Quinone-class anesthetic agents and sedatives / hypnotics

Abstract

The disclosure relates to a method of inducing anesthesia or sedation in a subject in needs thereof using Coenzyme Q2. The disclosure also relates to pharmaceutical compositions comprising Coenzyme Q2 and processes of preparing pharmaceutical compositions comprising Coenzyme Q2.

Description

01001 / 012990-WG0 QUINONE-CLASS ANESTHETIC AGENTS AND SEDATIVES / HYPNOTICSFEDERALLY SPONSORED RESEARCH

[0001] The invention was made with Government support under Agreement Number RO 1 GM148716, awarded by the National Institutes of Health. The Government has certain rights in the invention.CROSS-RERENCE TO RELATED APPLCATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 748,562 filed on January 23, 2025 and U.S. Provisional Patent Application No. 63 / 943,106 filed on December 17, 2025. Each of the foregoing applications is incorporated herein by reference in its entirety.BACKGROUND

[0003] Anesthetic agents, such as propofol (2,6-diisopropylphenol), are widely used for inducing and maintaining anesthesia in surgical and critical care settings. Propofol and similar agents act on the central nervous system to achieve unconsciousness but are associated with significant risks, including respiratory depression, cardiovascular instability, propofol infusion syndrome, and other complications leading to morbidity and mortality (Paramsothy et al.Propofol in ICU Settings: Understanding and Managing Anti-Arrhythmic, Pro-Arrhythmic Effects, and Propofol Infusion Syndrome. Cureus 2023, 15(6)). Opioid-based sedatives are frequently used for pain management and sedation. However, overuse of these sedatives poses challenges of tolerance, dependency, and abuse, further limiting their utility (Morgan et al. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br. J. Pharmacol. 2011, 164(4), 1322-1334). These issues highlight the need for safer and more effective anesthetic and sedative options, particularly for use in surgical, emergency and intensive care unit (ICU) settings.

[0004] Interest in targeting mitochondrion to effect anesthesia-induced unconsciousness has accelerated over the last few decades and specific mitochondrial targets have been identified. In particular, loss-of-function studies have linked genetic mutations in Complex I of the electron transport chain with anesthetic hypersensitivity in various species across evolutionary biology. From a mechanistic standpoint, anesthetic-mediated Complex I inhibition is thought to silence synapses by disrupting bioenergy availability required for presynaptic neuronal endocytosis and neurotransmitter recycling. Accordingly, targeting Complex I is a promising strategy for the rational design of next-generation anesthetics.

[0005] Quinone-class compounds, such as Coenzyme(also known as ubiquinone), are naturally occurring molecules involved in the mitochondrial electron transport chain, critical for ATP production (Pallotti et al. The Roles of Coenzyme Q in Disease: Direct and Indirect Involvement in Cellular Functions. Int. J. Mol. Sci. 2021, 23(1), 128). While quinone analogs have classically been used in vitro to test and measure mitochondrial function,Coenzyme-Dimethoxy-5-methyl-6-geranyl- 1 ,4-benzoquinone) is a novel anesthetic and sedative / hypnotic agent. Indeed, coenzyme Q2 induces unconsciousness through mitochondrial proton leak and inhibition of the electron transport chain, mimicking the mechanism of propofol while offering a distinct pharmacological profile. Coenzyme Q2 has demonstrated rapid and effective anesthesia in multiple animal models (e.g., mice and rabbits), and its targeting of mitochondrial pathways provides a unique avenue for anesthesia.

[0006] Thus, Coenzyme Q2 is an effective anesthetic and sedative / hypnotic for surgical anesthesia, ICU sedation (e.g., chronic sedation in the ICU setting), emergency medicine, veterinary anesthesia, sleep disorder treatment, and research into mitochondrial function and central nervous system activity. The pharmaceutical compositions and methods described herein are directed toward this end.SUMMARY

[0007] In one aspect, the present disclosure provides a pharmaceutical compositioncomprising a compound having the structurepharmaceutically acceptable carrier.

[0008] In some embodiments, the pharmaceutically acceptable carrier is an oil-in-water emulsion. In some embodiments, the compound having the structure ofstabilized by means of a surfactant. In some embodiments,the compound having the structuredissolved in a water-immiscible solvent. In some embodiments, the compound having the structure ofemulsified with water.

[0009] In some embodiments, the pharmaceutical composition further comprises an excipient selected from the group consisting of amino acids, vitamins, and minerals, or a combination of any of the foregoing.

[0010] In some embodiments, the compound having the structure ofpresent in an amount from about 0.01 % (w / v) to about 5% (w / v).

[0011] In some embodiments, the pH of the pharmaceutical composition ranges from about 5.0 to about 8.0.

[0012] In some embodiments, the pharmaceutical composition further comprises a tonicity modifier. In some embodiments, the pharmaceutical composition is isotonic with blood.

[0013] In some embodiments, the pharmaceutical composition further comprises ascorbic acid, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound having the structure of"present in a therapeutically effective amount.

[0015] In another aspect, the present disclosure provides a method of inducing anesthesia or sedation in a subject, the method comprising administering to the subject a therapeuticallyeffective amount of a compound having the structurepharmaceutical composition thereof.

[0016] In some embodiments, the method of administration is by a single bolus injection or in 2 to 10 bolus injections. In some embodiments, the method of administration is by continuous infusion.

[0017] In some embodiments, the subject is administered a dose of a compound having thestructuresufficient to achieve a desired clinical anesthetic endpoint, wherein the desired anesthetic endpoint is elected from the group consisting of general anesthesia, mild sedation, moderate sedation, tranquilization, immobility, amnesia, analgesia, deep sedation, and autonomic quiescence.

[0018] In some embodiments, the compound having the structure ofadministered at a dose of 0.1 mg / kg - 1000 mg / kg. In some embodiments, the dose is 1 mg / kg - 500 mg / kg. In some embodiments, the dose is 10 mg / kg -250 mg / kg. In some embodiments, the dose is 50 mg / kg - 150 mg / kg. In some embodiments, the dose is 90 mg / kg - 110 mg / kg. In some embodiments, the dose is about 100 mg / kg.

[0019] In some embodiments, the compound of having the structure ofr the pharmaceutical composition thereof, is administered by intravenous administration, inhalational administration, subcutaneous administration, intramuscular administration, or transdermal administration

[0020] In another aspect, the present disclosure provides a process for preparing a pharmaceutical composition of a compound having the structure of", the process comprising:a. dispersing at least one surfactant in water;b. dissolving the compound having the structurein at least one water-immiscible solvent to form a non-aqueous solution; andc. adding the non-aqueous solution to the surfactant dispersion to form a crude oil-in-water emulsion. In some embodiments, the process further comprises:d. dissolving ascorbic acid or its pharmaceutically acceptable salts thereof in water to form an aqueous solution; ande. adding the surfactant dispersion of step (a) to the aqueous solution to form a mixture, wherein the mixture is added to the non-aqueous solution in step (c) to form the crude oil-in-water emulsion.01001 / 012990-WG0 BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 depicts the structure of Coenzyme Q10, and its synthetic analogs, Coenzyme QI and Coenzyme Q2.

[0022] FIGs. 2-5 relate to the anesthetic properties of Coenzyme Q2.FIG. 2 depicts the dose-dependent loss of righting reflex (LORR) caused by administration of Coenzyme Q2. Subsequent regression analysis yielded n = 35.FIG. 3 depicts the latency to the return of righting reflex (RORR) after administration of Coenzyme Q2. Subsequent regression analysis yielded n = 7.FIG. 4 depicts the latency of LORR after administration of Coenzyme Q2. Subsequent regression analysis yielded n = 7.FIG. 5 depicts a representative electroencephalogram (EEG) trace during LORR and RORR in a mouse injected with 200 mg / kg Coenzyme Q2.

[0023] FIGs. 6-9 relate to the ability of Coenzyme Q2 to induce excessive and uncompensated proton leak.FIG. 6 depicts Complex I-dependent oxygen (O2) consumption in isolated forebrain mitochondria exposed to 100 pM Coenzyme Q2. EtOH served as a vehicle control.Abbreviations: Oligomycin: Oligo; dinitrophenol: DNP.FIG. 7 depicts Complex Il-dependent oxygen (O2) consumption in isolated forebrain mitochondria exposed to 100 pM Coenzyme Q2. EtOH served as a vehicle control.Abbreviations: Oligomycin: Oligo; dinitrophenol: DNP.FIG. 8 depicts simultaneous measurement of O2 consumption and mitochondrial membrane potential (A m) during leak respiration in isolated forebrain mitochondria (mito) exposed to 100 pM Coenzyme Q2. Representative traces of O2 consumption (solid line, top trace) with A'Pm (dashed line, bottom trace). Numbers are O2 consumption rates (nmol- min hmg mitochondrial protein1). ATm was measured following tetraphenylphosphonium ion (TPP+) calibration.FIG. 9 depicts steady-state ETC complex kinetic activities in unexposed isolated forebrain mitochondria or mitochondria exposed to Coenzyme Q2 or EtOH. First-order rate constants expressed as turnover number (TN) were determined for Complexes III and IV. Data means ± SD. For FIG 2A and FIG 2C n = 6. P values were calculated by one-way ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

[0024] FIG. 10 depicts the mechanism by which Coenzyme Q2 compromises the mitochondrial membrane potential. Coenzyme Q2 induces excessive proton leak and simultaneously inhibits Complexes I and IV within the ETC. The combined effects dissipateATm while preventing a compensatory increase in substrate oxidation to restore or maintain the proton motive force.

