof can also be administered by direct application onto or through a breathing mask, also termed an open circuit, as is known to persons skilled in the art of anesthesia. In animals, TTD or composition may also be administered into a closed chamber or container containingAttorney Docket: XXP-005X-PCT the animal subject, whereby TTD is delivered by the respiratory tract as the animal breathes, as is known to persons skilled in the art of animal anesthesia.

[0086] In some embodiments, an administered amount of a pharmaceutical composition comprising propofol, to induce and / or maintain a desired effect in a subject, is between about 0.1 milligrams (mg) of propofol per kilogram (kg) of the subject’s body weight, to about 5.0 mg / kg, preferably about 0.1 mg / kg - about 1.0 mg / kg, or about 0.5 mg / kg - about 1.5 mg / kg, or about 1 mg / kg - about 1.5 mg / kg, or about 1 mg / kg - about 2 mg / kg, or about 2 mg / kg - about 2.5 mg / kg, or about 2.5 mg / kg - about 3.5 mg / kg. In some embodiments, an administered amount of the pharmaceutical composition comprising propofol, to induce and / or maintain the effect in the subject, is a rate between about 1 microgram (pg) of propofol per kg of the subject’s body weight per minute (min), to about 500 pg / kg / min, preferably about 1 pg / kg / min, or about 5 pg / kg / min, or about 5 pg / kg / min - about 10 pg / kg / min, or about 5 pg / kg / min - about 50 pg / kg / min, or about 25 pg / kg / min - about 75 pg / kg / min, or about 25 pg / kg / min - about 100 pg / kg / min, or about 50 pg / kg / min - about 100 pg / kg / min, or about 100 pg / kg / min - about 150 pg / kg / min, or about 100 pg / kg / min - about 200 pg / kg / min, or about 125 pg / kg / min - about 300 pg / kg / min. In some embodiments, an administered amount of the pharmaceutical composition comprising propofol, to induce and / or maintain the effect in the subject, is not dependent on the subject’s body weight, e.g., intermittent administrations of a bolus amount of propofol, the bolus amount being between about 1 mg propofol and about 100 mg propofol, preferably about 5 mg, about 10 mg, about 20 mg, about 25 mg, or about 50 mg propofol. A provider often adjusts the amount of, and / or administration regime of, the propofol administered to the subject, e.g., switching from administering a bolus amount to induce anesthesia to administering at a variable rate to maintain anesthesia, or administering a bolus amount in addition to and during a separate variable rate administration. Adjustments to amounts and rates are generally based on the present characteristics, e.g., physical signs, biological signs, etc. of the subject.

[0087] Detailed information about the delivery of TTD and compositions thereof, in the form of vapors or gases is available in the art. TTD is typically vaporized using a vaporizer using a carrier gas such as oxygen, air, or helium, or a mixture thereof, to achieve a desired concentration of TTD suitable for inhalation by use of a semi-open or semi-closed anesthetic circuit, as is known to individuals familiar with the art of anesthesia. The compound in a gaseous form can also be directly mixed with a carrier gas such as oxygen, air, or helium, or a mixture thereof, to achieve a desired amount of TTD suitable for inhalation by use of a semi-open or semi-closed anesthetic circuit, as is known to persons skilled in the art of anesthesia.Attorney Docket: XXP-005X-PCT

[0088] TTD or composition thereof can also be administered by direct application onto or through a breathing mask, also termed an open circuit, as is known to persons skilled in the art of anesthesia. In animals, TTD or its composition may also be administered into a closed chamber or container containing the animal subject, whereby TTD is delivered by the respiratory tract as the animal breathes, as is known to persons skilled in the art of animal anesthesia.

[0089] In some embodiments of the invention, TTD or composition thereof may be dissolved or suspended in a suitable solvent, such as water, ethanol, or saline, and administered by nebulization. A nebulizer produces an aerosol of fine particles by breaking a liquid into fine droplets and dispersing them into a flowing stream of gas. Medical nebulizers are designed to convert water or aqueous solutions or colloidal suspensions to aerosols of fine, inhalable droplets that can enter the lungs of a patient during inhalation and deposit on the surface of the respiratory airways. Typical pneumatic (compressed gas) medical nebulizers develop approximately 15 to 30 microliters of aerosol per liter of gas in finely divided droplets with volume or mass median diameters in the respirable range of 2 to 4 micrometers. Predominantly, water or saline solutions are used with low solute concentrations, typically ranging from 1.0 to 5.0 mg / mL.

