WO2024006841A2 - Compositions pour la perte de poids et le traitement du cancer - Google Patents

Compositions pour la perte de poids et le traitement du cancer Download PDF

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Publication number
WO2024006841A2
WO2024006841A2 PCT/US2023/069273 US2023069273W WO2024006841A2 WO 2024006841 A2 WO2024006841 A2 WO 2024006841A2 US 2023069273 W US2023069273 W US 2023069273W WO 2024006841 A2 WO2024006841 A2 WO 2024006841A2
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Prior art keywords
salt
bhb
derivative
compound
administration
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PCT/US2023/069273
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English (en)
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WO2024006841A3 (fr
Inventor
James M. Sonner
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Knowledge Pharmaceuticals Inc.
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Publication of WO2024006841A2 publication Critical patent/WO2024006841A2/fr
Publication of WO2024006841A3 publication Critical patent/WO2024006841A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the second therapeutic can be selected from the group consisting of: orlistat, topiramate, naltrexone, semaglutide, tirzepatide, a derivative of any of these, and a salt of any of these.
  • the subject in need thereof can have increased weight loss as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • the second therapeutic can be orlistat, a derivative thereof, or a salt thereof.
  • the second therapeutic is semaglutide, a derivative thereof, or a salt thereof.
  • the second therapeutic is tirzepatide, a derivative thereof, or a salt thereof.
  • the subject can be a human or an animal.
  • the second therapeutic can be administered concurrently or consecutively.
  • the beta hydroxybutyric acid (BHB), the salt thereof, or the derivative thereof can be administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, or transdermally.
  • the BHB the salt thereof, or the derivative thereof can be administered orally.
  • the BHB the salt thereof, or the derivative thereof can be administered by a device and the device can be a pump.
  • the second therapeutic can be administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intradermally, intrathecally, intravenously, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • the second therapeutic can be administered orally.
  • the method can comprise further administering a therapy.
  • the therapy can be an exercise, a psychotherapy, a diet, or any combination thereof.
  • the method can further comprise administering a surgery.
  • the surgery can be a bariatric surgery.
  • the BHB, the salt thereof, or the derivative thereof, and the second therapeutic can be administered as needed, or for about a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, or chronically.
  • the method can further comprise diagnosing the subject with obesity or overweight.
  • the method can further comprise administering a third therapeutic.
  • the third therapeutic can be selected from the group consisting of: orlistat, phentermine, topiramate, naltrexone, bupropion, liraglutide, and a salt of any of these.
  • the method can further comprise measuring a level of the BHB, the salt thereof, or the derivative thereof in the subject.
  • the level of the BHB the salt thereof, or the derivative thereof can be measured after the administration of the BHB the salt thereof, or the derivative thereof, before the administration of the BHB, the salt thereof, or the derivative thereof, or both.
  • kits comprising beta hydroxybutyric acid (BHB), a salt thereof, or a derivative thereof, and a second therapeutic wherein the second therapeutic can be selected from the group consisting of: orlistat, topiramate, naltrexone, semaglutide, tirzepatide, a derivative of any of these, and a salt of any of these and a container.
  • a kit can comprise beta hydroxybutyric acid (BHB), a salt thereof, or a derivative thereof, and a second therapeutic or a salt thereof.
  • BHB beta hydroxybutyric acid
  • the second therapeutic can comprise Bacillus Calmette-Guérin (BCG) or a mutated BCG.
  • BCG Bacillus Calmette-Guérin
  • the second therapeutic can be selected from the group consisting of: orlistat, topiramate, naltrexone, semaglutide, tirzepatide, a derivative of any of these, and a salt of any of these.
  • Also disclosed herein are methods for treating a cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof.
  • the subject in need thereof upon administration, can have a decreased number of cancer cells as compared to administration of the BHB, the salt thereof, or the derivative thereof to a subject not in need thereof.
  • the subject in need thereof upon administration, can have a decreased tumor size as compared to administration of the BHB, the salt thereof, or the derivative thereof to a subject not in need thereof.
  • the subject can be a human or an animal.
  • the second therapeutic can be administered concurrently or consecutively.
  • the BHB, the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • the BHB, the salt thereof, or the derivative thereof can be administered orally.
  • the second therapeutic can be administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intradermally, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • the second therapeutic can be administered orally.
  • the BHB, the salt thereof, or the derivative thereof, and the second therapeutic can be administered as needed, or for about a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, or chronically.
  • the cancer can comprise a bladder cancer.
  • the method can further comprise diagnosing the subject with a cancer. [6] Also disclosed herein are methods for treating a cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof, and a second therapeutic.
  • the second therapeutic can be selected from the group consisting of: a surgery, a chemotherapy, a hormone therapy, a hyperthermia therapy, an immunotherapy, a photodynamic therapy, a radiation therapy, a stem cell transplant therapy, a targeted therapy, and any combination thereof.
  • the subject in need thereof upon administration the subject in need thereof can have a decreased number of cancer cells as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • the subject in need thereof upon administration the subject in need thereof can have a decreased tumor size as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • the second therapeutic can be a chemotherapy.
  • the second therapeutic can be an immunotherapy.
  • the immunotherapy can comprise Bacillus Calmette-Guérin (BCG) or a mutated BCG.
  • BCG Bacillus Calmette-Guérin
  • the second therapeutic can be a radiation therapy.
  • the subject can be a human or an animal.
  • the second therapeutic can be administered concurrently or consecutively.
  • the BHB, the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • the BHB, the salt thereof, or the derivative thereof can be administered orally.
  • the second therapeutic can be administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intradermally, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • the second therapeutic can be administered orally.
  • the BHB, the salt thereof, or the derivative thereof, and the second therapeutic can be administered as needed, or for about a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, or chronically.
  • the cancer can comprise a bladder cancer.
  • the method can further comprise diagnosing the subject with a cancer. [7] Also disclosed herein are methods for enhancing cognitive function in a subject comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof.
  • a traumatic brain injury comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof, and a second therapeutic.
  • the second therapeutic is selected from the group consisting of: a speech therapy, a physical therapy, an occupational therapy, a cognitive training, an anti-seizure drug, a coma-inducing drug, a diuretic, a surgery, and any combination thereof.
  • the subject in need thereof has a reduction in a number of headaches as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • methods for screening for an anti-cancer compound comprising: i) providing a beta hydroxybutyric acid (BHB) analog; ii) administering the BHB analog to an animal at a predetermined dose; iii) measuring a duration of the anesthesia; and iv) selecting the BHB analog with a threshold duration of anesthesia as a candidate for an anti-cancer compound.
  • the animal can be a mouse or a rat.
  • the measuring can further comprise measuring the potency of the BHB analog.
  • the BHB analog with the threshold duration of anesthesia can be compared to a BHB threshold duration of anesthesia.
  • methods for treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a BHB, a salt thereof, or a derivative thereof, thereby treating the cancer in the subject in need thereof.
  • the cancer comprises a solid tumor, and wherein after administering, the subject in need thereof has a decreased solid tumor volume as compared to a solid tumor volume prior to the administering.
  • the subject is a human or an animal.
  • the BHB, the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • the administration of the BHB, the salt thereof, or the derivative thereof comprises intravesical administration.
  • the BHB, the salt thereof, or the derivative thereof, and a second therapeutic are administered as needed, or for about: a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, weekly, biweekly, once every other week, for about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, a period from about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 to 12 weeks, or chronically.
  • the cancer comprises a bladder cancer.
  • the method further comprises diagnosing the subject with a cancer.
  • the BHB, the salt thereof, or the derivative thereof is administered as needed.
  • the BHB, the salt thereof, or the derivative thereof is administered as an aqueous solution that is pH adjusted to a pH range ranging from 5.2-7.6, and wherein optionally the aqueous solution is heated. In some embodiments, the aqueous solution is heated to a temperature ranging from about 23 degrees C to about 37 degrees C. In some embodiments, the BHB, the salt thereof, or the derivative thereof is administered as an aqueous solution which is optionally pH adjusted, and wherein a concentration of the BHB the salt thereof, or the derivative thereof in the aqueous solution ranges from about: 0.01 nM – 1 M.
  • the concentration of the BHB the salt thereof, or the derivative thereof in the aqueous solution is about: 0.01 nM, 0.1 nM, 1.0 nM, 10 nM, 100 nM, 1000 nM, 0.01 mM, 0.1 mM, 1.0 mM, 10 mM, 100 mM, 1000 mM.
  • the aqueous solution containing the BHB the salt thereof, or the derivative thereof, after intravesical administration is allowed to reside in the bladder for about: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 hours.
  • R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with
  • One aspect of the current disclosure is a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl,
  • One aspect of the current disclosure is a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -
  • One aspect of the current disclosure is a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • One aspect of the current disclosure is a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, wherein the method is selected from inducing sedation, sedating, treating a central nervous system disorder, treating a peripheral nervous system disorder, treating a convulsing disorder, treating a psychiatric disorder, treating ischemia, treating pain, treating spasticity, treating itching, and any combination thereof.
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • One aspect of the current disclosure is a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, and wherein the method comprises treating a symptom associated with a bladder cancer.
  • Another aspect of the current disclosure is a pharmaceutical composition comprising a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optional
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • Another aspect of the current disclosure is a pharmaceutical composition comprising a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, and a pharmaceutically-acceptable excipient.
  • R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -X-R 4 , - N(R 4 ) 2 ,
  • R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -X-R 4 , - N(R 4
  • the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -
  • the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -
  • the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkyn
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, wherein the method is selected from inducing sedation, sedating, treating a central nervous system disorder, treating a peripheral nervous system disorder, treating a convulsing disorder, treating a psychiatric disorder, treating ischemia, treating pain, treating spasticity, treating itching, and any combination thereof.
  • the compound or a salt thereof is a racemic mixture.
  • the compound or a salt thereof has an enantiomeric excess of greater than 80%. In some embodiments, the compound or a salt thereof has a diastereomeric excess of greater than 80%. In some embodiments, the compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry. In some embodiments, the compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry. In some embodiments, the compound or a salt thereof is administered in a formulation. In some embodiments, the formulation further comprises a pharmaceutically-acceptable excipient. In some embodiments, the formulation is administered orally. In some embodiments, the formulation is administered topically.