[0025] FIGs. 11-15 relate to the source of Coenzyme Q2-induced proton leak. Oxygen consumption and mitochondrial membrane potential (A'Pm) were simultaneously measured during leak respiration in isolated forebrain mitochondria exposed to CoQ2 (100 pM). Various inhibitors were used to determine the source of leak. Representative traces of O2 consumption (dotted line, top trace) with A'Pm (dashed line, bottom trace) in mitochondria (mito) after exposure to the inhibitor. Numbers are O2 consumption rates (nmol- min1- mg mitochondrial protein1). A'Pm was measured following tetraphenylphosphonium ion (TPP+) calibration. Data are means ± SD. N = 3-6 per group. P values were calculated by paired Student’s t-test. *p <0.05, **p < 0.01.FIG. 11 depicts representative traces in uninhibited mitochondria from Aralar+ / +or Aralar / _mouse forebrain.FIG. 12 depicts mitochondria exposed to pyridoxal 5'-phophate (PLP).FIG. 13 depicts mitochondria exposed to hydroxy mercuribenzoate (p-HMB). Inhibition of leak was identified in FIG. 13 as a decrease in O2 consumption with a concomitant increase in A'Pm (dashed line, bottom trace depicts recovery to baseline after several minutes).FIG. 14 depicts mitochondria exposed to equal volume vehicle.FIG. 15 depicts AO2 consumption and Amembrane potential during CoQ2 leak, which were quantified following the addition of p-HMB or vehicle.

[0026] FIGs. 16-18 relate to the effect of specific inhibitors on coenzyme Q2-induced proton leak. Oxygen (O2) consumption and mitochondrial membrane potential (A'Pm) were simultaneously measured during leak respiration in isolated forebrain mitochondria (mito) exposed to CoQ2 (100 pM). Carboxyatractyloside (cAT); cyclosporine (CsA); and guanosine diphosphate (GDP) were added to specifically inhibit the adenine nucleotide translocase, the mitochondrial permeability transition pore, and uncoupling proteins. Representative traces of O2 consumption (top trace) with A'Pm (bottom trace) are depicted. Numbers are O2 consumption rates (nmol- min1- mg mitochondrial protein1). A'Pm was measured following tetraphenylphosphonium ion (TPP+) calibration, n = 3-5 biological replicates from 3-5 different mice.FIG. 16 depicts mitochondria exposed to Carboxyatractyloside (cAT).FIG. 17 depicts mitochondria exposed to cyclosporine (CsA).FIG. 18 depicts mitochondria exposed to guanosine diphosphate (GDP).

[0027] FIG. 19 depicts real-time arterial blood pressure measurements for rabbits injected intravenously with Coenzyme QI (CoQi) (top) or Coenzyme Q2 (CoQ2) (bottom). Oscillations are the result of respiratory variation due to mechanical ventilation.DETAILED DESCRIPTION

[0028] Disclosed herein are pharmaceutical compositions comprising CoQ2, methods of using said compositions, and method of making said compositions.General Definitions

[0029] The term “herein” means the entire application.

[0030] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skilled in the art to which this disclosure belongs. Generally, nomenclature used in connection with the compounds, compositions and methods described herein are those well-known and commonly used in the art.

[0031] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples) can be combined with one or more other embodiments of the disclosure, unless explicitly disclaimed or improper. Combination of embodiments are not limited to those specific combinations claimed via the multiple dependent claims. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and element(s) can be removed from the group.

[0032] Throughout this specification, the word “comprise,” or variations such as “comprises” or “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” will be understood to imply the inclusion of a stated integer (or component or element) or group of integers (or components or elements), but not the exclusion of any other integer (or component or element) or group of integers (or components or elements).

[0033] The term “including,” as used herein, means “including but not limited to,” “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (or component, element, or method) or group of integers (or components or elements), but not the exclusion of any other integer (or component or element) or group of integers (or components or elements).

[0034] The use of terms “a” and “an" and “the” and similar referents in the context of describing elements (especially in the context of the following claims) are to be constmed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0035] The tern “or" as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise.

[0036] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and including the endpoints, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0037] Throughout the specification, where compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated that the compositions also may consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific steps, the methods or processes also may consist essentially of, or consist of, the recited specific steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable.Moreover, two more steps or actions can be conducted simultaneously.

[0038] The use of any and all examples, or exemplary language (“such as,” “for example,” “e.g. ” etc.) herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No Language in the specification should be construed as indicating non-claimed element as essential.

[0039] All of the publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skilled in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.Chemical Definitions

[0040] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the01001 / 012990-WQ0 Elements, CAS version, Handbook of Chemistry and Physics, 75"' Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry’, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0041] Coenzyme Q2 is a member of the family of ubiquinones. All ubiquinones analogs share an identical 1 ,4-benzoquinone head, but differ in the length of their isoprenoid tail.Coenzyme Q10 (i.e., ubiquinone) comprises ten isoprene units. Likewise, Coenzyme QI (i.e., CoQi) comprises a single isoprene unit, Coenzyme Q2 i.e., CoQ2) comprises two isoprene units, CoQ3 comprises three isoprene, CoQ4 comprises four isoprene units, etc. Coenzyme Q2(i.e., CoQ2) is a compound having the structureChemical names for CoQ2 include 2,3-dimethoxy-5-methyl-6-geranyl-l,4-benzoquinone and (E)-2-(3,7-dimethylocta-2,6-dien-l-yl)-5,6-dimethoxy-3-methylcyclohexa-2,5-diene-l, 4-dione.

[0042] Coenzyme QI (i.e., CoQi) is a compound having the structure of. Certain compositions comprising CoQi and methods of use thereof are described in WO2022192633A1, which is incorporated herein by reference in its entirety.

[0043] Biologically derived Coenzyme Q compounds are lipid soluble components of cell membranes. They perform multiple functions such as electron and proton transport. Coenzyme Q10 (CoQlO) is a component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. Crane, F.L. Biochemical functions of coenzyme Q10. J. Am. Coll. Nutr. 2001, 20(6), 591-598.

[0044] Ubiquinone analogs, including CoQ2, impact mitochondrial permeability transition pore (PTP) formation, as well as PTP-dependent cell death, in an analog- and cell-specific manner. Devun et al. Ubiquinone analogs: A mitochondrial permeability transition poredependent pathway to selective cell death. PLoS One 2010, 5(7).

[0045] Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like.

[0046] Compounds described herein may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids, which include aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0047] The term “pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.Other Definitions

[0048] 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 present disclosure, and is relatively non-toxic, i.e., the material may be administeredto an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0049] The term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

[0050] A “pharmaceutically acceptable carrier” refers to compositions, carriers, diluents, and reagents which are pharmaceutically acceptable materials that are capable of administration to or upon a subject. A pharmaceutically acceptable carrier can be involved with carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. The carrier can be in the form of a solid, semi-solid or liquid diluent, cream, or a capsule. The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts for use in the methods described herein. Suitable excipients include water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.

[0051] The terms "effective amount," "pharmaceutically effective amount," “or therapeutically effective amount” refer to the amount and / or dosage, and / or dosage regime of one or more compounds necessary to bring about the desired result e.g., an amount sufficient to effect anesthesia, render the subject unconscious and / or immobilize the subject. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0052] The terms "patient," "individual," "subject" interchangeably refer to any mammal, e.g., a human or non-human mammal, e.g., a non-human primate, a domesticated mammal (e.g., canine, feline), an agricultural mammal (e.g., equine, bovine, ovine, porcine), or a laboratory mammal (e.g., rattus, murine, lagomorpha, hamster).

[0053] The phrases “administering,” “administration of, "cause to be administered" refer to the actions taken by a medical professional (e.g., a physician), or a person controlling medical care of a subject, that control and / or permit 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.

[0054] A compound or agent can be administered intravenously (i.v.), arterially, intradermally, intramuscularly, intraperitoneally (i.p.), subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). Administration can be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0055] The phrase “treated or administered in combination” as used herein for the combined therapeutic use or administration of CoQ2 means that in addition to at least one other agent, at least one dose of CoQ2 is given within a time frame. CoQ2 may be administered concomitantly or sequentially. This phrase includes treatments in which CoQ2 is administered either by the same route or different routes of administration.

[0056] As used herein the term “initial dose” is synonymous to the term “loading dose” and is defined as the first dose of a drug given in the context of a medical sedative treatment.

[0057] The term “fixed dose” as used in the present disclosure relates to an amount of a drug given to a patient irrespective of his body weight.

[0058] ‘Anesthesia” refers to a medical procedure that uses drugs to prevent pain and discomfort during surgical and medical procedures. Through actions on nerves in the brain or spinal cord, an anesthetic or sedative can either render a subject insensible to painful stimuli, or decrease a subject’s perceived sensations or awareness, or induce within a subject an amnestic and / or calming effect.

[0059] The term “general anesthesia” refers to a drug-induced loss of consciousness (LoC) during which the patient is not arousable, even to painful stimuli.

[0060] In the description that follows, the term "inhalational anesthetic" refers to gases or vapors that possess anesthetic qualities that are administered by breathing through an anesthesia mask or ET tube connected to an anesthetic machine. Exemplary inhalational anesthetics include, without limitation, volatile anesthetics (halothane, isoflurane, sevoflurane and desflurane) and the gases (ethylene, nitrous oxide and xenon).

[0061] The term "injectable anesthetic or sedative drug" refers to anesthetics or sedatives that can be injected, e.g., under the skin, into a vein, etc. The injection may be via a hypodermic needle and syringe.

[0062] The term “sedation” refers to a relaxed, calm state of the body and mind which is induced pharmacologically, e.g., by the use of sedatives. Furthermore, as defined herein, the term sedation includes also deep sedation, preoperative sedation, anxiolysis, and amnestic use for perioperative events, conscious sedation during short diagnostic, operative or endoscopicprocedures, and sedation prior and / or concomitant to the administration of other anesthetic or analgesic agents.

[0063] The term “minimal sedation” or “mild sedation” refers to a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are unaffected. Minimal sedation is also known as anxiolysis.

[0064] The term “moderate sedation” (synonymously with conscious sedation) refers to a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No interventions are necessary to maintain a patent airway. During moderate sedation spontaneous ventilation is adequate and the cardiovascular function is usually maintained.

[0065] The term “deep sedation” refers to a drug-induced depression of consciousness during which the patient cannot be easily aroused but responds purposefully following repeated or painful stimulation. Independent ventilatory function may be impaired. The patient may require assistance to maintain a patent airway. During deep sedation the spontaneous ventilation may be inadequate and cardiovascular function is usually maintained.

[0066] The term “procedural sedation” refers to a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardio-respiratory function. Procedural sedation and analgesia is intended to result in a depressed level of consciousness that allows the patient to maintain oxygenation and airway control independently.