[0090] Metered dose inhalers are also known and available. Breath-actuated inhalers typically contain a pressurized propellant and provide a metered dose automatically when the patient's inspiratory effort either moves a mechanical lever or the detected flow rises above a preset threshold, as detected by a hot wire anemometer. See, for example, U.S. Pat. Nos. 3,187,748; 3,565,070; 3,814,297; 3,826,413; 4,592,348; 4,648,393; 4,803,978; and 4,896,832, the disclosures of which are incorporated by reference in their entireties.

[0091] In some embodiments, the TTD compound or composition thereof can be administered to reduce fluctuations in one or more physical signs in a subject, comprising administering to the subject via one or more routes of administration an effective amount of the TTD active compound.

[0092] Inhaled anesthetics that are commonly used in general anesthesia in animals and humans can present patient risks in terms of cardiovascular and respiratory depression, and all volatile anesthetics in clinical use today were developed in the 1970s or before (see Terrell, Anesthesiology (2008) 108: 531-3, the disclosure of which is incorporated by reference in its entirety).

[0093] In some embodiments, the relative amounts of TTD and any additional compound(s) in a pharmaceutical composition are varied, depending upon one or more characteristics and / or conditions of the subject. In another embodiment, a composition comprising TTD can further comprise one or more additional analgesic compounds, non-limiting examples of which can include opioids, non-Attorney Docket: XXP-005X-PCT steroidal anti-inflammatories (NSAIDs), acetaminophen, gabapentinoids, cyclooxygenase-2 inhibitors, A-methyl-D-aspartate (NMDA) receptor agonists, tricyclic antidepressants, anxiolytics, and anesthetics. Such combinations in the presence of an opioid may reduce the amount of opioid required to achieve a desired analgesic effect. For example, U.S. Patent 8,034,801, herein incorporated by reference in its entirety, describes a synergistic combination of acetaminophen, ibuprofen, and codeine achieving an analgesic effect on neuropathic pain in a rat model. In another example, U.S. Patent 8,268,821, herein incorporated by reference in its entirety, describes the use of a flupirtine, which had been developed in the 1970’s to treat acute pain, as a treatment for neuropathic cancer pain in combination with morphine, and which enabled morphine to be administered at ten times fewer than its median effective dose (EDso) value.

[0094] In another embodiment, TTD or a composition thereof is formulated either for administration by itself or co-admini strati on with any of the analgesic compounds listed above, by any acceptable administration route(s). Non-limiting examples of suitable administration routes include oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastric, topical, and oropharyngeal routes.

[0095] In another embodiment, TTD is administered in an effective amount to induce and / or maintain a desired effect, such as analgesia. In another embodiment, the desired effect comprises a reduction of pain experienced by the subject, as a result of receiving an effective amount of the compound. In another embodiment, the desired effect includes the complete or partial removal of the pain experienced by the subject. In another embodiment, the desired effect increases the pain threshold of the subject, relative to the subject’s baseline pain threshold level. In another embodiment, the desired effect increases a subject’s pain threshold to a level associated with a control subject. In another embodiment, the pain threshold of the subject increases in a dose-dependent manner. Without being limited by a particular theory, and in another embodiment, it is believed that administration of TTD to a subject can be accomplished without increasing their pain threshold beyond that of a healthy subject, an effect that is commonly observed when opiates are administered.

[0096] In another embodiment, the appropriate amount and number of analgesic compounds varies according to several factors, including the formulation of the composition(s) comprising the compound(s), subject response, the severity of the condition(s), the subject’s weight, and the a person directing or controlling administration, e.g., a prescribing physician. The amount can be increased or decreased over time, as required by an individual subject. For example, the subject initially is given a reduced amount, which is then increased to an amount providing the desired effect, yet tolerable to the subject.Attorney Docket: XXP-005X-PCT

[0097] The ability to determine an effective amount, based in-part on the factors described above, as well as others, is well-understood by those having ordinary skill in the art. Generally, an efficacious or effective amount of a combination of one or more such analgesic compounds is determined by first administering a low dose or small amount of the analgesic, and then incrementally increasing the administered dose or dosages, adding a second or third medication as needed, until a desired effect is observed in the subject with minimal or no toxic or undesired side effects.