  • the formulation is administered by inhalation. In some embodiments, the formulation is administered intravenously. In some embodiments, the formulation is administered intramuscularly. In some embodiments, the formulation is administered intravascularly. In some embodiments, the formulation is administered by intravesical administration. In some embodiments, the formulation is administered intravesicularly. In some embodiments, the formulation is administered intradermally. In some embodiments, the formulation is administered by spinal delivery. In some embodiments the formulation is administered by epidural delivery. In some embodiments, the administering of a compound or a salt thereof alters distribution of lipids in a cell membrane. In some embodiments, the administering of a compound or a salt thereof alters cell membrane thickness.
  • the compound or a salt thereof induces lower than about 50% of sides effects, comprising nausea, vomiting, sore throat, confusion, hypothermia, respiratory depression, low blood pressure, or any combination thereof, when compared to an anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, etomidate, ketamine, ropivicaine, bupivicaine, propofol, and alfentanil.
  • an anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, etomidate, ketamine, ropivicaine, bupivicaine, propofol, and alfentanil.
  • the compound or salt thereof demonstrates a lower level of toxicity to a subject when compared to anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, alfentanil, etomidate, propofol, ketamine, isoflurane, sevoflurane, ropivicaine, and bupivicaine.
  • anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, alfentanil, etomidate, propofol, ketamine, isoflurane, sevoflurane, ropivicaine, and bupivicaine.
  • the method is a method of inducing sedation or sedating said subject.
  • the method induces minimal sedation.
  • the method is a method of treating a central nervous system disorder.
  • the central nervous system disorder is one selected from the group consisting of schizophrenia, bipolar disorder, autism, Alzheimer’s disease, Parkinson’s disease, attention deficit-hyperactivity disorder, and sleep disorders.
  • the method is a method of treating a peripheral nervous system disorder.
  • the peripheral nervous system disorder is one selected from the group consisting of traumatic nerve damage, diabetic neuropathy, chemotherapy induced neuropathy, spinal muscular atrophy, restless leg syndrome, and motor neuron disease.
  • the method is a method of treating a convulsing disorder.
  • the convulsing disorder is epilepsy.
  • the method reduces the frequency and/or severity of a twitching in a subject.
  • the method reduces the frequency and/or severity of a seizure in a subject.
  • the method is a method of treating a psychiatric disorder.
  • the psychiatric disorder is one selected from the group consisting of attention deficit hyperactivity disorder, alcohol abuse, depression, panic disorder, posttraumatic stress disorder, and schizophrenia.
  • the method is a method of treating an ischemia.
  • the ischemia is one selected from the group consisting of myocardial ischemia, cerebral ischemia, and limb ischemia.
  • the method is a method of treating pain.
  • the pain is acute pain.
  • the pain is chronic pain.
  • the pain is associated with a disease.
  • the method is a method of treating spasticity.
  • the spasticity level in said subject decreases after a treatment with said compound or a salt thereof.
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • the present disclosure provides a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, wherein the method is a method of treating a bladder cancer.
  • the compound or a salt thereof is a racemic mixture.
  • the compound or a salt thereof has an enantiomeric excess of greater than 80%. In some embodiments, the compound or a salt thereof has a diastereomeric excess of greater than 80%. In some embodiments, the compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry. In some embodiments, the compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry. In some embodiments, the compound or a salt thereof is administered in a formulation. In some embodiments, the formulation further comprises a pharmaceutically-acceptable excipient. In some embodiments, the formulation is administered orally. In some embodiments, the formulation is administered topically.
  • the formulation is administered by inhalation. In some embodiments, the formulation is administered intravenously. In some embodiments, the formulation is administered intramuscularly. In some embodiments, the formulation is administered intravascularly. In some embodiments, the formulation is administered by intravesical administration. In some embodiments, the formulation is administered intravesicularly. In some embodiments, the formulation is administered intradermally. In some embodiments, the formulation is administered by spinal delivery. In some embodiments, the formulation is administered by epidural delivery. In some embodiments, the administering of a compound or a salt thereof alters distribution of lipids in a cell membrane. In some embodiments, the administering of a compound or a salt thereof alters cell membrane thickness.
  • the compound or a salt thereof induces lower than about 50% of sides effects, comprising nausea, vomiting, sore throat, confusion, hypothermia, respiratory depression, low blood pressure, or any combination thereof, when compared to an anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, etomidate, ketamine, ropivicaine, bupivicaine, propofol, and alfentanil.
  • an anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, etomidate, ketamine, ropivicaine, bupivicaine, propofol, and alfentanil.
  • the compound or salt thereof demonstrates a lower level of toxicity to a subject when compared to anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, alfentanil, etomidate, propofol, ketamine, isoflurane, sevoflurane, ropivicaine, and bupivicaine
  • anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, alfentanil, etomidate, propofol, ketamine, isoflurane, sevoflurane, ropivicaine, and bupivicaine
  • the method is a method of inducing sedation or sedating said subject. In some embodiments, the method induces minimal sedation. In some embodiments, the method further comprises administering a pharmaceutically- acceptable excipient.
  • the compound or a salt thereof is administered in an amount from about 0.001 mg to about 10,000 mg per kg body weight. In some embodiments, the compound or a salt thereof is administered in an amount from about 0.1 mg to about 1,000 mg per kg body weight. In some embodiments, the compound or a salt thereof is administered at least 1 time per week. In some embodiments, the compound or a salt thereof is administered at least 1 time per day. In some embodiments, the administering occurs for a length of time from about 1 second to about 100 minutes.
  • the compound or salt thereof is selected from the group consisting of: (S)-3-hydroxybutanoic acid, (R)-3-hydroxybutanoic acid, 3,3-dimethylbutanoic acid, 2-benzamido-2-hydroxyacetic acid, butyric acid, 2-ethylmalonic acid, glutamine, and a salt of any one thereof.
  • the compound or salt thereof is selected from the group consisting of: butyric acid, 3-hydroxybutyric acid, ethylmalonic acid, diethyl ethyl malonate, ethyl (S)-(+)-mandelate, ethyl isovaleric acid, ethyl butyrate, diethyl ethylphenylmalonate, and a salt of any one thereof.
  • the compound or salt thereof is selected from the group consisting of: butyric acid, 3-hydroxybutyric acid, ethylmalonic acid, diethyl ethyl malonate, and a salt of any one thereof.
  • the compound or salt thereof is butyric acid. In some embodiments, the compound or salt thereof is 3-hydroxybutyric acid.
  • the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • the present disclosure provides a pharmaceutical composition comprising a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, and a pharmaceutically-acceptable excipient.
  • the compound or salt thereof is butyric acid.
  • the compound or salt thereof is 3-hydroxybutyric acid.
  • the pharmaceutically-acceptable excipient is selected from the group consisting of water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, PEG, polyvinylpyrrolidone, cellulose, sterile saline, syrup, methyl cellulose, and any combination thereof.
  • the compound or a salt thereof is a racemic mixture.
  • the compound or a salt thereof has an enantiomeric excess of greater than 80%. In some embodiments, the compound or a salt thereof has a diastereomeric excess of greater than 80%. In some embodiments, the compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry. In some embodiments, the compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry.
  • the present disclosure provides a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -X-R 4 , - N(R 4 )2, -
  • the compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • the present disclosure provides a compound or a salt thereof listed in Table 1 or Table 2.
  • the compound or a salt thereof is a racemic mixture.
  • the compound or a salt thereof has an enantiomeric excess of greater than 80%.
  • the compound or a salt thereof has a diastereomeric excess of greater than 80%.
  • the compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry.
  • the compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry.
  • the present disclosure provides a method of combining a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 al
  • the excipient is selected from the group consisting of water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, PEG, polyvinylpyrrolidone, cellulose, sterile saline, syrup, methyl cellulose, and any combination thereof.
  • the method further comprises employing the compound of Formula I.
  • the method further comprises employing the salt of the compound of Formula I.
  • compositions as used herein can be a pharmaceutical composition.
  • a compound as used herein refers to a compound in a pharmaceutical composition.
  • the term “salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • the term “substantially” or “essentially” can refer to a qualitative condition that exhibits an entire or nearly total range or degree of a feature or characteristic of interest. In some cases, substantially can refer to at least about: 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of the total range or degree of a feature or characteristic of interest.
  • a sample includes a plurality of samples, including mixtures thereof.
  • pharmaceutically-acceptable carrier or “pharmaceutically-acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • compositions and carriers capable of being co-administered with a compound to facilitate the performance of its intended function.
  • the use of such media for pharmaceutically active substances is well known in the art.
  • examples of such vehicles and carriers include solutions, solvents, dispersion media, delay agents, emulsions and the like. Any other conventional carrier suitable for use with the multi-binding compounds also falls within the scope of the present disclosure.
  • subject includes, but is not limited to, humans of any age group, e.g., a pediatric subject (e.g., infant, child or adolescent) or adult subject (e.g., young adult, middle- aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys or rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.
  • a pediatric subject e.g., infant, child or adolescent
  • adult subject e.g., young adult, middle- aged adult or senior adult
  • primates e.g., cynomolgus monkeys or rhesus monkeys
  • mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or
  • the subject can be a pet such as a cat, a dog, a rodent, or a bird.
  • the methods described herein can be useful in both human therapeutics and veterinary applications.
  • the compounds described herein can be used to treat diseases and conditions of humans and/or animals.
  • the patient is a mammal, and in some embodiments, the patient is human.
  • a subject herein can be a member of the armed forces, or the armed forces reserve.
  • a compound of the current disclosure is administered to a subject in need thereof.
  • a compound such as BHB can be used as in human therapeutics and veterinary applications.
  • a disease or condition herein can be a disease of a human or a disease or condition of an animal and/or mammal.