[0067] The term “analgesia” as used herein refers to the pharmacologically induced absence or deadening of the sense of pain, e.g., by the use of analgesics, such as opioids.

[0068] The term “opioid” which is synonymous to the term “opioid drug” as used herein refers to compounds which have the same mode of action as the constituents of opium, the dried milky liquid of the poppy seed, Papaver somniferum.

[0069] The term “analgosedation” refers to a pharmacologically induced analgesia with concurrent sedation. Dependent on the dose of the sedative and / or the analgesic drug the analgosedation can, intentionally or not, reach the state of general anesthesia.

[0070] For assessment of the various states of sedation and analgosedation the so-called Modified Observer's Assessment of Alertness and Sedation scale (MOAA / S) (Nonaka, Takashi et. al., 2018, Can sedation using a combination of propofol and dexmedetomidine enhance the satisfaction of the endoscopist in endoscopic submucosal dissection? Endoscopy International Open. 06. E3-E10. 10.1055 / s-0043-122228) and, alternatively, the Ramsey Scale (Rasheed AM, et. al, A. Ramsay Sedation Scale and Richmond Agitation Sedation Scale: A Cross-01001 / 012990-WQ0 sectional Study. Dimens Crit Care Nurs. 2019 Mar / Apr;38(2):90-95, doi:10.10977DCC.0000000000000346. PMID: 30702478) often are used. These scales are as follows:

[0071] Table 1.Modified Observer’s Assessment of Alertness / Sedation Scale Responsiveness Score Agitated 6 Responds readily to name spoken in normal tone (alert) 5 Lethargic response to name spoken in normal tone 4 Responds only after name is called loudly and / or repeatedly 3 Responds only after mild prodding or shaking 2Does not respond to mild prodding or shaking 1Does not respond to deep stimulus 0

[0072] Table 2.Ramsey Sedation ScaleResponsiveness ScorePatient is anxious and agitated or restless, or both 1Patient is cooperative, oriented and tranquil 2Patient responds to commands only 3Patient exhibits brisk respond to light glabellar tap orloud auditory stimulus 4Patient exhibits a sluggish respond to light glabellartap or loud auditory stimulus 5Patient exhibits no response 6

[0073] The term “amnestic use” as used herein relates to the induction of amnesia, which represents the partial or total loss of memory.

[0074] The term "molar water solubility" refers to the calculated or measured number of moles per liter of a compound present at a saturated concentration in pure water at 25° C. and at pH=7.0.

[0075] The term “intensive care unit” (“ICU”) encompasses any setting that provides intensive care.

[0076] The term “operative procedure” as used herein refers to all kind of medical intervention into the living body, either invasive or non-invasive, for diagnostic and / or therapeutic purposes. Medical intervention in particular comprises medical treatments which, on a regular basis, are expected to cause post-operative pain for the patient. As a synonymous term for “operative procedure” the term “surgery” is also used herein.

[0077] Manual or mechanical ventilation is defined as external assistance in breathing by manual or mechanical methods such as e.g., mask ventilation, or intubation.Pharmaceutical Compositions

[0078] In one aspect, the disclosure provides a pharmaceutical composition comprisingCoQ2 (z.e., a compound having the structurepharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0079] In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of CoQ2 i.e., a compound having the structure of

[0080] In some embodiments, the pharmaceutical composition of the disclosure is designed for administration by a route selected from the group consisting of intravenous, inhalational, subcutaneous, intramuscular, transdermal, and parenteral administration. In some embodiments, the pharmaceutical composition is designed to be administered parenterally. In some embodiments, the pharmaceutical composition is sterile.

[0081] In one embodiment, the pharmaceutically acceptable carrier is a parenteral, oral or topical carrier. In some embodiments, the pharmaceutically acceptable carrier is an oral carrier. In some embodiments, the pharmaceutically acceptable carrier is a topical carrier. In some embodiments, the pharmaceutically acceptable carrier is a parenteral carrier. In some embodiments, the pharmaceutically acceptable carrier is an oil-in-water emulsion.

[0082] Water-immiscible solvents suitable for the preparation of oil-in-water emulsions suitable for parenteral administration are known to those skilled in the pharmaceutical arts Handbook of Pharmaceutical Excipients Wade and Weller, Eds. ( 1994), AmericanPharmaceutical Association, The Pharmaceutical Press: London, pp 451-453). Suitable water-immiscible solvents include vegetable oils, for example, soybean oil, safflower oil, cottonseed oil, com oil, sunflower oil, arachis oil, castor oil or a combination of any of the foregoing. The water-immiscible solvent can also be a mono-, di-, and triglycerides, fatty acid esters, or chemically modified vegetable oils, physically modified vegetable oils or a combination of any of the foregoing. In some embodiments, the pharmaceutical composition comprises a combination of water-immiscible solvents. In some embodiments, the pharmaceutical composition comprises up to 30% (w / w) of the water-insoluble solvent. In some embodiments, the pharmaceutical composition comprises 5% to 25% (w / w) of the water-insoluble solvent. In some embodiments, the pharmaceutical composition comprises about 5% to about 25% (w / w) of the water-insoluble solvent. In some embodiments, the pharmaceutical composition comprises 10% to 20% (w / w) of the water-insoluble solvent. In some embodiments, the pharmaceutical composition comprises about 10% to about 20% (w / w) of the water-insoluble solvent. In some embodiments, the pharmaceutical composition comprises 10% (w / w) of the water-insoluble solvent. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) of the water-insoluble solvent.

[0083] In some embodiments, the oil-in-water emulsion is a total-parenteral-nutrition formulation. In some embodiments, the total-parenteral-nutrition formulation comprises a concentrated caloric content. In some embodiments, the total-parenteral-nutrition formulation comprises other nutrients, for example, amino acids, vitamins, and minerals. In some embodiments, the total -parenteral-nutrition formulation is INTRALIPID® (trademark Pharmacia), LIPOFUNDINO® (trademark Braun), and TRA V AMULSION® (trademark Baxter).

[0084] In some embodiments, the pharmaceutical composition of the present disclosure comprises a pharmaceutically acceptable surfactant. In some embodiments, the pharmaceutically acceptable surfactant aids in the emulsification of the water-immiscible phase in water. In some embodiments, the pharmaceutically acceptable surfactant stabilizes the emulsion. Suitable surfactants include, but are not limited to, naturally occurring surfactants, such as egg or soy phosphatides, either in a native or modified forms; non-ionic surfactants, such as a polyethylene glycol or esters thereof, NP-40, or Triton X-100; or a mixture of any of the foregoing. In some embodiments, the surfactant is egg-yolk phospholipid. The amount of surfactant effective in producing and maintaining a stable oil-in-water emulsion will depend on the particular formulation. The factors and their relationships are well known to skilled practitioners in the pharmaceutical arts. These factors include the presence or absence of a01001 / 012990-WQ0 water-immiscible solvent, the particular water-immiscible solvent used, the particular surfactant employed, the presence of salts, and the pH of the composition.

[0085] In some embodiments, CoQ2 is dissolved in a pharmaceutically acceptable water-immiscible solvent and emulsified in water. In certain embodiments, the emulsion is stabilized by means of a surfactant. In yet other embodiments, the CoQ2 may itself be emulsified in water without addition of a water-immiscible solvent, wherein the emulsion stabilized by means of a surfactant.

[0086] In certain embodiments, the pharmaceutical composition of the present disclosure is formulated with a pH in the range of 5.0 to 8.0. In certain embodiments, the pharmaceutical composition of the present disclosure is formulated with a pH in the range of about 5.0 to about 8.0. The pH may be adjusted as required by means of addition of a base, e.g., sodium hydroxide, or an acid, e.g., hydrochloric acid.

[0087] In some embodiments, the pharmaceutical composition of the present disclosure comprises a tonicity modifier. In some embodiments, the tonicity modifier is glycerin, dextrose, mannitol, or sodium chloride. In some embodiments, the pharmaceutical composition is isotonic with blood.

[0088] In some embodiments, the pharmaceutical composition of the present disclosure comprises an excipient selected from the group consisting of amino acids, vitamins, and minerals, or a combination of any of the foregoing.

[0089] In some embodiments, the pharmaceutical composition of the present disclosure is a sterile aqueous formulation and is prepared by standard manufacturing techniques using, for example, aseptic manufacturing methods and sterilization by autoclaving.

[0090] In some embodiments, the pharmaceutical composition of the present disclosure comprises ascorbic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of ascorbic acid is selected from the group consisting of sodium ascorbate, potassium ascorbate, calcium ascorbate, and magnesium ascorbate, or a combination thereof.

[0091] In some embodiments, the pharmaceutical composition comprises from 0.05 % (w / wj to 0.1 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises from 0.05 % (w / w) to 0.2 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 0.05 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises 0.1 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical composition comprises 0.2 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the pharmaceutical composition comprises from about 0.05 % (w / w) to about 0.1 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises from about 0.05 % (w / w) to about 0.2 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.05 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.1 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.2 % (w / w) ascorbic acid or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the pharmaceutical composition comprises 0.01% (w / v) to 5% (w / v) of CoQ2. In some embodiments, the pharmaceutical composition comprises 0.05% (w / v) to 2% (w / v) of CoQ2. In some embodiments, the pharmaceutical composition comprises about 0.01% (w / v) to about 5% (w / v) of CoQ2. In some embodiments, the pharmaceutical composition comprises 0.05% (w / v) and about 2% (w / v) of CoQ2.