[0098] Applicable methods for determining an appropriate amount or dose and dosing schedule for administration of anesthetics, including analgesics, are described, for example, in Goodman and Gilman ’s The Pharmacological Basis of Therapeutics, 12th Edition, 2010, supra,' in a Physicians’ Desk Reference (PDR), supra, in Remington: The Science and Practice of Pharmacy (Remington: The Science & Practice of Pharmacy), 21st Edition, 2011, Pharmaceutical Press, and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, et al., eds., 9th Edition, 2010, Lippincott Williams & Wilkins; and in Martindale : The Complete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press., and in Martindale, Martindale: The Extra Pharmacopoeia, 31st Edition., 1996, Amer Pharmaceutical Assn, each of which are incorporated herein by reference.

[0099] Administration of an amount of TTD can be adjusted individually to provide a level of the compound in a subject that is sufficient to induce and / or maintain a desired analgesic effect or state. In cases of local administration or selective uptake, the determined or measured amount of a compound may not be related to plasma or serum concentration thereof, or of its metabolite(s). One having skill in the art is able to optimize local administration of a compound, or administration of a compound having selective uptake, without undue experimentation.

[0100] In another embodiment, TTD is provided as a composition with one or more pharmaceutically acceptable carriers. In another embodiment, a carrier that is compatible does not abrogate the biological activity or properties of TTD, and is relatively non-toxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0101] Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington: The Science and Practice of Pharmacy (Remington: The Science & Practice of Pharmacy), 21stEdition, 2011, Pharmaceutical Press, and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, et al., eds., 9thEdition, 2010, Lippincott Williams & Wilkins, which are incorporated herein by reference.Attorney Docket: XXP-005X-PCTEXAMPLES

[0102] The following examples illustrate embodiments of the invention. However, it is to be understood that the following are only exemplary or illustrative of the present invention, and are not intended to limit the invention in any way, and numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention.Example 1; Anesthetic Activity of the isomer of TTP and Propofol in Dogs

[0103] A conventional plenum-type vaporizer was modified to deliver the Zzzzz / .s-isomer of TTD where the output of the vaporizer with up to a 1 L / min O2 flow rate was calibrated using gas chromatography prior to delivery of the / raws-isomer of TTD to animals.

[0104] Beagle dogs were administered the Zzzzzzs-isomer of TTD by mask induction and maintained at a concentration of the Zzzzzzs-isomer of TTD sufficient to induce anesthesia, at which time they were intubated and instrumented with a three-lead electrocardiograph (EKG), non-invasive blood pressure monitor, pulse oximetry, temperature probe, two bipolar electroencephalograph (EEG) leads, and external warming. End-tidal CO2 was monitored using a capnograph, and end-tidal concentrations of the zzzzzz.s-isomer of TTD were measured by gas chromatography.

[0105] It was observed that the Zzzzzz.s-isomer of TTD caused general anesthesia in dogs, with a minimum alveolar concentration (MAC) of 1.8% ± 0.1% (N=6) (a standalone effective amount of Zzzzzz.s-iso er of TTD). MAC was determined as follows: dogs were maintained at a constant end-tidal concentration of the Zzzzzz.s-isomer of TTD for 20 min. After this time, an alligator clamp was applied to the proximal tail for up to 60 sec or until the dog exhibits non-reflex movement. If the dog moved, the concentration of the Zzzzzz.s-isomer of TTD was increased 10-15% for 15 min. If the dog did not move, the inhaled anesthetic concentration was decreased 10-15% for 15 min. After this reequilibration period, the tail was again clamped as described. MAC was the average of the highest concentration of Zzzzzz.s-isomer of TTD that permitted movement and the lowest concentration of trcrns- isomer of TTD that prevented movement.