  • the subject is less than 18 years of age. In some cases, the subject is at least 18 years of age.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement may be observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • a derivative of a compound disclosed herein can refer to a chemical substance related structurally a compound disclosed herein.
  • a derivative can be made from the structurally- related parent compound in one or more steps.
  • the general physical and chemical properties of a derivative can be similar to a parent compound.
  • a derivative can be, for example, an analog or a homolog.
  • Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • isotopic variations of the compounds of the present disclosure are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium).
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
  • a compound of the disclosure, or its pharmaceutically acceptable salt comprises 1, 2, 3, 4, 5, or more deuterium atoms.
  • a hydrogen of a compound of the disclosure, or its pharmaceutically acceptable salt can be replaced with a deuterium atom.
  • a compound of the disclosure, or its pharmaceutically acceptable salt may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • a compound or a salt thereof may be dosed in their enantiomerically pure form.
  • the compound has an enantiomeric excess greater than about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • a compound or a salt thereof may be dosed in their diasteriomerically pure form. In some examples, the compound has a diasteriomeric excess greater than about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • Stereocenters may be defined using the Cahn–Ingold–Prelog priority rules. A compound or a salt thereof may have a stereocenter in the R-configuration. A compound or a salt thereof may have a stereocenter in the S-configuration.
  • a compound or a salt thereof may exhibit polymorphism. It is to be understood that the present disclosure encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the disclosure, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • the current disclosure provides a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -
  • a compound of the current disclosure is represented by Formula (I-A): (I-A), or a salt thereof.
  • a compound of the current disclosure is represented by Formula (II): R 51 -C(R 52 )(R 52’ )-C(R 53 )(R 53’ )-C(R 54 )(R 54’ )(R 54’’ ), or a salt thereof, wherein: R 51 is 5-tetrazolyl or 5-oxo-1,2,4-oxadiazol-3-yl; R 52 and R 52’ are independently selected at each occurrence from hydrogen, amine, or –COOH; or R 52 and R 52’ together form an oxo; R 53 is hydrogen, -OH, alkyl, or -COOH; R 53’ is hydrogen or methyl; or -H; R 53 and R 53’ together form an oxo; R 54 is hydrogen; and R 54 , R 54’’ , and R 54’’’
  • R 51 is -COOR e , wherein R e is -(CH2)nCH3, where n is 0-3.
  • R 51 is -CONHR a , where R a is hydrogen or alkyl.
  • R 51 is –CHO or -CH2OH.
  • R 51 is acyl-OCH2-.
  • R 51 is -COOR f , wherein R f is -(CH 2 ) n CH 3 , wherein n is 7-21.
  • R 51 is 3-acyloxybutyric acid, where the acyl group is a fatty acid (C8-21).
  • a hydrogen of a compound of the current disclosure may be replaced with a deuterium or a halogen, such as, for example, a fluorine.
  • a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof is listed in Table 1 or Table 2, wherein the method is selected from inducing sedation, sedating, treating a central nervous system disorder, treating a peripheral nervous system disorder, treating a convulsing disorder, treating a psychiatric disorder, treating ischemia, treating pain, treating spasticity, and treating itching.
  • a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof is listed in Table 1 or Table 2, wherein the method comprises treating a cancer.
  • a method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof is listed in Table 1 or Table 2, wherein the method comprises treating a bladder cancer.
  • the compound or a salt thereof is a racemic mixture.
  • the compound or a salt thereof has an enantiomeric excess of greater than 80%.
  • the compound or a salt thereof has a diastereomeric excess of greater than 80%.
  • the compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry.
  • the compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry.
  • the compound or a salt thereof is administered in a formulation.
  • the formulation further comprises an excipient.
  • the formulation is administered orally.
  • the formulation is administered topically.
  • the formulation is administered by inhalation.
  • the formulation is administered intravenously.
  • the formulation is administered intravascularly.
  • the formulation is administered by intravesical administration.
  • the formulation is administered intravesicularly.
  • the formulation is administered intramuscularly.
  • the formulation is administered intradermally.
  • the formulation is administered by spinal delivery. In some embodiments, the formulation is administered by epidural delivery. In some embodiments, the said administering of a compound of Formula (I), or a salt thereof, alters distribution of lipids in a cell membrane. In some embodiments, the administering of a compound of Formula (I) alters cell membrane thickness.
  • the compound or a salt thereof of Formula (I) induces lower than about 50% of sides effects, comprising nausea, vomiting, sore throat, confusion side effects, hypothermia, changes in blood pressure, respiratory depression, or any combination thereof, when compared to an anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, propofol, etomidate, ketamine and alfentanil.
  • sides effects comprising nausea, vomiting, sore throat, confusion side effects, hypothermia, changes in blood pressure, respiratory depression, or any combination thereof, when compared to an anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, propofol, etomidate, ketamine and alfentanil.
  • the compound or salt thereof of Formula (I) demonstrates a lower level of toxicity to a subject when compared to anesthetics selected from the group consisting of desflurane, procaine, lidocaine, cocaine, amobarbital, sevoflurane, isoflurane, etomidate, ketamine, ropivicaine, bupivicaine, propofol, and alfentanil.
  • the method is a method of inducing sedation or sedating said subject. In some embodiments, the method induces minimal sedation. In some embodiments, the method is a method of treating a central nervous system disorder.
  • the central nervous system disorder is one selected from the group consisting of schizophrenia, bipolar disorder, autism, Alzheimer’s disease, Parkinson’s disease, attention deficit-hyperactivity disorder, and sleep disorders.
  • the method is a method of treating a peripheral nervous system disorder.
  • the peripheral nervous system disorder is one selected from traumatic nerve damage, diabetic neuropathy, chemotherapy induced neuropathy, spinal muscular atrophy, and motor neuron disease.
  • the method is a method of treating a convulsing disorder.
  • the method is used to control and/or prevent seizures or to stop an ongoing series of seizures.
  • the convulsing disorder is epilepsy.
  • the convulsing disorder is Dravet syndrome. In some embodiments, the convulsing disorder is Nav 1.1 mutation of genetic epilepsy. [78] In some embodiments, the method is a method of treating a psychiatric disorder. [79] In some embodiments, the psychiatric disorder is one selected from attention deficit hyperactivity disorder, alcohol abuse, depression, panic disorder, posttraumatic stress disorder, and schizophrenia. In some embodiments, the method is a method of treating an ischemia. In some embodiments, the ischemia is one selected from myocardial ischemia, cerebral ischemia, and limb ischemia. In some embodiments, the method is a method of treating pain. In some embodiments, the pain is acute pain.
  • the pain is chronic pain. In some embodiments, the pain is associated with a disease. In some embodiments, the method is a method of treating spasticity. In some embodiments, the spasticity level in said subject decreases after a treatment with said compound. [80] In some embodiments, the method is a method of treating a cancer. In some embodiments, the cancer is a bladder cancer. In some embodiments, the bladder cancer is a urothelial bladder cancer. In some embodiments, the bladder cancer is a transitional cell bladder cancer. In some embodiments, the bladder cancer is a squamous cell bladder cancer. In some embodiments, the bladder cancer is a squamous cell carcinoma. In some embodiments, the bladder cancer is an adenocarcinoma.
  • a pharmaceutical composition comprises a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 ary
  • the pharmaceutical composition comprises a compound represented by Formula (I-A): (I-A), or a salt thereof, and a pharmaceutically-acceptable excipient.
  • the pharmaceutical composition comprises a therapeutically- effective amount of a compound or a salt thereof listed in Table 1 or Table 2, and a pharmaceutically-acceptable excipient.
  • the pharmaceutical composition comprises a compound, wherein the compound or a salt thereof is a racemic mixture.
  • the pharmaceutical composition comprises a compound, wherein the compound or a salt thereof has an enantiomeric excess of greater than 80%.
  • the pharmaceutical composition comprises a compound, wherein the compound or a salt thereof has a diastereomeric excess of greater than 80%. In some embodiments, the pharmaceutical composition comprises a compound, wherein the compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry. In some embodiments, the pharmaceutical composition comprises a compound, wherein the compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry.
  • a pharmaceutical composition disclosed herein comprises beta hydroxybutyric acid (BHB), a salt thereof, or a derivative thereof. In some cases, BHB can comprise and ester of BHB or a salt thereof.
  • BHB, a salt thereof, or a derivative thereof can be used with an additional therapeutic.
  • a pharmaceutical composition comprises beta hydroxybutyric acid (BHB), a salt thereof, or a derivative thereof in a therapeutically effective amount to treat a disease or condition.
  • BHB beta hydroxybutyric acid
  • a pharmaceutical composition can comprise BHB, a salt thereof, or a derivative thereof, in a therapeutically effective amount to treat obesity.
  • BHB, or any compound with a single stereoisomeric center can be enantiomerically pure or enantiomerically enriched.
  • BHB, or any compound with a single stereoisomeric center can be a racemate.
  • a compound herein can be achiral.
  • a compound herein can be a diastereomer. In some cases, a compound herein can be an epimer. In some instances, a compound herein can have a diastereomeric excess or percent diastereomeric excess of from about 1% to about 100%, for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or 100%. In some instances, BHB, or any compound with a single stereoisomeric center, can be of the (R) or (S) configuration.
  • BHB or any compound with a single stereoisomeric center
  • BHB can have an enantiomeric excess or percent enantiomeric excess of from about 1% to about 100%, for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or 100%.
  • percent enantiomeric excess can be defined as: wherein F R is the mole fraction of the compound with an R stereocenter and F S is the mole fraction of the compound with an S stereocenter and the two vertical lines indicate taking the absolute value of the difference.
  • the subject does not have a spasticity disease, or condition.
  • the subject can have a spasticity disease, or condition.
  • a pharmaceutical composition disclosed herein comprises a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2. Table 1.
  • a pharmaceutical composition disclosed herein may comprise a therapeutically-effective amount of a compound selected from:
  • a pharmaceutical composition disclosed herein may comprise a therapeutically-effective amount of a compound selected from: , or a salt of any one thereof.