[0094] In some embodiments, the pharmaceutical composition comprises 2 % (w / v) CoQ2; 5 % (v / v) ethanol; 95 % (v / v) intralipid. In some embodiments, the pharmaceutical composition comprises about 2 % (w / v) CoQ2; about 5 % (v / v) ethanol; about 95 % (v / v) intralipid. In some embodiments, the intralipid comprises 20 % soybean oil (v / v); 2.25% (v / v) glycerin; 1.2 % (v / v) egg-yolk phospholipid; and 76.55 % (v / v) water. In some embodiments, the intralipid comprises about 20 % soybean oil; about 2.25% (v / v) glycerin; about 1.2 % (v / v) egg-yolk phospholipid; and about 76.55 % (v / v) water. In some embodiments, the pharmaceutical composition comprises 2 % (w / v) CoQ2, 5 % (v / v) ethanol, 19 % (v / v) soybean oil, 2.1375 % (v / v) glycerin, 1.14 % (v / v) egg-yolk phospholipid, and 72.7225 % (v / v) water. In some embodiments, the pharmaceutical composition comprises about 2 % (w / v) CoQ2, about 5 % (v / v) ethanol, about 19 % (v / v) soybean oil, about 2.1375 % (v / v) glycerin, about 1.14 % (v / v) egg-yolk phospholipid, and about 72.7225 % (v / v) water.Methods of Inducing Anesthesia

[0095] The pharmaceutical compositions of the present disclosure are useful as anesthetics in, for example, inducing sedation, and for the induction and maintenance of general anesthesia. Thus, in another aspect, the present disclosure provides a method for inducing anesthesia or sedation in a subject in need thereof, the method comprising administering to the subject a01001 / 012990-WQ0 therapeutically effective amount of CoQ2 (i.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human.

[0096] In one aspect, the present disclosure provides CoQ2 (z.e., a compound having thestructurepharmaceutical composition thereof, for use in inducing anesthesia or sedation in a subject in need thereof.

[0097] In one aspect, the present disclosure provides CoQ2 (z.e., a compound having thestructureuse in the manufacture of a medicament for inducing anesthesia or sedation in a subject in need thereof.

[0098] In some embodiments, the present disclosure provides a method of inducing anesthesia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of CoQ2 (z.e., a compound having the structure of""pharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is an oil-in-water emulsion. In some embodiments, the oil-in-water emulsion is sterile.

[0099] In some embodiments, the present disclosure provides CoQ2 (z.<?., a compoundhaving the structurepharmaceutical composition thereof, for use in inducing anesthesia in a subject in need thereof.

[0100] In some embodiments, the present disclosure provides CoQ2 (z.e., a compoundhaving the stmctureuse in the manufacture of a medicament for inducing anesthesia in a subject in need thereof.

[0101] In some embodiments, the present disclosure provides a method of inducing anesthesia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of CoQ2 i.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is a sterile oil-in-water emulsion.

[0102] In some embodiments, the subject is a mammal. In some embodiments, the mammal is selected from the group consisting of a dog, a cat, a cow, and a horse. In some embodiments, the subject is a human.

[0103] In some embodiments, the present disclosure provides a method of inducing sedation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of CoQ2 (i.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is an oil-in-water emulsion. In some embodiments, the oil-in-water emulsion is sterile.

[0104] In some embodiments, the present disclosure provides CoQ2 (i.e., a compoundhaving the structurepharmaceutical composition thereof, for use in inducing sedation in a subject in need thereof.

[0105] In some embodiments, the present disclosure provides CoQ2 (z.e., a compoundhaving the structureuse in the manufacture of a medicament for inducing sedation in a subject in need thereof.

[0106] Dosage levels appropriate for the induction of desired degree of anesthesia, for example sedation, or induction of or maintenance of general anesthesia, by the pharmaceutical compositions of the present disclosure will depend on the type of mammal under treatment and the physical characteristics of the specific mammal under consideration. These factors and their relationship in determining this amount are well known to skilled practitioners in the medical arts. Approximate dosage levels may be derived from the literature, may be tailored to achieve optimal efficiency, and will be contingent on myriad factors recognized by those skilled in the medical arts including weight, diet, and concurrent medication.

[0107] In some embodiments, the pharmaceutical composition may be administered as a single bolus or a continuous infusion.

[0108] In some embodiments, the single bolus injection of the pharmaceutical composition can be in an amount dependent on the body mass of the subject. In some embodiments, CoQ2(i.e., a compound having the structureadministered at a dose of 5 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 50 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 20 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 50 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 20 mg / kg.

[0109] In some embodiments, CoQ2 is administered at a dose of 20 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 50 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 50 mg / kg.

[0110] In some embodiments, CoQ2 is administered at a dose of 50 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 75 mg / kg.

[0111] In some embodiments, CoQ2 is administered at a dose of 75 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 75 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 75 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 75 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 -about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 - about 100 mg / kg.

[0112] In some embodiments, CoQ2 is administered at a dose of 100 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 100 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 100 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 150 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 150 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 90 - 110 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 100 mg / kg. In some embodiments, CoQ2 is administered at a doseof about 100 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 -about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 150 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 150 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 90 - about 110 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 100 mg / kg.

[0113] In some embodiments, the single bolus injection of the pharmaceutical composition can be in an amount not dependent on the body mass of the subject. In some embodiments, the single bolus injection of the composition in an amount not dependent on the body mass of the subject. In some embodiments, CoQ2 (i.e., a compound having the structure ofadministered at a dose of 0.4 - 35000 mg. In some embodiments, CoQ2 is administered at a dose of 0.4 - 14000 mg. In some embodiments, CoQ2 is administered at a dose of 0.4 - 7000 mg. In some embodiments, CoQ2 is administered at a dose of 0.4 - 3500 mg. In some embodiments, CoQ2 is administered at a dose of 0.4 - 10 mg. In some embodiments, CoQ2 is administered at a dose of 0.4 - 1 mg. In some embodiments, CoQ2 is administered at a dose of about 0.4 - about 35000 mg. In some embodiments, CoQ2 is administered at a dose of about 0.4 - about 14000 mg. In some embodiments, CoQ2 is administered at a dose of about 0.4 - about 7000 mg. In some embodiments, CoQ2 is administered at a dose of about 0.4 - about 3500 mg. In some embodiments, CoQ2 is administered at a dose of about 0.4 - about 10 mg. In some embodiments, CoQ2 is administered at a dose of about 0.4 - about 1 mg.

[0114] In some embodiments, CoQ2 is administered at a dose of 1 - 35000 mg. In some embodiments, CoQ2 is administered at a dose of 1 - 14000 mg. In some embodiments, CoQ2 is administered at a dose of 1 - 7000 mg. In some embodiments, CoQ2 is administered at a dose of 1 - 3500 mg. In some embodiments, CoQ2 is administered at a dose of 1 - 10 mg. In some embodiments, CoQ2 is administered at a dose of about 1 - about 35000 mg. In some embodiments, CoQ2 is administered at a dose of about 1 - about 14000 mg. In some embodiments, CoQ2 is administered at a dose of about 1 - about 7000 mg. In some embodiments, CoQ2 is administered at a dose of about 1 - about 3500 mg. In some embodiments, CoQ2 is administered at a dose of about 1 - about 10 mg.

[0115] In some embodiments, CoQ2 is administered at a dose of 10 - 35000 mg. In some embodiments, CoQ2 is administered at a dose of 10 - 14000 mg. In some embodiments, CoQ2 is administered at a dose of 10 - 7000 mg. In some embodiments, CoQ2 is administered at a dose of 10 - 3500 mg. In some embodiments, CoQ2 is administered at a dose of 3500 - 35000 mg. In some embodiments, CoQ2 is administered at a dose of 3500 - 14000 mg. In some embodiments, CoQ2 is administered at a dose of 3500 - 7000 mg. In some embodiments, CoQ2 is administered at a dose of 7000 - 35000 mg. In some embodiments, CoQ2 is administered at a dose of 7000 - 14000 mg. In some embodiments, CoQ2 is administered at a dose of 14000 -35000 mg. In some embodiments, CoQ2 is administered at a dose of about 10 - about 35000 mg. In some embodiments, CoQ2 is administered at a dose of about 10 - about 14000 mg. In some embodiments, CoQ2 is administered at a dose of about 10 - about 7000 mg. In some embodiments, CoQ2 is administered at a dose of about 10 - about 3500 mg. In some embodiments, CoQ2 is administered at a dose of about 3500 - about 35000 mg. In some embodiments, CoQ2 is administered at a dose of about 3500 - about 14000 mg. In some embodiments, CoQ2 is administered at a dose of about 3500 - about 7000 mg. In some embodiments, CoQ2 is administered at a dose of about 7000 - about 35000 mg. In some embodiments, CoQ2 is administered at a dose of 7000 - about 14000 mg. In some embodiments, CoQ2 is administered at a dose of about 14000 - about 35000 mg.

[0116] In some embodiments, the method of administration is by one bolus injections. In some embodiments, the method of administration is by more than one bolus injections. In some embodiments, the method of administration is by 2 to 10 bolus injections. In some embodiments, the method of administration is by two bolus injections. In some embodiments, the method of administration is by three bolus injections. In some embodiments, the method of administration is by four bolus injections. In some embodiments, the method of administration is by five bolus injections. In some embodiments, the method of administration is by six bolus injections. In some embodiments, the method of administration is by seven bolus injections. In some embodiments, the method of administration is by eight bolus injections. In some embodiments, the method of administration is by nine bolus injections. In some embodiments, the method of administration is by ten bolus injections.

[0117] In some embodiments, the method of administration is by continuous infusion. In some embodiments, CoQ2 (i.e., a compound having the structure ofmg / kg / hr. In some embodiments, CoQ2 is administered at a rate of 1 mg / kg / hr to 100 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of 1 mg / kg / hr to 50 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of about 1 mg / kg / hr to about 50 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of 1 mg / kg / hr to 25 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of about 1 mg / kg / hr to about 25 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of 25 mg / kg / hr to 100 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of about 25 mg / kg / hr to about 100 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of 25 mg / kg / hr to 50 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of about 25 mg / kg / hr to about 50 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of 50 mg / kg / hr to 100 mg / kg / hr. In some embodiments, CoQ2 is administered at a rate of about 50 mg / kg / hr to about 100 mg / kg / hr.

[0118] In some embodiments, CoQ2 (i.e., a compound having the structure ofadministered at a dose sufficient to achieve a desired clinical anesthetic endpoint. In some embodiments, the clinical anesthetic endpoint can be achieved when there is general anesthesia, insensitivity to noxious stimulation, immobility, amnesia, analgesia, unconsciousness, sedation, and / or autonomic quiescence. In some embodiments, the desired clinical anesthetic endpoint is selected from the group consisting of general anesthesia, mild sedation, moderate sedation, tranquilization, immobility, amnesia, analgesia, deep sedation, and autonomic quiescence. In some embodiments, the desired clinical anesthetic endpoint is general anesthesia. In some embodiments, the desired clinical anesthetic endpoint is mild sedation. In some embodiments, the desired clinical anesthetic endpoint is moderate sedation. In some embodiments, the desired clinical anesthetic endpoint is deep sedation. In some embodiments, the desired clinical anesthetic endpoint is tranquilization.