[0106] Delivery of the Zzzzzz.s-isomer of TTD was discontinued, and the dogs were allowed to recover. Then, the dogs were administered an intravenous bolus amount of propofol (calculated based on each dog’s body weight) in order to induce anesthesia, and anesthesia was maintained with an intravenous infusion of propofol with an infusion rate that was initially constant (calculated based on each dog’s body weight), then titrated over at least 10 minutes based on each dog’s response to alligator clamp stimuli. An ED50 of propofol was determined in each individual dog as the average of a) the highest infusion rate of propofol that permits movement in response to the stimuli, and b) the lowest infusionAttorney Docket: XXP-005X-PCT rate of propofol that prevents movement in response to the stimuli. The EDso of propofol in the dogs was determined to be 263 ± 17 pg / kg / min (N=6) (a standalone effective amount of propofol). The Z / zzzz.s-isomer of TTD was then co-administered via inhalation to the dogs as described above, in a fractional amount of the previously-determined MAC of the Zzzzzz.s-isomer of TTD (e.g., 0.25 of MAC), and the propofol infusion rate was further titrated based on the dogs’ responses to alligator clamp stimuli. A new EDso of propofol was measured for each dog at this level of MAC of the trans- somer of TTD. The co-administered fractional amount of the Z / zzzz.s-isomer of TTD was then increased (e.g., to 0.50 of MAC), and the propofol infusion rate was again titrated and another EDso for propofol was determined. This process continued until the administered fractional amount of the / ra / z.s-isomer of TTD was 1.0 of MAC.

[0107] The EDso infusion rate of propofol at each MAC fraction of administered Zzzzzz.s-isomer of TTD, for each dog, was calculated as a fraction of the ED50 infusion rate of propofol (a fraction of the standalone effective amount of propofol). When a 0.25 MAC fraction of the Z / zz / 7.s-isomer of TTD (a fraction of the standalone effective amount of the Zzzzzz.s-isomer of TTD) was delivered, the resulting fraction of ED50 infusion rate of propofol was about 0.30, significantly less than the expected 0.75. When a 0.50 MAC fraction of the Z / zz / zs-isomer of TTD was delivered, the resulting fraction of ED50 infusion rate of propofol was about 0.13, significantly less than the expected 0.50. When a 0.75 MAC fraction of the Z / zzzz.s-isomer of TTD was delivered, the resulting fraction of ED50 infusion rate of propofol was about 0.05, significantly less than the expected 0.25. These findings are depicted in the isobologram shown in FIG. 1, and indicate that a significantly lower infusion rate of propofol was required, at a given administered amount of z / zz / z.s-isomer of TTD, to maintain anesthesia in the dogs. It was thus determined that co-administering propofol and the Z / zz / zs-isomer of TTD yielded a surprising and unexpected synergistic effect on maintaining anesthesia.

[0108] Example 2; The procedure as outlined in Example 1 is repeated, except that the anesthetic compound delivered to the dogs is the cz.s-isomer of TTD. A lower infusion rate of propofol is required since the fractional amount of administered propofol is less than a standalone effective amount of propofol, at a given administered amount of the cz.s-isomer of TTD, to maintain anesthesia in the dogs.

[0109] Example 3: The procedure as outlined in Example 1 is repeated, except that the anesthetic compound delivered to the dogs is a co-administered mixture of the cz.s-isomer and Z / zz / zs-isomer of TTD. A lower infusion rate of propofol is required since the fractional amount of administered propofol is less than the standalone effective amount of propofol, at a given administered amount of the TTD mixture, to maintain anesthesia in the dogs.

[0110] Example 4; The procedure as outlined in Example 1 is repeated, except that the subjects are rats instead of dogs. A lower infusion rate of propofol is required since the fractional amount ofAttorney Docket: XXP-005X-PCT administered propofol is less than the standalone effective amount of propofol, at a given administered amount of the trans-isomer of TTD, to maintain anesthesia in the rats.

[0111] Example 5; Antinociceptive Activity of the tra -isomer of TTD in Dogs

[0112] A conventional plenum-type vaporizer was modified to deliver the trans-isomer of TTD where the output of the vaporizer with up to a 1 L / min O2 flow rate was calibrated using gas chromatography prior to delivery of the trans-isomer of TTD to animals.