  • a pharmaceutical composition disclosed herein may comprise a therapeutically-effective amount of a compound selected from: isoflurane, halothane, ethanol, octanol, dodecanol, sodium octyl sulfate (SOS), octadecyltrimethylammonium bromide (OTABr), sodium dodecyl sulfate (SDS), 2,5-diacetoxyphenyl sulfonate (DAPS), dodecyl trimethyl ammonium chloride (DATCl), or a salt of any one thereof.
  • a pharmaceutical composition comprises a therapeutically- effective amount of (S)-3-hydroxybutanoic acid, (R)-3-hydroxybutanoic acid, 3,3- dimethylbutanoic acid, 2-benzamido-2-hydroxyacetic acid, butyric acid, 2-ethylmalonic acid, glutamine, 2-hydroxy-2-phenylacetic acid, 2-oxo-3-phenylpropanoic acid, 4-(aminomethyl)-2,6- difluorophenol, 3-(aminomethyl)-2,6-difluorophenol, 4-aminobutanoic acid, 5-oxohexanoic acid, 3-hydroxy-3-methylbutanoic acid, 3-methyl-2-oxopentanoic acid, (3-methylbenzoyl)glycine, 3- methylpentanoic acid, (4-methylbenzoyl)glycine, hexanedioic acid, dimethylmalonic acid, alanine, fumaric acid, glutamic acid
  • a pharmaceutical composition comprises (S)-3-hydroxybutanoic acid, (R)-3-hydroxybutanoic acid, 3,3-dimethylbutanoic acid, 2-benzamido-2-hydroxyacetic acid, butyric acid, 2-ethylmalonic acid, glutamine, ethylmalonic acid, or a salt thereof.
  • a pharmaceutical composition comprises 3-hydroxybutyric acid, butyric acid, ethylmalonic acid, or a salt thereof.
  • 3-hydroxybutyric acid can comprise beta hydroxybutyric acid (BHB).
  • a pharmaceutical composition comprises ethyl malonic acid, S-3- hydroxybutyric acid, R-3-hydroxybutyric acid, butyric acid, mandelic acid, glutamine, 3,3- dimethyl butyric acid, ⁇ lpha-hydroxyhippuric acid, phenylpyruvic acid, 3-hydroxy-3- methylbutyric acid, l-valine, 2-oxoglutaric acid, 4-methylvaleric acid, kynurenic acid, indole-3- acetic acid, 3-methylhippuric acid, l-tartaric acid, proline, 3-methylvaleric acid, fumaric acid, isopropyl malonic acid, choline, glutaric acid, arginine, tryptophan, 4-acetylbutyric acid, 4- methylhippuric acid, l-serine, isoleucine, dimethylmalonic acid, succinic acid, guanidine, adipic acid, quinaldic acid, suberic acid,
  • beta-hydroxybutyric acid is referred to herein as beta-hydroxybutyric acid (BHB), also identified by the following structure: .
  • the pharmaceutical composition comprises enantiopure BHB.
  • the pharmaceutical composition comprises racemic BHB.
  • the pharmaceutical composition comprises a mixture of enantiomers of BHB.
  • the pharmaceutical composition comprises BHB and an anion thereof.
  • the pharmaceutical composition comprises an anion of a compound described herein (i.e., hydroxybutyrate).
  • the pharmaceutical composition comprises an ester of BHB, for example, a methyl ester, an ethyl ester, a propyl ester, isopropyl ester, a butyl ester, a C1 ester, C2 ester, C3 ester, C4 ester, C5 ester, C6 ester, an ester of glycerol, which can contain 1, 2, or 3 BHB molecules in an esterified form.
  • a compound of the current disclosure may be described as a surfactant, wherein it comprises a polar moiety and a non-polar or less polar moiety.
  • a compound of the current disclosure may be used to form a dimer, trimer, or polymer. In some cases, a compound of the current disclosure may be used to form a gemini surfactant.
  • a pharmaceutical composition disclosed herein may comprise a therapeutically-effective amount of a compound that is a surfactant. In some embodiments, a pharmaceutical composition disclosed herein may comprise a therapeutically-effective amount of a compound that is derived from, made from, or synthesized from a surfactant.
  • a surfactant may be a compound that is amphiphilic, wherein the compound contains both hydrophobic groups and hydrophilic groups.
  • the surfactant may contain both a water- insoluble, or oil-soluble, group and a water-soluble group.
  • a surfactant may be nonionic, anionic, ampholytic, zwitterionic, cationic, or a combination thereof.
  • Nonionic surfactants may be polyethyleneoxide condensates of alkyl phenols or the condensation products of aliphatic alcohols with from about 1 to about 25 moles of ethylene oxide.
  • Anionic surfactants may be alkali metal soaps such as the sodium, potassium, ammonium and alkylolammonium salts of higher fatty acids containing from about 8 to about 24 carbon atoms, or water-soluble salts, such as alkali metal, ammonium and alkylolammonium salts, of organic sulfuric reaction products having in their molecular structure an alkyl group containing from about 10 to about 20 carbon atoms and a sulfonic acid or sulfuric acid ester group.
  • alkali metal soaps such as the sodium, potassium, ammonium and alkylolammonium salts of higher fatty acids containing from about 8 to about 24 carbon atoms
  • water-soluble salts such as alkali metal, ammonium and alkylolammonium salts, of organic sulfuric reaction products having in their molecular structure an alkyl group containing from about 10 to about 20 carbon atoms and a sulfonic acid or sulfuric acid ester group.
  • Ampholytic surfactants may be aliphatic derivatives of secondary or tertiary amines, or aliphatic derivatives of heterocyclic secondary and tertiary amines in which the aliphatic radical can be straight chain or branched and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and at least one contains an anionic water-solubilizing group.
  • Zwitterionic surfactants can be derivatives of secondary and tertiary amines, derivatives of heterocyclic secondary and tertiary amines.
  • Cationic surfactants may be quaternary ammonium surfactants.
  • surfactants include docusate (dioctyl sodium sulfosuccinate), perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl ether phosphates, cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB), octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, phosphine oxide, dimethyl sulfoxide, sodium and potassium salts of ethylene-1
  • a compound may be used to form a dimer, wherein the monomers are connected via a covalent bond.
  • a compound may be used to form a dimer, wherein the monomers are connected through a linker.
  • the linker may connect via a polar group on the monomer.
  • the polar group of a compound of the current disclosure may be a carbonyl group.
  • Non-limiting examples of linkers can include those which form an amide bond, an ester bond, an ether bond, a carbonate bond, a carbamate bond, or a thioether bond, and such functional groups on the linker can be, for example, amino groups; carboxyl groups; aldehyde groups; azide groups; alkyne and alkene groups; ketones; carbonates; carbonyl functionalities bonded to leaving groups such as cyano and succinimidyl and hydroxyl groups.
  • a linker moiety may be covalently bound to any position, valence permitting, on a compound or salt of Formula (I).
  • a linker may be bound to R 1 , R 2 , R 3 , R 6 , or R 7 .
  • a sugar moiety may be attached to a compound or salt of the current disclosure.
  • the sugar moiety may be a monosaccharide, a simple sugar, a disaccharide, a 5- carbon sugar, or a 6-carbon sugar.
  • Examples of a sugar include fructose, galactose, glucose, maltose, lactose, sucrose, and others.
  • a compound of the current disclosure may be linked to a fructose moiety, wherein the linkage may be via the polar end of the compound.
  • a compound of the current disclosure may be linked to a glucose moiety, wherein the linkage may be via the polar end of the compound.
  • a sugar moiety may be covalently bound to any position, valence permitting, on a compound or salt of Formula (I).
  • a sugar moiety may be bound to R 1 , R 2 , R 3 , R 6 , or R 7 .
  • a nonpolar group can be attached to a compound of the current disclosure.
  • Nonpolar groups include, for example, an alkyl group, an alkenyl group, an alkynyl group, an ethylene glycol group, a glycerol group, or a combination thereof.
  • the effective amount of a compound or a salt thereof of this disclosure to be employed depends on the level of anesthesia to which the mammal is to be brought, the rate at which anesthesia is to be induced, and the length of time over which anesthesia is to be maintained.
  • the amount used should be sufficient to provide a significant anesthetic effect but not so much as to produce unacceptable deleterious side effects.
  • the amount of anesthesia to be used can be regulated, starting with a small amount of the compound and gradually increasing the amount until the desired plane of anesthesia is reached. By then monitoring the physical reactions of the mammal, as is the usual procedure, the duration and plane of anesthesia can be readily controlled.
  • each compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
  • an effective dosage may be in the range of about 0.001 to about 10,000 mg per kg body weight per day, in single or divided doses. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the disclosure provides a method for administration of a compound of the current disclosure to a subject in need thereof.
  • a pharmaceutical composition comprising a compound of the current disclosure is administered to a subject in need thereof.
  • a pharmaceutical composition comprising a compound of the current disclosure is administered to a solid tumor of a subject in need thereof.
  • Subjects may be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a compound or a salt thereof of the current disclosure that is administered to a subject may be monitored by determining the level of the compound in a biological fluid, for example, in the blood, blood fraction (e.g., serum), in the urine, in expired air, or other biological sample or biological tissue from the subject.
  • blood fraction e.g., serum
  • a pharmaceutical composition is administered to a patient in a unit dose.
  • a unit dose that is administered to a patient may comprise from about 0.0001 g - 500 g, 0.001 g - 250 g, 0.01 g - 100 g, 0.1 g - 50 g, 10 g - 25 g, 1 g - 10 g of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure.
  • a pharmaceutical composition comprises an amount of at least about, or equal to about: 0.0001 g, 0.001 g, 0.01 g, 0.1 g, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, 20 g, 21 g, 22 g, 23 g, 24 g, 25 g, 26 g, 27 g, 28 g, 29 g, 30 g, 31 g, 32 g, 33 g, 34 g, 35 g, 36 g, 37 g, 38 g, 39 g, 40 g, 41 g, 42 g, 43 g, 44 g, 45 g, 46 g, 47 g, 48 g, 49 g, 50 g, 51 g, 52
  • a pharmaceutical composition comprises from 0.001 – 2 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure in a single dose. In some embodiments, a pharmaceutical composition comprises an amount between about 50-150 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure. In some embodiments, a therapeutic amount can be an amount from about 0.001-0.1 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure. In some embodiments, a therapeutic amount can be an amount from about 0.01-30 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure.