[0119] In some embodiments, CoQ2 is administered at a dose of 5 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 50 mg / kg. In some embodiments, CoQ2 is administered at a dose of 5 - 20 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 100mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 50 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 5 - about 20 mg / kg.

[0120] In some embodiments, CoQ2 is administered at a dose of 20 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of 20 - 50 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 20 - about 50 mg / kg.

[0121] In some embodiments, CoQ2 is administered at a dose of 50 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50- 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of 50 - 75 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 50- about 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about50 - about 75 mg / kg.

[0122] In some embodiments, CoQ2 is administered at a dose of 75 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 75 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 75 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 75 - 100 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 -about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 75 - about 100 mg / kg.

[0123] In some embodiments, CoQ2 is administered at a dose of 100 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 100 - 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of 100 - 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of 150 - 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of 150 - 200mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 - about 200 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 100 - about 150 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 150 - about 500 mg / kg. In some embodiments, CoQ2 is administered at a dose of about 150 - about 200 mg / kg.

[0124] In some embodiments, CoQ2 is administered at a dose of up to 200 mg / kg every 1 hour. In some embodiments, CoQ2 is administered at a dose of 80 to 200 mg / kg every 1 hour. In some embodiments, CoQ2 is administered at a dose of 20 to 200 mg / kg every 1 hour. In some embodiments, CoQ2 is administered at a dose of up to about 200 mg / kg every 1 hour. In some embodiments, CoQ2 is administered at a dose of about 80 to about 200 mg / kg every 1 hour. In some embodiments, CoQ2 is administered at a dose of about 20 to about 200 mg / kg every 1 hour.

[0125] In some embodiments, the pharmaceutical composition is administered by any route sufficient to achieve a desired anesthetic effect. In some embodiments, the pharmaceutical composition is administered by a route selected from the group consisting of perorally, transmucosally, intravenously, inhalationally, subcutaneously, intramuscularly, transdemially, and parenterally.

[0126] In some embodiments, the pharmaceutical composition is administered over a period of time. In some embodiments, the period of time ranges from about 0.1 hours to about 350 hours. In some embodiments, the period of time ranges from about 0.1 hours to about 48 hours. In some embodiments, the period of time ranges from about 0.1 hours to about 24 hours. In some embodiments, the period of time ranges from about 0.5 hours to about 350 hours. In some embodiments, the period of time ranges from about 0.5 hours to about 48 hours. In some embodiments, the period of time ranges from about 0.5 hours to about 24 hours. In some embodiments, the period of time ranges from about 1 hour to about 350 hours. In some embodiments, the period of time ranges from about 1 hour to about 48 hours. In some embodiments, the period of time ranges from about 1 hour to about 24 hours. In some embodiments, the period of time ranges from about 2 hours to about 350 hours. In some embodiments, the period of time ranges from about 2 hours to about 48 hours. In some embodiments, the period of time ranges from about 2 hours to about 24 hours. In some embodiments, the period of time ranges from about 3 hours to about 350 hours. In some embodiments, the period of time ranges from about 3 hours to about 48 hours. In some embodiments, the period of time ranges from about 3 hours to about 24 hours. In some embodiments, the period of time ranges from about 6 hours to about 350 hours. In some embodiments, the period of time ranges from about 6 hours to 48 hours. In some embodiments.the period of time ranges from about 6 hours to about 24 hours. In some embodiments, the period of time ranges from about 12 hours to about 350 hours. In some embodiments, the period of time ranges from about 12 hours to about 48 hours. In some embodiments, the period of time ranges from about 24 hours to about 350 hours. In some embodiments, the period of time ranges from 0.1 hours to 350 hours. In some embodiments, the period of time ranges from 0.1 hours to 48 hours. In some embodiments, the period of time ranges from 0.1 hours to 24 hours. In some embodiments, the period of time ranges from 0.5 hours to 350 hours. In some embodiments, the period of time ranges from 0.5 hours to 48 hours. In some embodiments, the period of time ranges from 0.5 hours to 24 hours. In some embodiments, the period of time ranges from 1 hour to 350 hours. In some embodiments, the period of time ranges from 1 hour to 48 hours. In some embodiments, the period of time ranges from 1 hour to 24 hours. In some embodiments, the period of time ranges from 2 hours to 350 hours. In some embodiments, the period of time ranges from 2 hours to 48 hours. In some embodiments, the period of time ranges from 2 hours to 24 hours. In some embodiments, the period of time ranges from 3 hours to 350 hours. In some embodiments, the period of time ranges from 3 hours to 48 hours. In some embodiments, the period of time ranges from 3 hours to 24 hours. In some embodiments, the period of time ranges from 6 hours to 350 hours. In some embodiments, the period of time ranges from 6 hours to 48 hours. In some embodiments, the period of time ranges from 6 hours to 24 hours. In some embodiments, the period of time ranges from 12 hours to 350 hours. In some embodiments, the period of time ranges from 12 hours to 48 hours. In some embodiments, the period of time ranges from 24 hours to 350 hours.

[0127] In some embodiments, the period of time ranges from about 0.1 hours to about 12 hours. In some embodiments, the period of time ranges from about 0.1 hours to about 6 hours. In some embodiments, the period of time ranges from about 0.1 hours to about 3 hours. In some embodiments, the period of time ranges from about 0.5 hours to about 12 hours. In some embodiments, the period of time ranges from about 0.5 hours to about 6 hours. In some embodiments, the period of time ranges from about 0.5 hours to about 3 hours. In some embodiments, the period of time ranges from about 1 hour to about 12 hours. In some embodiments, the period of time ranges from about 1 hour to about 6 hours. In some embodiments, the period of time ranges from about 1 hour to 3 hours. In some embodiments, the period of time ranges from about 2 hours to about 12 hours. In some embodiments, the period of time ranges from about 2 hours to about 6 hours. In some embodiments, the period of time ranges from about 2 hours to 3 hours. In some embodiments, the period of time ranges from about 3 hours to about 12 hours. In some embodiments, the period of time ranges from about 3hours to about 6 hours. In some embodiments, the period of time ranges from about 6 hours to about 12 hours. In some embodiments, the period of time ranges from about 12 hours to about 24 hours. In some embodiments, the period of time ranges from about 24 hours to about 8 hours. In some embodiments, the period of time ranges from 0.1 hours to 12 hours. In some embodiments, the period of time ranges from 0.1 hours to 6 hours. In some embodiments, the period of time ranges from 0.1 hours to 3 hours. In some embodiments, the period of time ranges from 0.5 hours to 12 hours. In some embodiments, the period of time ranges from 0.5 hours to 6 hours. In some embodiments, the period of time ranges from 0.5 hours to 3 hours. In some embodiments, the period of time ranges from 1 hour to 12 hours. In some embodiments, the period of time ranges from 1 hour to 6 hours. In some embodiments, the period of time ranges from 1 hour to 3 hours. In some embodiments, the period of time ranges from 2 hours to 12 hours. In some embodiments, the period of time ranges from 2 hours to 6 hours. In some embodiments, the period of time ranges from 2 hours to 3 hours. In some embodiments, the period of time ranges from 3 hours to 12 hours. In some embodiments, the period of time ranges from 3 hours to 6 hours. In some embodiments, the period of time ranges from 6 hours to 12 hours. In some embodiments, the period of time ranges from 12 hours to 24 hours. In some embodiments, the period of time ranges from 24 hours to 8 hours.

[0128] In some embodiments, the present disclosure provides a method of sedating a subject in need thereof prior to a medical procedure, during a medical procedure, or after a medical procedure, the method comprising administering to the subject a therapeutically effective amountof CoQ2 (i.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.

[0129] In some embodiments, the present disclosure provides a method of sedating a subject in need thereof, the method comprising administering to the subject a therapeutically effectiveamount of CoQ2 (z.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.

[0130] In some embodiments, the present disclosure provides a method of sedating a patient in the ICU, the method comprising administering to the patient a therapeutically effectiveamount of CoQ2 (i.e., a compound having the structurepharmacal composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier. In some embodiments, the patient is intubated. In some embodiments, the patient is not intubated.

[0131] In some embodiments, the present disclosure provides a method of sedating a patient experiencing seizures or withdrawal, the method comprising administering to the patient a therapeutically effective amount of CoQ2 (i.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.

[0132] In some embodiments, the present disclosure provides a method of sedating a combative patient that requires invasive monitoring, the method comprising administering to the patient a therapeutically effective amount of CoQ2 (i.e., a compound having the stmcture ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.

[0133] In some embodiments, the present disclosure provides a method of sedating a patient in the ICU, the method comprising administering to the patient a therapeutically effectiveamount of CoQ2 (i.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier, wherein the patient remains arousable and orientated. In some embodiments, the present disclosure provides a method of sedating a patient in the ICU, the method comprising administering to the patient a therapeutically effective amount of CoQ2(i.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier, wherein the patient is unarousable and not orientated. In some embodiments, the patient is unrousable due to illness. In some embodiments, the patient is unrousable due to an intentionally induced medical coma.

[0134] In some embodiments, the present disclosure provides a method of sedating a subject in need thereof, the method comprising administering to the subject a therapeutically effectiveamount of CoQ2 (z'.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier, wherein CoQ2 is used as a replacement for propofol.

[0135] In some embodiments, the present disclosure provides a method of sedating a subject in need thereof, the method comprising administering to the subject a therapeutically effectiveamount of CoQ2 (z.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier, in combination with an analgesic drug. In some embodiments, the analgesic drug is administered intravenously. In some embodiments, CoQ2, or a pharmaceutical composition thereof, and the analgesic will both be administered intravenously.