[0113] Beagle dogs were administered the trans-isomer of TTD by mask induction and maintained at a concentration of the / rans-isomer of TTD sufficient to induce anesthesia, at which time they were intubated and instrumented with a three-lead electrocardiograph (EKG), non-invasive blood pressure monitor, pulse oximetry, temperature probe, five bipolar electroencephalograph (EEG) leads, and external warming. End-tidal CO2 was monitored using a capnograph, and end-tidal concentrations of the trans-isomer of TTD were measured by gas chromatography.

[0114] It was observed that the trans-isomer of TTD induced general anesthesia in the dogs, with a minimum alveolar concentration (MAC) of 1.8% ± 0.1% (N=6). MAC was determined as follows: dogs were maintained at a constant end-tidal concentration of trans-isomer of TTD for 20 min. After this time, an alligator clamp was applied to the proximal tail for up to 60 sec or until the dog exhibits non-reflex movement. If the dog moved, the concentration of trans-isomer of TTD was increased 10- 15% for 15 min. If the dog did not move, the inhaled anesthetic concentration was decreased 10-15% for 15 min. After this re-equilibration period, the tail was again clamped as described. MAC was the average of the highest concentration of trans-isomer of TTD that permitted movement and the lowest concentration of trans-isomer of TTD that prevented movement. During the period of MAC determination, the pieces of equipment were monitoring the physical signs of the dogs, and physical signs such as heart rate (beats per minute) and mean arterial pressure (mmHg) of the dogs were determined prior to, and after, each alligator clamp stimulus. After MAC determination, delivery of the trans-isomer of TTD was discontinued, and the dogs were allowed to recover.

[0115] The above process was repeated, with administration of sevoflurane via inhalation exposure rather than the trans-isomer of TTD. The MAC of the sevoflurane was determined in each dog in accordance with the above process. During the period of MAC determination, the pieces of equipment were monitoring the physical signs of the dogs, and physical signs such as heart rate and mean arterial pressure were determined prior to, and after, each alligator clamp stimulus. After MAC determination, delivery of sevoflurane was discontinued, and the dogs were again allowed to recover.

[0116] Then, the dogs were administered an intravenous bolus amount of propofol (calculated based on each dog’s body weight) in order to induce anesthesia, and anesthesia was maintained with an intravenous infusion of propofol with an infusion rate that was initially constant (calculated based onAttorney Docket: XXP-005X-PCT each dog’s body weight), then titrated over at least 10 minutes based on each dog’s response to stimuli, such as an alligator clamp. An ED50 of propofol was determined in each individual dog as the average of a) the highest infusion rate of propofol that permitted movement in response to the stimuli, and b) the lowest infusion rate of propofol that prevented movement in response to the stimuli. The ED50 of propofol was determined to be 263 ± 17 qg / kg / min (N=6). The / ra / rs-isomer of TTD was then coadministered via inhalation to the dogs as described above, in a fractional amount of the previously- determined MAC of the / ra / / .s-isomer of TTD (e.g., 0.25 of MAC), and the propofol infusion rate was further titrated based on the dogs’ responses to alligator clamp stimuli. A new ED50 of propofol was measured for each dog at this level of MAC of the / / zw.s-isomer of TTD. The co-administered fractional amount of the / raz / .s-isomer of TTD was then increased (e.g., to 0.50 of MAC), and the propofol infusion rate was again titrated and another ED50 for propofol was determined. This process continued until the administered fractional amount of the / ra / / .s-i sorrier of TTD was 1.0 of MAC. During the period of ED50 determinations, the pieces of equipment were monitoring the physical signs of the dogs, and the physical signs such as heart rate and mean arterial pressure were determined prior to, and after, each alligator clamp stimulus. Deliveries of propofol and the / ra / / .s-isomer of TTD were discontinued, and the dogs were allowed to recover.