  • a therapeutically effective amount of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure can sufficiently provide any one or more of the therapeutic effects described herein.
  • the therapeutic effective amount can be in the range of about 0.001-1000 mg/kg body weight, 0.01-500 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30 mg/kg body weight, 0.1- 200 mg/kg body weight, 3-200 mg/kg body weight, 5 - 500 mg/kg body weight, 10 - 100 mg/kg body weight, 10 - 1000 mg/kg body weight, 50- 200 mg/kg body weight, 100- 1000 mg/kg body weight, 200 – 500 mg/kg body weight, 250-350 mg/kg body weight, or 300 - 600 mg/kg body weight of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure.
  • the effective amount is at least about 0.01 mg/kg body weight of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure. In some embodiments, the effective amount is an amount from about 0.01 – 30 mg/kg body weight of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure. In some embodiments, the therapeutic amount can be an amount from about 50-150 mg/kg body weight of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure.
  • the therapeutic amount can be an amount of at least about, or equal to about (compound per kg of body weight): 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 105 mg/kg, 110 mg/kg, 115 mg/kg, 120 mg/kg, 125 mg/kg, 130 mg/kg, 135 mg/kg, 140 mg/kg, 145 mg/kg, 150 mg/kg, 155 mg/kg, 160 mg/kg, 165 mg/kg, 170 mg/kg, 175 mg/kg, 180 mg/kg, 185 mg/kg, 190 mg/kg, 195 mg/kg, 200 mg/kg, 205 mg/kg,
  • a therapeutically effective amount of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure can sufficiently provide any one or more of the therapeutic effects described herein.
  • the therapeutic effective amount can be formulated into a unit dose, wherein the unit dose may have a concentration in the range of about 0.001 milligrams/milliliter (mg/mL) -1000 mg/mL, 0.01 mg/mL - 500 mg/mL, 0.01 mg/mL - 100 mg/mL, 0.01 mg/mL - 30 mg/mL, 0.1 mg/mL - 200 mg/mL, 1 mg/mL - 200 mg/mL, 5 mg/mL - 500 mg/mL, 10 mg/mL - 100 mg/mL, 10 mg/mL - 1000 mg/mL, 50 mg/mL - 200 mg/mL, 100 mg/mL - 1000 mg/mL, 200
  • the therapeutic effective amount can be formulated into a unit dose, wherein the unit dose may have a concentration of at least about, or equal to about: 0.1 mg/mL (, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 5 mg/mL, 10 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 65 mg/mL, 70 mg/mL, 75 mg/mL, 80 mg/mL, 85 mg/mL, 90 mg/mL, 95 mg/mL, 100 mg/mL, 105 mg/mL, 110 mg/mL, 115 mg/mL, 120 mg/mL,
  • a compound herein e.g., BHB
  • the compound in the aqueous solution can have a concentration of a about: 0.01 nM to about 1 M, 1 nM to about 100 mM, 10 nM to about 10 mM, 10 nM to about 1 mM, 1 mM to about 100 mM or 10 mM to about 1M.
  • the compound in the aqueous solution can have a concentration of more than, less than, or about: 0.01 nM, 0.1 nM, 1.0 nM, 10 nM, 100 nM, 1000 nM, 0.01 mM, 0.1 mM, 1.0 mM, 10 mM, 100 mM, or 1000 mM.
  • a composition is provided in one or more unit doses.
  • a composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered each day, for example in individual doses administered once, twice, or three or more times a day.
  • dosages stated herein on a per day basis should not be construed to require administration of the daily dose each and every day.
  • two or more daily dosage amounts can be administered at a lower frequency, e.g., as a depot every second day to once a month or even longer.
  • a unit dose may be administered daily.
  • a unit dose may be administered every other day.
  • a unit dose of a compound or a salt thereof of the current disclosure may be administered as a solution and may have a certain concentration or molarity.
  • a unit dose (of a compound) may have a molarity of equal to about, or at least about: 0.01 molar (M), 0.05 M, 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.625 M, 0.7 M, 0.8 M, 0.9 M, 1 M, 1.1 M, 1.2 M, 1.3 M, 1.4 M, 1.5 M, 1.6 M, 1.7 M, 1.8 M, 1.9 M, 2 M, 3 M, 4 M, 5 M, 6 M, 7 M, 8 M, 9 M, 10 M, 15 M, 20 M, or 25 M.
  • a unit dose may have a molarity of about 1 M, 1.5 M, 2 M, 3M, 4 M, or 5M. In some cases, a unit dose may have a molarity of about 1 M, 1.5 M, 2 M, or 3M. In some cases, a unit dose may have a molarity of about 2 M. In some cases, a unit dose may have a molarity of about 1.5 M. In some cases, a unit dose may have a molarity of about 0.1 M, 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, or 0.7 M.
  • a unit dose of a compound or a salt thereof of the current disclosure may be a solution wherein the volume of the dose is at least about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 mL, 2 mL, 5 mL, 10 mL, or 20 mL.
  • the unit doses can be administered simultaneously or sequentially.
  • the composition can be administered for an extended treatment period.
  • the treatment period can be at least about one month, for example at least about 3 months, at least about 6 months or at least about 1 year. In some cases, administration can continue for substantially the remainder of the life of the subject.
  • administering can be performed at least about: 1 time per day, 2 times per day, 3 times per day, 4 times per day, 5 times per day, 6 times per day, 7 times per day, or more than 7 times per day. In some cases, administering can be performed daily, weekly, monthly, or as needed. In some cases, administration or application of a composition or a therapy disclosed herein can be performed continuously throughout a 24 hour period, for example, when an implant can be used for administration. [123] In some cases, administration or application of a composition or a therapy disclosed herein can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times a week.
  • administration or application of composition or a therapy disclosed herein can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90 times a month.
  • a composition can be administered as a single dose or as divided doses.
  • a composition or a therapy described herein can be administered at a first time point and a second time point.
  • a composition or a therapy can be administered such that a first administration can be administered before the other with a difference in administration time of 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year or more.
  • administration of a composition or a therapy disclosed herein can be performed for a treatment duration of at least about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600
  • a treatment duration can be from about: 1 to about 30 days, 1 to about 60 days, 1 to about 90 days, 30 days to about 90 days, 60 days to about 90 days, 30 days to about 180 days, from 90 days to about 180 days, or from 180 days to about 360 days.
  • administration of a composition or a therapy disclosed herein can be performed for a treatment duration of at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, or for life.
  • administration can be performed repeatedly over a lifetime of a subject, such as once a month or once a year for the lifetime of a subject.
  • Administration can be performed repeatedly over a substantial portion of a subject’s life, such as once a month or once a year for at least about 1 year, 5 years, 10 years, 15 years, 20 years, 25 years, 30 years, or more.
  • a composition or a therapy can be administered as needed, or for about: one day, two days, three days, four days, five days, six days, a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, or chronically.
  • administering can be performed for about: 1 day to about 8 days, 1 week to about 5 weeks, 1 month to about 12 months, 1 year to about 3 years, 3 years to about 10 years, 10 years to about 50 years, 25 years to about 100 years, or 50 years to about 130 years.
  • more than one compound or a salt thereof of the current disclosure may be administered at a time to a subject.
  • two compounds of the current disclosure in combination make act synergistically or additively, and either compound may be used in a lesser amount than if administered alone.
  • a compound or a salt thereof of the current disclosure may be a prodrug.
  • any compounds or salts thereof disclosed herein may be excluded from the claims.
  • Solutions of varying molarity of a compound of Formula I can be prepared. In some cases, solutions may be administered subcutaneously. A subject may become anesthetized and/or lose consciousness for a certain period of time, and wake up a certain period of time later.
  • Combination Therapy [131] In certain embodiments, a compound or a salt thereof disclosed herein and/or pharmaceutical compositions thereof can be used in combination therapy with other therapeutic agents for the treatment of a disease or condition. For example, beta hydroxybutyric acid (BHB), a derivative thereof, an ester thereof, or a salt thereof can be used in a combination therapy.
  • BHB beta hydroxybutyric acid
  • BHB Bacillus Calmette-Guérin
  • a compound or a salt thereof disclosed herein and/or pharmaceutical compositions thereof and the therapeutic agent can act additively or, more preferably, synergistically.
  • a compound or a salt thereof disclosed herein and/or pharmaceutical compositions thereof are administered concurrently or consecutively with the administration of another therapeutic agent.
  • a compound or a salt thereof disclosed herein and/or pharmaceutical compositions thereof may be administered together with another therapeutic agent.
  • a compound or a salt thereof disclosed herein and/or pharmaceutical compositions thereof are administered prior or subsequent to administration of other therapeutic agents.
  • a compound or a salt thereof disclosed herein may be used in combination with an enzyme inhibitor.
  • An enzyme inhibitor may bind to an enzyme and at least partially inhibit or decrease its activity. While not wishing to be bound by theory, an enzyme inhibitor may reduce the rate at which a compound, a salt thereof, or a metabolite thereof, of the current disclosure is eliminated or metabolized in a subject.
  • a compound or a salt thereof of the current disclosure may be used in combination with an enzyme inhibitor selected from: 3-methyl-2-oxobutanoate dehydrogenase, 3-methyl-2-oxobutanoate dehydrogenase, methylmalonyl-CoA mutase, arginase, amino-acid N-acetyltransferase, 3-oxoacid CoA-transferase, alcohol dehydrogenase, short-chain acyl-CoA dehydrogenase, and any combination thereof.