[0136] In some embodiments, the analgesic drug is an opioid drug. In some embodiments, the opioid drug is selected from the group consisting of: morphine, codeine, thebain, papaverin, narcotine, heroin, hydromorphone, dihydrocodeine, thebacon, hydrocodone, oxymorphone, oxycodone, ketobemidone, pethidine, anileridine, piminodine, phenoperidine, furethidine, [alpha] -prodin, trimeperidine, meptazinol, profadol, methadone, dextromoramide, levomethadyl acetate, phenadoxone, dipipanone, themalon, dextropropoxyphene, N-methylmorphinan, levorphanol, dextrometorphane, butorphanol, pentazocine, phenazocine, ketocyclazocine, bremazocine, sufentanil, carfentanil, fentanyl, lofentanil, alfentanil, ohmefentanil, remifentanil,01001 / 012990-WQ0 pitramide, benztriamide, diphenoxylate, loperamide, tramadol, tilidine, U-50488, 1 -benzyl -4-(4-bromo-phenyl)-4-dimethylamino-cyclohexanol; alfentanil, buprenorphine, butorphanol, codeine, dextromoramide, dextropropoxyphene, dezocine, diamorphine, dihydrocodeine, diphenoxylate, ethylmorphine, etorphine, hydrocodone, hydromorphone, ketobemidone, levomethadone, levomethadyl-acetate, levorphanol, meptazinol, morphine, nalbuphine, nalorphine, oxycodone, oxymorphone, pentazocine, pethidine, piritramide, remifentanil, sufentanil, tilidine, tramadol, tapentadol, met-enkephalin, leu-enkephalin, nociceptin, B-endorphin, endomorphin- 1, endomorphin-2, metorphamid, dynorphin-A, dynorphin-B, and a-neoendorphin.

[0137] In some embodiments, CoQ2 is administered as a fixed dose. In some embodiments, the opioid is administered at a fixed dose. In some embodiments, CoQ2 and the opioid are administered at a fixed dose. In some embodiments, the dose of CoQ2 is about 2 to about 1000 mg. In some embodiments, the dose of CoQ2 is about 3 mg to about 900 mg. In some embodiments, the dose of CoQ2 is about 5 to about 800 mg. In some embodiments, the dose of CoQ2 is about 10 mg. In some embodiments, the dose of CoQ2 is 2 to 1000 mg. In some embodiments, the dose of CoQ2 is 3 mg to 900 mg. In some embodiments, the dose of CoQ2 is 5 to 800 mg. In some embodiments, the dose of CoQ2 is 10 mg.

[0138] In some embodiments, the pharmaceutical composition comprising CoQ2 is administered as a single bolus injection, wherein the concentration of CoQ2 is about 1 mg / ml to about 20 mg / ml. In some embodiments, the pharmaceutical composition comprising CoQ2 is administered as a single bolus injection, wherein the concentration of CoQ2 is 1 mg / ml to 20 mg / ml.

[0139] In some embodiments, an additional top-up dose of CoQ2 is administered after the initial dose of CoQ2. In some embodiments, the top-up dose of CoQ2 is about 1.5 mg to about 14000 mg. In some embodiments, the top-up dose of CoQ2 is about 1.5 mg to about 1400 mg. In some embodiments, the top-up dose of CoQ2 is about 1.5 mg to about 3 mg. In some embodiments, the top-up dose of CoQ2 is about 3 mg to about 1400 mg. In some embodiments, the top-up dose of CoQ2 is about 1400 mg to about 14000 mg. In some embodiments, the top-up dose of CoQ2 is 1.5 mg to 14000 mg. In some embodiments, the top-up dose of CoQ2 is 1.5 mg to 1400 mg. In some embodiments, the top-up dose of CoQ2 is 1.5 mg to 3 mg. In some embodiments, the top-up dose of CoQ2 is 3 mg to 1400 mg. In some embodiments, the top-up dose of CoQ2 is 1400 mg to 14000 mg.

[0140] In some embodiments, initial dose is 8 mg and the top-up dose is 2 or 3 mg. In some embodiments, initial dose is 7 mg and the top-up dose is 2 or 3 mg. In some embodiments, initial dose is 5 mg and the top-up dose is 2 or 3 mg. In some embodiments, initial dose is 4 mgand the top-up dose is 2 or 3 mg. In some embodiments, initial dose is 3 mg and the top-up dose is 2 or 3 mg.

[0141] In some embodiments, initial dose is 8 mg and the top-up dose is 3 mg. In some embodiments, initial dose is 7 mg and the top-up dose is 2 mg. In some embodiments, initial dose is 5 mg and the top-up dose is 3 mg.

[0142] In some embodiments, the initial dose and the top-up doses will be selected to provide a maximum dose of 10 mg per treatment.

[0143] In some embodiments, the patient will receive an initial single intravenous dose of CoQ2 over about 1 minute. In some embodiments, CoQ2 top-up dose will be administered not less than 2 minutes after the initial dose. In some embodiments, a subsequent top-up dose is not administered less than 2 minutes after the previous top-up dose. In some embodiments, a subsequent top-up dose is administered within 3 - 4 minutes after the initial dose. In some embodiments, a subsequent top-up dose is administered within 3 -4 minutes after the previous top-up dose. In some embodiments, a maximum of 6 top-up doses of CoQ2 will be administered to the subject. In some embodiments, not more than 7 doses of CoQ2 are administered to the patient per treatment. In some embodiments, less than 3 top-up doses are administered. In some embodiments, less than 2 top-up doses are administered. In some embodiments, separate top-up doses can comprise an identical or a different amount of CoQ2.

[0144] In some embodiments, the dosing regimen will be adjusted in order to maintain a MOAA / S score of less than or equal to than 4. In some embodiments, the dosing regimen will be adjusted in order to maintain a MOAA / S score of 1 to 4. In some embodiments, the dosing regimen will be adjusted in order to maintain a MOAA / S score of 2 to 4. In some embodiments, the adjustment is performed by alteration of the top-up dose. In some embodiments, dose of the top-up dose is adjusted. In some embodiments, the time interval between top-up doses is adjusted. In some embodiments, the dose of the top-up dose and the time interval between top-up doses are adjusted.

[0145] In some embodiments, the time interval between the top-up doses will be adjusted to maintain the level of the MOAA / S score. For example, the time interval will be shortened in case that the patient exhibits reduced sedation and prolonged in case of increased sedation.

[0146] In some embodiments, the dosing regimen will be adjusted in order to induce and / or maintain a mild to moderate sedation. In some embodiments, the level of sedation is assessed by the MOAA / S score and categorized by the following scheme:

[0147] Table 3.Level of Sedation MOAA / S ScoreFully Alert 5Mild Sedation 4Moderate Sedation 2-3Deep Sedation 0-1Loss of Consciousness 0

[0148] In one embodiment the sedation profile of the subject will be characterized by an MOAA / S score that is less than 4 at 3 consecutive measurements. In one embodiment the sedation profile of the subject will be characterized by an MOAA / S score that is less than 3 at 3 consecutive measurements. In one embodiment the sedation profile of the subject will be characterized by an MOAA / S score that is less than 2 at 3 consecutive measurements. In one embodiment the sedation profile of the subject will be characterized by an MOAA / S score that is less than 1 at 3 consecutive measurements. In one embodiment the sedation profile of the subject will be characterized by an MOAA / S score that is between 0 and 1 at 3 consecutive measurements. In one embodiment the sedation profile of the subject will be characterized by an MOAA / S score that is 0 at 3 consecutive measurements. In some embodiments, the measurement is taken every minute. In some embodiments, the subject will not require a further sedative (e.g., a rescue sedative). In some embodiments, the subject will not require manual or mechanical ventilation. In some embodiments, a supplemental oxygen supply is provided to the subject.

[0149] In some embodiments, the present disclosure provides a method of sedating a subject in need thereof, the method comprising administering to the subject a therapeutically effectiveamount of CoQ2 (z.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier, in combination with an opioid drug. In some embodiments, the combination is administered prior to a medical procedure. In some embodiments, the procedure is an upper GI endoscopy. In some embodiments, the procedure is a colonoscopy. In some embodiments, the subject is 18 years or older. In some embodiments, the subject does not require mechanical or manual ventilation. In some embodiments, the subject requiresmechanical or manual ventilation. In some embodiments, the subject is provided supplemental oxygen supply.

[0150] In some embodiments, the pharmaceutical composition comprising CoQ2 is administered as an intravenous (IV) bolus application. In some embodiments, the pharmaceutical composition comprising CoQ2 is administered as an IV bolus in less than 1 minute. In some embodiments, the pharmaceutical composition comprising CoQ2 is administered as an IV bolus in less than 30 seconds. In some embodiments, the pharmaceutical composition comprising CoQ2 is administered as an IV bolus in approximately 15 seconds.

[0151] In some embodiments, one or more doses of an opioid will be administered to the subject prior to the administration of CoQ2 to the subject. In some embodiments, an opioid is administered before or together with an initial fixed dose of CoQ2. In some embodiments, the opioid is fentanyl. In some embodiments, 100 pg of fentanyl is administered immediately before or together with an initial fixed dose of CoQ2. In some embodiments, a short time interval between fentanyl dosing and CoQ2 results in a maximum analgesic coverage at the start of the diagnostic or therapeutic intervention.

[0152] In some embodiments, the fentanyl is administered about 10 minutes before administration of CoQ2. In some embodiments, the fentanyl is administered within at least 5 minutes prior to CoQ2 administration. In some embodiments, the fentanyl is administered within at least 3 minutes prior to CoQ2 administration. In some embodiments, the fentanyl is administered together with CoQ2.

[0153] In some embodiments, at least one top-up dose of fentanyl will is administered to the patient. In some embodiments, the top-up dose is 10 pg to 100 pg. In some embodiments, the top-up dose is 10 pg to 75 pg. In some embodiments, the top-up dose is 25 pg.In some embodiments, the time interval between the first fentanyl dose and a first top-up dose will be 2 to 10 minutes. In some embodiments, the time interval between a first top-up dose and a subsequent top-up dose will be 2 to 10 minutes.

[0154] In some embodiments, the pharmacological effects of the opioid will be reversed by a reversal agent. In some embodiments, the reversal agent is an opioid receptor antagonist. In some embodiments, opioid receptor antagonist is naloxone.

[0155] In some embodiments, the present disclosure provides a method of preoperative sedation, the method comprising administering to a subject in need thereof a therapeutically effective amount of CoQ2 (i.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.