[0117] The heart rate value in the dogs measured prior to each alligator clamp stimulus was subtracted from the heart rate value measured after each respective alligator clamp stimulus, to arrive at a change in heart rate. When measured, the mean arterial pressure value in the dogs measured prior to each alligator clamp stimulus was subtracted from the mean arterial pressure value measured after each respective alligator clamp stimulus, to arrive at a change in mean arterial pressure. The values of change in heart rate during each of: MAC determination for the / ra / z.s-i sorrier of TTD, MAC determination for sevoflurane, and each of the ED50 determinations of propofol, were separately compiled.

[0118] FIG. 2 shows that alligator clamp stimuli elicited an average increase in heart rate of about 13 ± 3.5 beats per minute when the dogs were anesthetized with the Zra / zs-i sorrier of TTD, while eliciting an average increase in heart rate of about 22.5 ± 4.5 beats per minute when anesthetized with sevoflurane. This finding indicates that the trazis-isomer of TTD was a statistically significantly superior compound at reducing fluctuations in heart rate due to alligator clamp stimuli, compared to sevoflurane.

[0119] FIG. 3 shows that alligator clamp stimuli elicited an average increase in heart rate of about 70 ± 12 beats per minute when the dogs were administered propofol alone, about 59 ± 10 beats per minute when propofol and a fractional amount of 0.25 MAC / ra / .s-isomer of TTD (i.e., 0.45% / ra».s-i sorrier of TTD) were administered, about 34 ± 8 beats per minute when propofol and a fractional amount ofAttorney Docket: XXP-005X-PCT 0.50 MAC / ra / / .s-isomer of TTD were administered, and about 32 ± 8 beats per minute when propofol and a fractional amount of 0.75 MAC / ra / .s-isomer of TTD were administered. FIG. 4 shows that the alligator clamp stimuli elicited an average increase in mean arterial pressure of about 42 ± 11 mmHg when the dogs were administered propofol alone, about 42 ± 10 mmHg when propofol and a fractional amount of 0.25 MAC trans-isomer of TTD were administered, about 29 ± 6 mmHg when propofol and a fractional amount of 0.50 MAC trans-isomer of TTD were administered, and about 24 ± 9 mmHg when propofol and a fractional amount of 0.75 MAC / ra / / .s-isomer of TTD were administered. These findings indicate that, at certain administered amounts, the / ra / / .s-isomer of TTD was a statistically significantly superior compound at reducing fluctuations in heart rate and mean arterial pressure due to alligator clamp stimuli, compared to propofol.

[0120] Example 6: The procedure as outlined in Example 5 is repeated, except rather than the trans- isomer of TTD, the cA-isomer of TTD is delivered to the dogs. The cA-isomer of TTD is better at reducing fluctuations in heart rate due to alligator clamp stimuli, compared to sevoflurane. Further, the cA-isomer of TTD is better at reducing fluctuations in mean arterial pressure due to alligator clamp stimuli, compared to propofol.

[0121] Example 7: The procedure as outlined in Example 5 is repeated, except rather than the trans- isomer of TTD, a co-administered mixture of the cA-isomer and / ra -isomer of TTD is delivered to the dogs. The TTD mixture isbetter at reducing fluctuations in heart rate due to alligator clamp stimuli, compared to sevoflurane. Further, the TTD mixture isbetter at reducing fluctuations in mean arterial pressure due to alligator clamp stimuli compared to propofol.

[0122] Example 8: The procedure as outlined in Example 5 is repeated, except that the procedure is performed on rats rather than dogs. The trans-isomer of TTD isbetter at reducing fluctuations in heart rate of the rats due to alligator clamp stimuli, compared to sevoflurane. Further, the trans-isomer of TTD isbetter at reducing fluctuations in mean arterial pressure of the rats due to alligator clamp stimuli compared to propofol.Example 9; Analgesic Activity of the cA-isomer of TTD in Mice

[0123] A sample of the cA-isomer of TTD is administered to mice via inhalation exposure in a microcircuit connected using unidirectional airflow valves to a CO2 absorbent chamber and a glass syringe. A small amount of the cA-isomer of TTD is transferred into the glass syringe where it is volatilized. The mice are transferred to the small cylindrical chamber, and the glass syringe is connected to the microcircuit in series. The syringe is then slowly pumped to circulate the vaporized cA-isomer of TTD / air mixture through the microcircuit, until the mice indicate a loss-of-righting- reflex (LORR).Attorney Docket: XXP-005X-PCT