  • an enzyme inhibitor selected from: 3-methyl-2-oxobutanoate dehydrogenase, 3-methyl-2-oxobutanoate dehydrogenase, methylmalonyl-CoA mutase, arginase, amino-acid N-acetyltransferase, 3-oxoacid CoA-transferase, alcohol dehydrogenase, short-chain acyl-CoA dehydr
  • an enzyme inhibitor may be selected from: 2-chloro-4- methylpentanoate,2-chloroisocaproate, 2-oxobutanoate, 2-oxoglutarate, 2-oxopentanoate, 3- methyl-2-oxobutanoate, 3-methyl-2-oxopentanoate, 3-methylbutanoyl-CoA, 4-(2-thienyl)-2-oxo- 3-butenoate, 4-(3-thienyl)-2-oxo-3-butenoate, 4-methyl-2-oxopentanoate, alpha-ketoisocaproate, cinnamylpyruvate, D-3-methyl-2-oxopentanoate, furfurylidenepyruvate, L-3-methyl-2- oxopentanoate, and a salt of any one thereof.
  • an enzyme inhibitor may be selected from: 2-(N- morpholino)propane sulfonate buffer, 2-chloroisohexanoate, 2-oxo-3-methylpentanoate, 2- oxobutanoate, 2-oxohexanedioate, 2-oxohexanoate, 2-oxoisocaproate, 2-oxoisopentanoate, 2- oxopentanoate, 3-methyl-2-oxobutanoate, 4-(2-thienyl)-2-oxo-3-butenoate, 4-(3-thienyl)-2-oxo- 3-butenoate, 4-hydroxyphenylacetate, 4-hydroxyphenyllactate, 4-hydroxyphenylpyruvate, 4- methyl-2-oxopentanoate, alpha-chloroisocaproate, alpha-ketoisocaproate, alpha-ketoisovalerate, branched-chain
  • an enzyme inhibitor may be selected from: 2-(N,N- diethylamino)-diazenolate-2-oxide, 5,5'-dithiobis(2-nitrobenzoic acid), p-chloromercuribenzoate, p-hydroxymercuribenzoate, and a salt of any one thereof.
  • an enzyme inhibitor may be selected from: (-)-epicatechin, (2S)-2-amino-3-(2-amino-1H-imidazol-5-yl)propanoic acid, (2S)-2-amino-5-(1H-imidazol-2- ylamino)pentanoic acid, (2S,5E)-2-amino-7-oxohept-5-enoic acid, (R)-2-amino-6-borono-2-[2- (piperidin-1-yl)ethyl]hexanoic acid, (R)-2-amino-6-borono—2[1-(3,4-dichlorobenzyl)piperidin- 4-yl]hexanoic acid, (S)-(2-boronoethyl)-L-cysteine, (S)-2-amino-7-oxoheptanoic acid, 2(S)- amino-6-boronohexa
  • an enzyme inhibitor may be selected from: 2,2- difluorosuccinate, 2,4-Dinitrophenylacetate, 2-Nitro-5-(thiocyanato)benzoate, 3-sulfopropanoate, 4-nitrophenylacetate, 5,5'-dithiobis(2-nitrobenzoic acid), acetylimidazole, desulfopantetheine, dtnb, glutarate, iodoacetamide, malate, maleamate, maleimide, monomethylsuccinate, N- acetylaletheine, N-acetylcysteamine, N-ethylmaleamate, N-ethylmaleimide, pantothenol, perfluorosuccinate, succinamate, and a salt of any one thereof.
  • an enzyme inhibitor may be selected from: 1,10- phenanthroline, 1,2-dithioglycerol, 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-butanedithiol, 1,4- dioxane, 1,4-dithioerythritol, 1,4-dithiothreitol, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-hydroxypyridine-2-thione, 1-thio-1-phenylmethane, 1-thioacetamide, 1-thioacetate, 1- thiobutane, 1-thioethane, 1-thioglycerol, 1-thiopropane, 1-thiosorbitol, 12-hydroxydodecanoate, 2,2'-bipyridine, 2,2'-bipyridyl, 2,2'-dipyridyl, 2,2,2-trifluoroethanol, 2,4-dinitrophenol, 2-
  • an enzyme inhibitor may be selected from: 1-azepan-1-yl-2- phenyl-2-(4-thioxo-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-yl)-ethanone, 3-Chloro-3- butenoylpantetheine, 3-Pentenoylpantetheine, 4-chloromercuribenzoate, diethyl dicarbonate, iodoacetamide, N-ethylmaleimide, p-hydroxymercuribenzoate, and a salt of any one thereof.
  • a compound or a salt thereof disclosed herein may be used in combination with a weight loss therapeutic.
  • a compound disclosed herein can be used in combination with a weight loss therapeutic for the treatment of obesity.
  • a weight loss therapeutic can comprise orlistat, phentermine, topiramate, fenfluramine, naltrexone, bupropion, liraglutide, zonisamide, 5-hydroxytryptophan, carbidopa, pramlintide, metreleptin, tirzepatide, ephedrine, caffeine, acetylsalicylic acid, sibutramine, metformin, semaglutide, a derivative of any of these, a salt of any of these, or any combination thereof.
  • a weight loss therapeutic can comprise a noradrenergic drug or a salt thereof.
  • a weight loss therapeutic can comprise Glucagon-like peptide 1 (GLP-1) or a derivative thereof.
  • GLP-1 Glucagon-like peptide 1
  • a weight loss therapeutic can comprise an analogue of a gastric inhibitory polypeptide such as a tirzepatide or a salt thereof.
  • a weight loss therapeutic can comprise a GLP-1 receptor agonist.
  • a weight loss therapeutic can comprise exenatide, liraglutide, lixisenatide, a salt of any of these, or any combination thereof.
  • a weight loss therapeutic can be administered in a therapeutically effective amount.
  • a weight loss therapeutic can comprise, a therapy (e.g., an exercise, a psychotherapy, a diet, or any combination thereof).
  • a weight loss therapeutic can comprise a surgery, for example, a bariatric surgery.
  • a bariatric surgery can comprise a gastric band, a sleeve, a bypass, or a combination thereof.
  • a compound or salt thereof disclosed herein can be administered alone or in combination with an additional therapy to treat a cancer in a subject.
  • BHB, a derivative thereof, or a salt thereof can be administered with an additional cancer therapy to treat a cancer in a subject.
  • an additional cancer therapy can comprise a surgery, a chemotherapy, a hormone therapy, a hyperthermia therapy, an immunotherapy, a photodynamic therapy, a radiation therapy, a stem cell transplant therapy, a targeted therapy or any combination thereof.
  • a targeted therapy can comprise a small molecule drug, or a monoclonal antibody.
  • a surgery can comprise a surgery to remove a tumor.
  • a radiation therapy can comprise an external beam radiation therapy, an internal radiation therapy, or both.
  • an external beam radiation therapy can comprise a three-dimensional conformal radiation therapy (3D-CRT), an intensity modulated radiation therapy (IMRT), a proton beam therapy, an image-guided radiation therapy (IGRT), a stereotactic radiation therapy (SRT), or a combination thereof.
  • a radiation therapy can comprise a permanent implant, a temporary internal radiation therapy, or both.
  • a radiation therapy can comprise an intraoperative radiation therapy (IORT), a systemic radiation therapy, a radioimmunotherapy, a radiosensitizer and radioprotector or any combination thereof.
  • a hormone therapy can comprise an aromatase inhibitor, an anastrozole, an exemestane, a letrozole, a selective estrogen receptor modulator, a tamoxifen, a raloxifene, an estrogen receptor antagonist, a fulvestrant, a toremifene, a luteinizing hormone- releasing hormone agonist, a goserelin, a leuprolide, a triptorelin, a n anti-androgen, an apalutamide, an enzalutamide, a darolutamide, a bicalutamide, a flutamide, a nilutamide, an androgen deprivation therapy, a CYP17 inhibitor, an abiraterone, a ketoconazole, a degarelix, a progestin, a medroxyprogesterone acetate, a megestrol acetate, an adrenolytic
  • a chemotherapy can comprise an altretamine, a busulfan, a carboplatin, a carmustine, a cisplatin, a cyclophosphamide, a dacarbazine, an ifosfamide, a lomustine, a melphalan, a temozolomide, a trabectedin, a 5- fluorouracil, a 6-mercaptopurine, an azacitidine, a capecitabine, a clofarabine, a cytarabine, a floxuridine, a fludarabine, a gemcitabine, a methotrexate, a pemetrexed, a pentostatin, a pralatrexate, trifluridine and tipiracil, a vincristine, a vinblastine, a vinorelbine, a paclitaxel, a docetaxel, an etoposide, a
  • an immunotherapy can comprise pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, tisotumab vedotin- tftv, relatlimab, a tumor-infiltrating lymphocyte (TIL) therapy, an engineered T-cell receptor (TCR) therapy, a CAR T-cell therapy, a natural killer (NK) cell therapy, a monoclonal antibody, a conjugated monoclonal antibody, a bispecific monoclonal antibody, a HEPLISAV-B, quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine, sipuleucel-T, talimogene laherparepvec (T-VEC), Bacillus Calmette-Guérin (BCG), an interleukin an interferon, an immunomodulator, imiqui
  • BHB, a derivative thereof, or a salt thereof can be administered with a Bacillus Calmette- Guérin therapy to treat a cancer (e.g., a bladder cancer) in a subject.
  • a second therapy can comprise an immune system modulator, a cancer vaccine, an oncolytic virus therapy, an adoptive cell therapy, an immune checkpoint inhibitor or any combination thereof.
  • an immune checkpoint inhibitor can comprise a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TF inhibitor, a LAG-3 inhibitor or any combination thereof.
  • Bacillus Calmette-Guérin (BCG) can comprise a mutated version of Bacillus Calmette-Guérin (BCG).
  • a mutated version of BCG can comprise a bacteria with at least about: 97%, 98%, 99% sequence identity to the whole genome of the 16s rRNA sequence of the wild type BCG.