[0156] In some embodiments, the present disclosure provides a method of amnestic use for perioperative events, the method comprising administering to a subject in need thereof a therapeutically effective amount of CoQ2 (z.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.

[0157] In some embodiments, the present disclosure provides a method of conscious sedation during short diagnostic, operative, or endoscopic procedures, the method comprising administering to a subject in need thereof a therapeutically effective amount of CoQ2 (i.e., acompound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier. In some embodiments, the procedure is limb resetting or wound dressing. In some embodiments, the procedure is analgosedation. In some embodiments, the use of CoQ2 is contraindicated for subjects with known hypersensitivity to benzodiazepines. In some embodiments, the use of CoQ2 is contraindicated for subjects with acute narrow-angle glaucoma. In some embodiments. CoQ2 may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy.

[0158] In some embodiments, the present disclosure provides a method of conducting a procedure involving sedation in a subject in need thereof, wherein the method comprises (a) administering intravenously to the subject one or more fixed doses of a therapeutically effectiveamount of CoQ2 (i.e., a compound having the structurepharmaceutical composition comprising a therapeutically effective amount of CoQ2 and apharmaceutically acceptable carrier, wherein the amount of CoQ2 is sufficient to sedate the subject to induce moderate anesthesia; and (b) passing an endoscope into the subject.

[0159] In some embodiments, pharmaceutical composition is administered as one or more fixed doses to the subject over a time period of one minute or less. In some embodiments, each fixed dose of the pharmaceutical composition administered to the subject will comprise about 2 mg to about 10 mg of the CoQ2. In some embodiments, each fixed dose of the pharmaceutical composition administered to the subject will comprise about 3 mg to about 10 mg of CoQ2. In some embodiments, each fixed dose of the pharmaceutical composition administered to the subject will comprise about 3 mg to about 9 mg of CoQ2. In some embodiments, each fixed dose of the pharmaceutical composition administered to the subject will comprise about 5 mg of CoQ2. In some embodiments, the one or more doses of the pharmaceutical composition will comprise an amount of CoQ2 necessary to achieve an MOAA / S score of less than or equal to 4 in the subject.

[0160] In some embodiments, the present disclosure provides a method of inducing hypnosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of CoQ2 (i.e., a compound having the structure ofpharmaceutical composition comprising a therapeutically effective amount of CoQ2 and a pharmaceutically acceptable carrier.Processes of Preparing Pharmaceutical Compositions

[0161] In one aspect, the present disclosure is directed to a process for preparing a pharmaceutical composition comprising CoQ2 (i.e., a compound having the structure ofsome embodiments, the process comprises: dispersing at least one surfactant in water; dissolving CoQ2 in at least one water-immiscible solvent to form a non-aqueous solution; and adding the non-aqueous solution to the surfactant dispersion to form a crude oil-in-water emulsion. In some embodiments, the process further comprises sterilizing the crude oil-in-water emulsion of CoQ2 to obtain a sterile oil-in-water emulsion of CoQ2.

[0162] In some embodiments, the surfactant can be selected from the group consisting of native egg phosphatide, modified egg phosphatide, native soy phosphatide, modified soy01001 / 012990-WQ0 phosphatide, polyethylene glycol, and polyethylene glycol, or a combination of any of the foregoing.

[0163] In some embodiments, the water-immiscible solvent is selected from the group consisting of soybean oil, safflower oil, cottonseed oil, com oil, sunflower oil, arachis oil, castor oil, monoglycerides, diglycerides, triglycerides, fatty acid esters, chemically modified vegetable oils, and physically modified vegetable oils, or a combination of any of the foregoing.

[0164] In some embodiments, CoQ2 is dissolved in an ethanol / intralipid solvent.

[0165] In some embodiments, the composition is made by further dissolving ascorbic acid, or a pharmaceutically acceptable salt thereof, in water to form an aqueous solution and adding the surfactant dispersion of step (a) to the aqueous solution to form a mixture, wherein the mixture is added to the non-aqueous CoQ2 solution in step (c) to form the crude oil-in-water emulsion.Materials and Methods

[0166] Animals

[0167] The care of mice in this work was in accordance with NIH and Columbia University Irving Medical Center Institutional Animal Care and Use Committee and ARRIVE guidelines and conformed to the provisions of the Animal Welfare Act (NIH; DHHS) and the Association for Assessment and Accreditation of Laboratory Animal Care (MAI. AC). C57B1 / 6 N male mice were acquired (Charles River, Wilmington MA) and utilized for all experiments except when otherwise stated.

[0168] Aralar Knockout Mice

[0169] Mice with a heterozygotic mutation of the Aralar (Slc25al2) gene on a SVJ129 x C57BL / 6 background were acquired (Taconic Biosciences, Germantown, NY) and mated to yield Aralar / _knockout mice and wild-type (Aralar+ / +) littermate controls. Genotype was determined by standard PCR. Aralar knockout mice and wild-type controls were studied at 10 days of life given the progressive neurologic impairment and shortened lifespans in mutants.

[0170] Electroencephalogram Acquisition

[0171] The OpenBCI Cyton board (OpenBCI, MY, USA) was used with subdermal needle electrodes (Rhythmlink, SC, USA) to extract single-channel electroencephalogram (EEG) features. Reference and ground electrodes were attached as clips, one to each ear. Data were recorded at 250 Hz using the OpenBCI™ graphical user interface (v6.0.0-beta.1, 2023-9-28, 64-BIT, Windows 10) and saved as a .txt file. MATLAB R2024b (The MathWorks, Natick, MA,01001 / 012990-WG0 USA) was used for processing and plotting. The signal was filtered between 0.5-45 Hz using a Butterworth MATLAB-based zero-phase shift routine (filtfilt).

[0172] Mitochondrial Isolation

[0173] Forebrain was harvested, homogenized in ice-cold isolation buffer (225 mM mannitol, 75 mM sucrose, 1 mM EGTA, 5 mM HEPES-KOH (pH 7.2) and 1 mg / mL of fattyacid-free bovine serum albumin (BSA)), and centrifuged (1100 g) for 5 min at 4 °C. Supernatant was mixed with 80 vol% Percoll solution and layered on 10% Percoll solution and then spun (18,500 g for 10 min at 4 °C). The pellet was resuspended in 250 mM sucrose, 5 mM HEPES-KOH (pH 7.2), 0.1 mM EGTA and 1 mg / mL of BSA and centrifuged (10,00 g for 5 min at 4 °C). The mitochondrial pellet was resuspended and protein concentrations were determined using the Lowry method.

[0174] Mitochondrial Oxygen Consumption

[0175] Forebrain mitochondria (0.2 mg) were added to 1 mL of respiration buffer (200 mM sucrose, 25 mM KC1, 2 mM K2HPO4, 5 mM HEPES-KOH (pH 7.2), 5 mM MgCl2, 0.2 mg / mL BSA). Oxygen consumption was measured using a Clark-type electrode (Oxytherm, Hansatech, UK) with Complex I-dependent substrates (10 mM glutamate and 5 mM malate) or Complex II-dependent substrate (10 mM succinate in the presence of 5 pM rotenone) at 32 °C. ADP (150 pM) initiated state 3 respiration. Oligomycin (2.5 pg / mL) induced state 4 respiration and dinitrophenol (DNP) (70 pM) induced maximal rate of uncoupled state 3 respiration.

[0176] For leak respiration, oxygen consumption and A'Pm were simultaneously measured with 5 mM succinate using forebrain mitochondria (0.2 mg) in 1 mL respiration buffer (200 mM sucrose, 25 mM KC1, 2 mM K2HPO4, 5 mM HEPES-KOH (pH 7.2), 5 mM MgCl2, 0.2 mg / mL BSA) containing 60 ng / mL nigericin (to collapse ApH). 5 pM rotenone and oligomycin (2.55 pg / mL) at 37 °C. A'Pm was quantified using a selective ion sensitive electrode for tetraphenylphosphonium (TPP+) (World Precision Instruments, Sarasota, FL) and calculated using the Nernst equation.

[0177] In separate experiments, cyclosporine A (1 pM), carboxyatractyloside (1 pM), guanosine diphosphate (0.75 mM), and pyridoxal 5’-phosphate (200 pM) were added to inhibit the mitochondrial permeability transition pore, the adenine nucleotide translocase, uncoupling proteins, and Aralar, respectively, to determine the source of the proton leak, p-Hydroxymercuribenzoate (10 pM) was added as a non-specific leak inhibitor. Equal volume water served as a control vehicle.

[0178] Electron Transport Chain Enzyme Stead-State Activities

[0179] Inhibitor sensitive ETC complex activity was measured in 1 mL using spectrophotometry. Rotenone-sensitive Complex I specific activity was measured in isolatedmitochondria (40 pg) using 4.6 mM '-cm’1as the extinction coefficient of NADH at 340 nm with a reference wavelength of 380 nm. 2-Thenoyltrifluoroacetone-sensitive Complex II activity was measured in mitochondria (40 pg) using 4.6 mM’1-cm’1as the extinction coefficient of 2,6-dichlorophenolindophenol at 600 nm. For Complexes III and IV, inhibitor-sensitive first-order rate kinetics were calculated using 18.5 mM '-cm1as the extinction coefficient of cytochrome C at 550 nm in 4 pg and 2 pg mitochondria, respectively. Oligomycin-sensitive Complex V specific activity was measured in isolated mitochondria (40 pg) using 6.2 mM’1-cm'1as the extinction coefficient of NADH at 340 nm. Rotenone-sensitive Complex I + III linked activity and antimycin A-sensitive Complex II + III linked activity was measured in mitochondria (40 pg) using 18.5 mM '-cm1as the extinction coefficient of cytochrome C at 550 nm

[0180] Statistical Analysis

[0181] Statistical analysis was performed with GraphPad Prism 10 software (GraphPad Software, La Jolla, CA). Data are presented in the figures as means ± SD (unless otherwise specified in the figure legends). The sample number of mice or replicates (n) studied for each outcome is indicated for each figure. Sample size was chosen a priori for each outcome measure to provide 80% power to detect an effect size of 15% between groups at a significance level of 0.05. Statistical tests utilized are detailed in each figure legend. Student’s t test (two-tailed) was used to determine significance between two groups and one-way analysis of variance (ANOVA) with Tukey’s post hoc test was used to calculated significance between more than two groups. Regression analysis was utilized to assess dose-dependent effect. Significance was set at p < 0.05.Examples

[0182] Example 1: Loss of Righting Reflex Assessment

[0183] Awake mice were randomly injected via the tail vein with a single dose of Coenzyme Q2 (20 mg / mL in intralipid), with a maximum dose of 300 mg / kg, resulting in induced unconsciousness within several seconds. Coenzyme Q2 rendered the mice insensitive to aggressive tail and toe pinch (surgical plane of anesthesia) and the unconsciousness lasted for up to about 6 minutes. The mice then emerged from sedation.