[0124] Then, the minimum alveolar concentration for loss-of-righting-reflex (MACLORR) of the cisisomer of TTD is determined in each mouse and averaged. MACLORR is determined as follows: the cA-isomer of TTD is maintained constant at a concentration for at least 20 minutes and then is checked to see if it has lost its righting reflex in response to a rotation of the cylindrical chamber. If the mouse rights itself, the concentration of the cA-isomer of TTD is increased 10-15% for at least 20 minutes. If the mouse does not right itself, the concentration of the cA-isomer of TTD is decreased 10-15% for at least 20 minutes. After this re-equilibration period, the mouse is then checked to see if it has lost its righting reflex in response to a rotation of the cylindrical chamber. MACLORR is the average of the highest concentration of cA-isomer of TTD that permits righting and the lowest concentration of cisisomer of TTD that prevents righting. Delivery of the cA-isomer of TTD is discontinued, and the mice are allowed to recover.

[0125] Subsequently, a pain threshold of mice from a mechanical stimulus is measured using the von Frey assay, which generally utilizes a filament, fiber, or hair to test a rodent’s sensitivity to a mechanical stimulus (see Carter, M. and Shi eh, J.C. (2010). "Nociception". Guide to Research Techniques in Neuroscience. Burlington, MA: Academic Press. 51-52. ISBN 978-0-12-374849-2). A series of nylon monofilaments calibrated at a range of forces from about 0.0700-5.8000 g are applied to the plantar surface of each hind paw to determine mechanical allodynia, with the threshold force required to elicit withdrawal of the paw determined using the up-down method across a series of trials. To study the effects of the cA-isomer of TTD, the mice are divided into four treatment groups and one control group, with each treatment group corresponding to one of several different amounts (doses) of the cA-isomer of TTD: 0% of MACLORR, 2.5% of MACLORR, 5% of MACLORR, 7.5% of MACLORR, and 10% of MACLORR. The mice exposed to the cis-isomer of TTD as described to measure MACLORR for at least 20 minutes, and then are removed from the cylindrical chamber for evaluation. The mice are assessed at five time points: pre-admini strati on of the cA-isomer of TTD to provide a baseline measurement (t = 0 minutes) and at 5, 10, 15, and 30 minutes post-administration.

[0126] The cA-isomer of TTD exhibits a dose-dependent analgesic response to the mechanical stimulus. Specifically, the amount of 5% of MACLORR raises the mice’s pain threshold to an amount that is identical to baseline response within 15 minutes. This indicates that the cA-isomer of TTD is a potent analgesic, and may be effective at treating mechanical nociceptive pain.

[0127] Example 10: The procedure of Example 9 is repeated, except that the analgesic compound delivered to the mice is the / ra / / .s-i sorrier of TTD. The / ra / / .s-isoiner of TTD is a potent analgesic, and may be effective at treating mechanical nociceptive pain.Attorney Docket: XXP-005X-PCT

[0128] Example 11: The procedure of Example 9 is repeated, except that the analgesic compound delivered to the mice is a co-administered mixture of the Zzzzz / .s-isomer and cz.s-isomer of TTD. The TTD mixture is a potent analgesic, and may be effective at treating mechanical nociceptive pain.

[0129] Example 12: The procedure of Example 9 is repeated, except that the analgesic compound is delivered to a mammal selected from the group consisting of human, non-human primate, canine, feline, equine, bovine, ovine, porcine, and a laboratory mammal selected from the group consisting of rattus, lagomorpha, and hamster. The cz.s-isomer of TTD is a potent analgesic in the selected mammal, and may be effective at treating mechanical nociceptive pain.

[0130] Example 13: The procedure of Example 9 is repeated, except that the effect of the cz.s-i sorrier of TTD on the pain threshold of mice from a thermal stimulus is measured using the Hargreaves Assay (see Carter, M. and Shieh, J.C., above). The cz.s-isomer of TTD is a potent analgesic, and may be effective at treating thermal nociceptive pain.