  • an additional therapy can comprise a nadofaragene firadenovec-vncg, an avelumab, an erdafitinib, an avelumab, a cisplatin, a doxorubicin hydrochloride, an enfortumab vedotin-ejfv, a mitomycin, a pembrolizumab, a mitomycin, a nadofaragene firadenovec-vncg, a nivolumab, a nivolumab, an enfortumab vedotin-ejfv, a pemigatinib, a pembrolizumab, a pemigatini
  • a compound or a salt thereof of the current disclosure may be dosed in combination with another class of drugs, including, but not limited to, antidepressants, tricyclic antidepressants, amiodarone, antihistamines, beta adrenergic agonists, cyclosporine a, depakote, lamotrigine, lithium, metoclopramide, monoamine oxidase inhibitors, neuroleptics, nicotine, nifedipine, theophylline, thyroid hormones, valproic acid, and any combination thereof.
  • a combination therapy e.g., a second therapeutic or a third therapeutic
  • a composition disclosed herein can be administered by any method.
  • a composition or an additional therapeutic is administered orally, for example, in the form of a liquid, a pill, or a capsule.
  • a composition can be delivered by parenchymal injection, intra-thecal injection, intra-ventricular injection, intra-tumoral injection, intra-cisternal injection, or any combination thereof.
  • a method of administration can be by inhalation, intraarterial injection, intracerebroventricular injection, intracisternal injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intravenous injection, intraventricular injection, stereotactic injection, subcutaneous injection, or any combination thereof.
  • delivery can comprise buccal administration, by infusion administration, nasal administration, otic administration, ophthalmic administration, sublingual administration, or transdermal administration.
  • Delivery can include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular or infusion), oral administration, nasal administration, inhalation administration, anal administration, intraduodenal administration, rectal administration.
  • delivery can include delivery of a composition by a surgery, or by an injection. Delivery can include topical administration to an external surface of a surface, such as a skin.
  • a therapy disclosed herein can be administered consecutively or concurrently to an additional therapy. [147]
  • an additional therapy is administered to a patient in a unit dose.
  • a unit dose that is administered to a patient may comprise from about 0.0001 g - 500 g, 0.001 g - 250 g, 0.01 g - 100 g, 0.1 g - 50 g, 10 g - 25 g, 1 g - 10 g of a pharmaceutical composition, a compound, or a salt thereof of the current disclosure.
  • an additional therapy comprises an amount of at least about, or equal to about: 0.0001 g, 0.001 g, 0.01 g, 0.1 g, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, 20 g, 21 g, 22 g, 23 g, 24 g, 25 g, 26 g, 27 g, 28 g, 29 g, 30 g, 31 g, 32 g, 33 g, 34 g, 35 g, 36 g, 37 g, 38 g, 39 g, 40 g, 41 g, 42 g, 43 g, 44 g, 45 g, 46 g, 47 g, 48 g, 49 g, 50 g, 51 g, 52 g
  • an additional therapy comprises from 0.001 g – 2 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure in a single dose. In some embodiments, an additional therapy comprises an amount between about 50 g -150 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure. In some embodiments, an additional therapy can be an amount from about 0.001 g -0.1 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure. In some embodiments, an additional therapy can be an amount from about 0.01 g -30 g of a therapeutic composition, a compound, or a salt thereof of the current disclosure.
  • a therapeutically effective amount of an additional therapy of the current disclosure can sufficiently provide any one or more of the therapeutic effects described herein.
  • the therapeutic effective amount can be in the range of about 0.001-1000 mg/kg body weight, 0.01-500 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30 mg/kg body weight, 0.1- 200 mg/kg body weight, 3-200 mg/kg body weight, 5 - 500 mg/kg body weight, 10 - 100 mg/kg body weight, 10 - 1000 mg/kg body weight, 50- 200 mg/kg body weight, 100- 1000 mg/kg body weight, 200 – 500 mg/kg body weight, 250-350 mg/kg body weight, or 300 - 600 mg/kg body weight of an additional therapy.
  • the effective amount is at least about 0.01 mg/kg body weight of an additional therapy. In some embodiments, the effective amount is an amount from about 0.01 – 30 mg/kg body weight of an additional therapy. In some embodiments, the therapeutic amount can be an amount from about 50-150 mg/kg body weight of an additional therapy.
  • the therapeutic amount can be an amount of at least about, or equal to about (compound per kg of body weight): 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 105 mg/kg, 110 mg/kg, 115 mg/kg, 120 mg/kg, 125 mg/kg, 130 mg/kg, 135 mg/kg, 140 mg/kg, 145 mg/kg, 150 mg/kg, 155 mg/kg, 160 mg/kg, 165 mg/kg, 170 mg/kg, 175 mg/kg, 180 mg/kg, 185 mg/kg, 190 mg/kg, 195 mg/kg, 200 mg/kg, 205 mg/kg,
  • the (R)- and (S)-isomers of the compounds, or salts thereof, of the present disclosure may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diasteroisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • compositions which contain, as the active ingredient, one or more of the compounds of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, carriers, diluents, permeation enhancers, solubilizers and adjuvants.
  • One or more compounds of Formula I may be administered alone or in combination with other therapeutic agents (e.g., vasoconstrictors, anti-inflammatory agents, antibiotics, other monobinding anesthetic bases and salts, counter-irritants), carriers, adjuvants, permeation enhancers, and the like.
  • therapeutic agents e.g., vasoconstrictors, anti-inflammatory agents, antibiotics, other monobinding anesthetic bases and salts, counter-irritants
  • carriers e.g., vasoconstrictors, anti-inflammatory agents, antibiotics, other monobinding anesthetic bases and salts, counter-irritants
  • adjuvants e.g., permeation enhancers
  • permeation enhancers e.g., permeation enhancers, and the like.
  • Pharmaceutically acceptable salts of the active agents e.g., acid addition salts
  • a compound or a salt thereof of Formula I or any compound or therapy of the disclosure may be administered by any of the accepted modes of administration of agents having similar utilities, for example, by oral, topical, intradermal, intravenous, subcutaneous, intramuscular, intra-articular, intraspinal or spinal, epidural, rectal, vaginal, or transdermal/transmucosal routes. The most suitable route will depend on the nature and severity of the condition being treated. Subcutaneous, intradermal and percutaneous injections can be routes for a compound or a salt thereof of this disclosure. In some embodiments, a compound, a salt thereof, or a therapy of the present disclosure may be administered by intravesical administration.
  • BCG and/or BHB can be administered by intravesical administration for a bladder cancer.
  • urine can be replaced with a chemotherapy or immunotherapy alone or in combination with BHB to treat the bladder cancer.
  • a compound or a salt thereof of the current disclosure may be administered subcutaneously.
  • a compound or a salt thereof of the current disclosure may be administered intravenously.
  • Sublingual administration may be a route of administration for a compound or a salt thereof of this disclosure.
  • the active ingredient can be diluted by an excipient.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, PEG, polyvinylpyrrolidone, cellulose, water, sterile saline, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • a pharmaceutically acceptable excipient can comprise acacia, acesulfame potassium, acetic acid, glacial, acetone, acetyl tributyl citrate, acetyl triethyl citrate, agar, albumin, alcohol, alginic acid, aliphatic polyesters, alitame, almond oil, alpha tocopherol, aluminum hydroxide adjuvant, aluminum oxide, aluminum phosphate adjuvant, aluminum stearate, ammonia solution, ammonium alginate, ascorbic acid, ascorbyl palmitate, aspartame, attapulgite, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, but
  • stearic acid pregelatinized, sterilizable maize
  • stearyl alcohol sucralose, sucrose, sugar, compressible, sugar, confectioner’s, sugar spheres, sulfobutylether b-cyclodextrin, sulfuric acid, sunflower oil, suppository bases, hard fat, talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, vegetable oil, hydrogenated, water, wax, anionic emulsifying, wax (e.g.
  • a compound or a salt thereof of the current disclosure is allowed to reside in the bladder for about: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 hours.
  • a compound or a salt thereof of the current disclosure is allowed to reside in the bladder for up to: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 hours. In some embodiments, a compound or a salt thereof of the current disclosure is allowed to reside in the bladder for: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 hours.
  • a compound or a salt thereof is allowed to reside in the bladder for about: 10 min to about 24 hours, 5 min to about 60 min, 10 min to about 30 min, 30 min to about 2 hours, 1 hour to about 6 hours, or 4 hours to about 12 hours.
  • a compound or salt thereof such as BHB or a salt thereof, can be administered in an aqueous solution.
  • an aqueous solution can be heated or it can be cooled as compared to room temperature.
  • a pH of a composition comprising a compound can be adjusted.
  • the pH of a composition comprising compound or a salt thereof can be about: 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.
  • the pH of a composition comprising compound of a salt thereof can range from about: 5.0 to about 8.0, 5.2 to about 7.6, 5.5 to about 7.5, 6.0 to about 7.0 or about 6.5 to about 7.5.
  • an aqueous solution can be about: 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, or 38°C. In some cases, an aqueous solution can be about: 20°C to about 38°C, 23°C to about 37°C, 25°C to about 33°C, or 30°C to about 35°C.
  • a pharmaceutical composition (e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, sublingual delivery, or other method) may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • a composition herein can be administered as a food or a beverage.
  • At least one of the compounds described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • a compound or a salt thereof may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a compound included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the compounds described herein may be formulated for sustained or slow release (also called timed release or controlled release).
  • sustained or slow release also called timed release or controlled release
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release.
  • Non-limiting examples of excipients include water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the amount of compound contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.
  • a compound or a salt thereof of this disclosure may be solubilized and encapsulated (e.g., in a liposome or a biodegradable polymer), or used in the form of microcrystals coated with an appropriate nontoxic lipid.
  • a compound or a salt thereof of the current disclosure may be dissolved in intralipid before administration to a subject.
  • the concentration of intralipid may be 10%, 20%, or 30%.
  • the intralipid may be purchased or manufactured.
  • the compositions may be formulated to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across tissue barriers.
  • these compositions may be formulated as oral sprays.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. A nebulizer may be used to create a mist from a liquid dosage form.
  • compositions can be in the form of emulsions, creams, jelly, solutions, ointments containing, for example, up to 5% by weight of the active compound.
  • compositions can be in the form of sterile injectable solutions and sterile packaged powders.