[0184] Righting reflex was tested after tail vein injection for each mouse. Mice had an intact righting reflex if they successfully returned to prone position twice in a row. Otherwise, they were considered to have lost the righting reflex. Latency to onset of loss of righting and return of righting were recorded. CoQ2 caused short-lived LORR over a range of doses (see FIG. 2). Mice typically regained their righting reflex within ~8 min and latency to RORR demonstrated a01001 / 012990-WG0 significant and positive correlation with CoQ2 dose (p <0.05) (see FIG. 3). Moreover, there was a delay in the onset of CoQ2-induced LORR following injection in all animals (see FIG. 4). The mean duration of latency to LORR was 95.0 s (95 % CI: 23.3-166.7) across CoQ2 doses (see FIG. 4). However, the correlation between latency to onset of LORR and CoQ2 dose was weak and lack significance, indicating a dose-independent relationship (see FIG. 4). Murine electroencephalograms were then assed upon LORR and following RORR after injection of 200 mg / kg CoQ2. Slow waves in the delta range (1-4 Hz) were prominent during loss of righting while higher frequency activity was seen upon return of righting (see FIG. 5). The slow-wave EEG activity during LORR indicated COQ-2induced change in cortical activity comparable to a hypnotic state. Additionally, Coenzyme Q2 was tested in rabbits and found that bolus doses rendered the rabbit unconscious. Thus, Coenzyme Q2 demonstrated anesthetic and sedative / hypnotic properties.

[0185] Example 2: Coenzyme Q2 Compromises A m in Forebrain Mitochondria

[0186] Isolated mouse forebrain mitochondria was exposed to CoQ2 in vitro to determine how it affects the ability of mitochondria to generate and maintain A m. First, oxygen consumption in actively respiring forebrain mitochondria was measured using polarography. Ethanol, the control vehicle, had no significant effect on oxygen consumption (see FIG. 6). In contrast, CoQ2 significantly decreased Complex I-dependent state 3 respiration and significantly reduced maximal oxygen consumption induced by dinitrophenol (state 3DNP) independent of substrate (see FIG. 6). On the other hand, CoQ2 significantly increased Complex II -dependent state 4 and oligomycin-induced state 4 respiration (see FIG. 7). Thus, CoQ2 inhibited electron transport and stimulated Complex II -dependent proton leak.

[0187] Next, oxygen consumption and ATm during Complex Il-dependent leak respiration was simultaneously measured to determine the effect of CoQ2 on A m. CoQ2 immediately increased leak respiration as evidenced by a sudden increase in the rate of oxygen consumption and caused a concomitant and precipitous decline in A m (see FIG. 8). Thus, CoQ2 induced uncompensated proton leak, preventing mitochondria from generating and maintaining adequate AT'm.

[0188] Next, the kinetic activity of each ETC enzyme complex during exposure to CoQ2 or the ethanol vehicle in isolated mitochondria was quantified to determine where CoQ2 interfered with the A m-generating capacity. Ethanol had no effect on any ETC enzyme complex and CoQ2 had no significant effect on Complex V (see FIG. 9). In contrast, CoQ2 significantly inhibited stead-state Complex I activity, linked Complex I + III activity, and Complex IV activity in a concentration-independent manner (see FIG. 9). In addition, the highest concentration of CoQ2 also inhibited stead-state Complex III activity (see FIG. 9). Both CoQ2concentrations stimulated linked Complex II + III activity and the highest concentration increased steady-state Complex II activity (see FIG. 9). However, the combined inhibitory effects on Complexes I and IV best explain the disruption in A'Pm-generation capacity in the setting of CoQ2 -induced excessive proton leak. Thus, CoQ2 caused a precipitous decline in A'Pm in forebrain mitochondria due to excessive mitochondrial proton leak combined with ETC inhibition.

[0189] Example 3: Blockade of Coenzyme Q2-Induced Protein Leak

[0190] The main source of CoQ2-mediated proton leak isolated forebrain mitochondria was determined by screening several specific and non-specific inhibitors for the ability to block the proton link. Specifically, a decline in oxygen consumption with a concomitant rise in A'Pm during leak respiration was evidence of a successful blockade.

[0191] First, non-specific inhibitor pyridoxal 5’-phosphate (PLP) was tested to determine the role Aralar in CoQ2-mediated leak. Initial results demonstrated that PLP had little to no effect (see FIG. 11). To confirm this finding, the effect of CoQ2 on leak respiration in Aralar knockout mouse and wild-type littermate control mouse forebrain were assessed. CoQ2 caused a similar increase in the rate of oxygen consumption and precipitous decline in A'Pm in both strains, indicating that CoQ2-induced leak is not mediated by Aralar. This is in contrast to Coenzyme QI, which is demonstrated to have Aralar-mediated mechanism of action to induce unconsciousness. See Somnay, Y. R. et al., Effects of the Quinone Analog Ubiquinone-5 on Murine Mitochondria and Hypnosis. Anesthesiology 2025; 143(3) :641-660.

[0192] Second, specific inhibitors of adenine nucleotide translocase (ANT), uncoupling proteins (UCPs), and the mitochondrial permeability transition pore (mPTP) were tested. These inhibitors minimally affected the rate of leak respiration and A'Pm during CoQ2 exposure, indicating that the ANT, UCPs, and mPTP were not major sources of CoQ2-mediated leak (see FIGs. 16-18).

[0193] Finally, non-specific inhibitor p-hydroxymercuribenzoate (p-HMB) was tested. The rate of oxygen consumption decreased immediately following addition of p-HMP and A'Pm recovered to pre-CoQ2 levels following a slow and steady rise (see FIG. 13). These effects indicated that p-HMB blocked the major source of CoQ2-induced leak. The changes in the rate of oxygen consumption and A'Pm following p-HMP were both significantly different from vehicle -exposed values (.see FIG. 14 and FIG. 15). However, despite the ability to successfully inhibit CoQ2-mediated leak, the exact source was not identified due to the non-specific nature of p-HMP inhibition.

[0194] Example 4: Arterial Blood Pressure Measurements

[0195] New Zealand White male rabbits weighing approximately 3 kg were intubated and mechanically ventilated. Each rabbit was then injected intravenously with either Coenzyme QI (CoQi) or Coenzyme Q2 (CoQ2) as a single 6 mg / kg bolus. Arterial blood pressure was measured in real-time via a percutaneously placed cannula in an auricular artery. Representative tracings are depicted in FIG. 19. CoQ2 caused a brief and limited drop in blood pressure whereas CoQi caused a more substantial drop in blood pressure, which did not recover over the course of the measurement. Accordingly, these results demonstrate that CoQ2 is less cardiotoxic than CoQi.

Claims

01001 / 012990-WQ0CLAIMS1. A pharmaceutical composition comprising a compound having the structure of"pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable carrier is an oil-in-water emulsion.

3. The pharmaceutical composition according to claim 2, wherein the compound having thestructurestabilized by means of a surfactant.

4. The pharmaceutical composition according to any one of claims 1-3, wherein thecompound having the structuredissolved in a water-immiscible solvent.

5. The pharmaceutical composition according to any one of claims 1-4, wherein thecompound having the structureemulsified with water.

6. The pharmaceutical composition according to any one of claims 1-5, wherein the pharmaceutical composition further comprises an excipient selected from the group consisting of: amino acids, vitamins, and minerals, or a combination of any of the foregoing.

7. The pharmaceutical composition according to any one of claims 1-6, wherein thecompound having the structurepresent in an amount from about 0.01% (w / v) to about 5% (w / v).

8. The pharmaceutical composition according to any one of claims 1-7, wherein the pH of the pharmaceutical composition ranges from about 5.0 to about 8.0.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the pharmaceutical composition further comprises a tonicity modifier.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is isotonic with blood.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the pharmaceutical composition further comprises ascorbic acid, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to any one of claims 1-11, wherein thecompound having the structurepresent in a therapeutically effective amount.

13. A method of inducing anesthesia or sedation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having the structurepharmaceutical composition according to any one of claims 1-12.

14. The method according to claim 13, the method of administration is by a single bolus injection or in 2 to 10 bolus injections.

15. The method according to claim 13, wherein the method of administration is by continuous infusion.

16. The method according to any one of claims 13-15, wherein the subject is administered adose of a compound having the structuresufficient to achieve a desired clinical anesthetic endpoint, wherein the desired anesthetic endpoint is elected from the group consisting of general anesthesia, mild sedation, moderate sedation, tranquilization, immobility, amnesia, analgesia, deep sedation, and autonomic quiescence.

17. The method according to claim 16, wherein the compound having the structure of19. The method according to claim 18, wherein the compound having the structure of "21. The method according to claim 20, wherein the compound having the structure of23. The method according to any one of claims 13-22, wherein the compound of having the structurethe pharmaceutical composition according anyone of claims 1-12, is administered by intravenous administration, inhalational administration, subcutaneous administration, intramuscular administration, or transdermal administration.

24. A process for preparing a pharmaceutical composition of a compound having thestructurethe process comprising:dispersing at least one surfactant in water;dissolving the compound having the structurein at least one water-immiscible solvent to form a non-aqueous solution; andc. adding the non-aqueous solution to the surfactant dispersion to form a crude oil-in-water emulsion.

25. The process of claim 24, further comprisingd. dissolving ascorbic acid or its pharmaceutically acceptable salts thereof in water to form an aqueous solution; ande. adding the surfactant dispersion of step (a) to the aqueous solution to form a mixture, wherein the mixture is added to the non-aqueous solution in step (c) to form the crude oil-in-water emulsion.

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