[0131] Example 14: The procedure of Example 13 is repeated, except that the analgesic compound delivered to the mice is the / zvzzz.s-isomer of TTD. The trazz -isomer of TTD is a potent analgesic, and may be effective at treating thermal nociceptive pain.

[0132] Example 15: The procedure of Example 13 is repeated, except that the analgesic compound delivered to the mice is a co-administered mixture of the trazzs-isomer and cz.s-isomer of TTD. The TTD mixture is a potent analgesic, and may be effective at treating thermal nociceptive pain.

[0133] Example 16: The procedure of Example 13 is repeated, except that the analgesic compound is delivered to a mammal selected from the group consisting of human, non-human primate, canine, feline, equine, bovine, ovine, porcine, and a laboratory mammal selected from the group consisting of rattus, lagomorpha, and hamster. The cz.s-isomer of TTD is a potent analgesic in the selected mammal, and may be effective at treating thermal nociceptive pain.

Claims

Attorney Docket: XXP-005X-PCTWe claim:

1. A method of inducing anesthesia, maintaining anesthesia, or inducing and maintaining anesthesia in a subject, comprising co-administering to the subject an amount of a propofol compound and an amount of a compound 2,4,5-trifluoro-2-(trifluoromethyl)-l,3-dioxolane (TTD).

2. The method of Claim 1, wherein: the co-administered amount of propofol is a fraction of a standalone effective amount for propofol based on one or more characteristics of the subject, and the co-administered amount of TTD is a fraction of a standalone effective amount for TTD based on one or more characteristics of the subject; and wherein the sum of the fractions of the co-administered amounts of propofol and TTD is less than 1.0.

3. The method of either Claim 1 or 2, wherein the administering to the subject is of a composition comprising propofol and a composition comprising TTD.

4. The method of any of Claims 1-3, wherein the administered amount of propofol is a synergistically effective amount of propofol, and the administered amount of TTD is a synergistically effective amount of TTD.

5. The method of any of Claims 1-4, wherein propofol is administered concurrently with TTD.

6. The method of any of Claims 1-4, wherein propofol is administered independently of TTD.

7. The method of any of Claims 1-6, wherein propofol is administered to the subject to induce anesthesia, and then propofol is co-administered with TTD to maintain anesthesia.

8. A method of providing antinociceptive activity in a subject under general anesthesia, comprising administering to the subject an effective amount of a compound 2,4,5-trifluoro-2-(trifluoromethyl)- 1,3 -di oxolane (TTD), wherein the subject experiences a reduction in fluctuation of one or more physical signs in response a noxious stimulus to the subject while under the general anesthesia.

9. The method of Claim 8, wherein the one or more physical signs is selected from the group consisting of: heart rate; blood pressure; mean arterial pressure; activity measured on an electrocardiograph (EKG); activity measured on an electroencephalograph (EEG); body temperature; and a combination thereof.Attorney Docket: XXP-005X-PCT10. The method of either Claim 8 or 9, wherein the noxious stimulus occurs during a surgical procedure.

11. A method of inducing analgesia, maintaining analgesia, or inducing and maintaining analgesia in a subject, comprising administering to the subject an effective amount of a compound 2,4,5- trifluoro-2-trifluoromethyl-l,3-dioxolane (TTD).

12. The method of Claim 11, wherein the subject is administered a composition comprising TTD.

13. The method of either Claim 11 or 12, wherein the effective amount of TTD is administered by at least one route sufficient to achieve the induction and / or maintenance of analgesia.

14. The method of Claim 13, wherein the route of administration is selected from the group consisting of oral, inhalation, nebulization, sublingual, intravenous, subcutaneous, transcutaneous, epidural, intranasal, buccal, rectal, enteral, nasogastric, topical, and oropharyngeal, including combinations thereof.

15. The method of any of Claims 11-14, wherein TTD is co-administered with a compound selected from the group consisting of an opioid, non-steroidal anti-inflammatory (NSAID) compound, acetaminophen, gabapentinoid, cyclooxygenase-2 inhibitor, A-methyl-D-aspartate (NMDA) receptor agonist, tricyclic antidepressant, anxiolytic, and an anesthetic, including combinations thereof.

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