  • Another formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound or a salt thereof of the present disclosure in controlled amounts. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the compositions are preferably formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., an ampoule).
  • a suitable pharmaceutical excipient e.g., an ampoule.
  • a compound or a salt thereof described herein can be formulated as pharmaceutical compositions which are suitable for intravenous administration.
  • a compound or a salt thereof of the present disclosure can be formulated in aqueous media using water-immiscible solvents, solubilizers, emulsifiers, surfactants or other solubilizing agents.
  • Individual formulations may include one or more additional components such as stabilizers, tonicity modifiers, bases or acids to adjust pH, and solubilizers.
  • the formulations can also optionally contain a preservative, such as ethylenediaminetetraacetic acid (EDTA) or sodium metabisulfate, to prevent the growth of microorganisms.
  • EDTA ethylenediaminetetraacetic acid
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non- toxic in the amounts employed.
  • the pharmaceutical formulations can also include stabilizing agents, which can alternatively be considered as co-emulsifiers.
  • Anionic stabilizers include phosphatidylethanolamines, conjugated with polyethylene glycol, (PEG-PE) and phosphatidylglycerols, a specific example of which is dimyristolphosphatidylgylcerol (DMPG).
  • Additional examples of useful stabilizers include oleic acid and its sodium salt, cholic acid and deoxycholic acid and their respective salts, cationic lipids such as stearylamine and oleylamine, and 3 ⁇ -[N-(N′,N′-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol).
  • the pharmaceutical compositions of the disclosure can be made isotonic with blood by the incorporation of a suitable tonicity modifier.
  • Glycerol is most frequently used as a tonicity modifier.
  • Alternative tonicity modifying agents include xylitol, mannitol, and sorbitol.
  • the pharmaceutical compositions are typically formulated to be at physiologically neutral pH, typically in the range 6.0–8.5.
  • the pH can be adjusted by the addition of base, for example sodium hydroxide or sodium bicarbonate, or in some cases acid, such as hydrochloric acid.
  • Solutions containing a compound or a salt thereof of present disclosure may be administered by injection or infusion, using suitable devices such as regular syringes or infusion devices, in the form of a pharmaceutical preparation which contains at least one compound or a salt thereof of the disclosure either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, such as for example hydrochloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier.
  • the concentration of active compound in a solution for injection may be from 0.01% to 10% by weight of the preparation.
  • Preferred solutions for injection or infusion or infiltration may be prepared as aqueous solutions of a water soluble, pharmaceutically acceptable salt of the active compound.
  • solutions may also contain stabilizing agents, antibacterial agents, buffering agents and may be manufactured in different dosage unit ampoules, single-use syringes or bottles.
  • quantity of the formulation containing the drug to be administered will be determined on an individual basis, and will be based on the pharmacological potency of the drug, the route of administration and at least in part on consideration of the individual’s size, the severity of the symptoms to be treated and the results sought.
  • quantities of a compound or a salt thereof of the disclosure sufficient to eliminate the unwanted condition will be administered.
  • the actual dosage (concentration and volume) and the number of administrations per day will depend on the pharmacokinetic properties of the drug and the mode of drug administrations, for example, for infiltration anesthesia of the skin.
  • a compound herein, such as BHB or a derivative thereof can be administered by a device.
  • a device can comprise a pump.
  • a pump can be an infusion pump.
  • a pump can be a closed loop pump.
  • a pump can measure a concentration of a compound administered herein.
  • a pump can administer a therapeutically effective amount of a compound disclosed herein.
  • a pump can measure a concentration of a compound administered herein or a metabolite thereof and deliver a therapeutically effective amount of a compound disclosed herein depending on the concentration measured.
  • a pump can be operably connected to a device that measures a concentration of a compound administered herein or a metabolite thereof.
  • the device that measures a concentration of a compound administered herein or a metabolite thereof can provide instructions to a pump to administer a compound disclosed herein.
  • a pump can measure the BHB concentration in a subject and can deliver an appropriate dose depending on the BHB concentration in the subject. If the subject has a low BHB concentration the pump can administer a therapeutically effective amount of BHB.
  • a pump can be used for the treatment of epilepsy, obesity (overweight), and any other condition disclosed herein.
  • the BHB concentration can be measured in a biological sample of a subject.
  • the biological sample can comprise blood, saliva, urine, or any other biological substance.
  • a compound or a salt thereof of the present disclosure can be administered topically to ocular mucous membranes of the eye or the mucous membranes surrounding the eye.
  • Formulations such as for example solutions, suspensions, gels or ointments may be useful.
  • Compatible carriers which may be used in this disclosure, comprise e.g. an aqueous solution, such as saline solutions, oil solutions or ointments.
  • Formulations for ocular use may also contain compatible and pharmaceutically acceptable excipients, such as preservatives, surfactants, stabilizing agents, antibacterial agents, buffering agents and agents such as for example polymers to adjust viscosity, vasoconstrictors, antihistaminic agents or anti- inflammatory agents. These formulations may be manufactured in different dosage units, suitable for ocular administration. Also drug inserts, either soluble or insoluble, may be used. [173] In the present method, a compound or a salt thereof of the present disclosure can be administered topically to non-ocular mucous membranes, such as for example oral, otic, nasal, respiratory, pharyngeal, tracheal, esophageal, urethral, or vaginal membranes.
  • non-ocular mucous membranes such as for example oral, otic, nasal, respiratory, pharyngeal, tracheal, esophageal, urethral, or vaginal membranes.
  • Formulations containing at least one compound or a salt thereof of the disclosure useful for such membranes may be for example solutions, sprays, suspensions, gels, creams or ointments.
  • Compatible and pharmaceutically acceptable carriers which may be used in this disclosure, comprise e.g., an aqueous solution, such as saline solutions, oil solutions or ointments.
  • Formulations for ocular use may also contain compatible and pharmaceutically acceptable excipients, such as preservatives, surfactants, stabilizing agents, antibacterial agents, buffering agents and agents such as for example polymers to adjust viscosity, vasoconstrictors, antihistaminic agents or anti- inflammatory agents.
  • Said formulations may be manufactured in different dosage units, suitable for ocular administration.
  • injectable solutions may contain a vasoconstrictor (e.g., epinephrine or vasopressin); a solution for infusion or regional anesthesia may contain glucose or dextrose, a gel for urogenital topical procedures may contain thickening agents (e.g., hydroxypropylmethylcellulose); a preparation for topical or dermal application may contain penetration promoting agents (e.g., hydroxypolyethoxydodecane, DMSO, DMAC); sprays for topical anesthesia of the mouth and oropharynx may contain saccharin and alcohol, ointments for accessible mucous membranes may contain a lubricant.
  • vasoconstrictor e.g., epinephrine or vasopressin
  • a solution for infusion or regional anesthesia may contain glucose or dextrose
  • a gel for urogenital topical procedures may contain thickening agents (e.g., hydroxypropylmethylcellulose)
  • a compound or a salt thereof of the present disclosure can also be administered together with other membrane stabilizers (local anesthetics), for example to form eutectic mixtures.
  • a compound or a salt thereof of the present disclosure can also be administered together with other therapeutically active compounds, such as capsaicin, Substance-P inhibitors or antagonists, vaso-active compounds, anti-inflammatory agents, etc.
  • compound or a salt thereof of the current disclosure may be used for local injection (agents for local anesthesia).
  • composition for local anesthesia of the present disclosure can be provided as a composition for injection in a form of an aqueous solution in which the aforementioned components and optional pharmaceutical additives, which are available for those skilled in the art as additives to be formulated in compositions for topical injections, are dissolved in distilled water for injection.
  • the composition for local anesthesia of the present disclosure can also be prepared as a pharmaceutical preparation in a dried form such as a lyophilized preparation, and dissolved when used. Generally, the composition is provided for clinical use after being filled in ampoules, vials, cartridges or the like under sterile condition.
  • a dosage of a composition herein may be administered once per day or several or multiple times per day.
  • BHB can be administered once per day or once every 2 days.
  • BHB, a derivative thereof, an ester thereof, or salt thereof and a second therapeutic can be administered 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times per day.
  • a composition disclosed herein can be administered once, twice, or three times in a 24- hour period.
  • a composition herein can be administered every: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more than 12 months.
  • a composition herein can be administered once every other week for about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some cases, a composition herein can be administered for a period of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more than 12 months. In some cases, a composition herein can be administered as needed.
  • the amount of the drug administered to practice methods of the present invention will of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the dose used to practice the invention can produce the desired therapeutic or prophylactic effects, without producing undesired side effects.
  • a compound or a salt thereof of the present disclosure are administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician or clinician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • a compound or a salt thereof of the present disclosure can be prepared by a method well-known to those skilled in the art. However, methods for preparing the composition of the present disclosure are not limited to those described in the examples, and appropriate alterations and modifications can be added to these methods.
  • Indications [181] A compound or a salt thereof as described herein can be used for the treatment of a disease or condition. In some cases, a compound or a salt can be used in the manufacture of a medicament for the treatment a disease or condition. In some cases, a disease or condition can comprise an obesity, an overweight, a cancer (e.g., a bladder cancer), a traumatic brain injury (TBI), or any combination thereof.
  • TBI traumatic brain injury
  • a compound or a salt thereof of the present disclosure can be used for the induction and/or maintenance of general anesthesia, for example to permit the performance of surgery or other painful procedures; for the initiation and/or maintenance of sedation with patients spontaneously breathing, and for the induction and/or maintenance of sedation for intubated, mechanically ventilated patients.
  • a compound or a salt thereof of the present disclosure can also be administered in combination with other therapeutic agents, such as, for example, other anesthetics or sedatives, or analgesics (e.g., an opioid).
  • the compositions of the disclosure can optionally further comprise another therapeutic agent, for example, an anesthetic, sedative, or analgesic.
  • the therapeutic methods of the disclosure can also optionally comprise administering another therapeutic agent (e.g., an anesthetic, sedative, or analgesic) to the mammal.
  • another therapeutic agent e.g., an anesthetic, sedative, or analgesic
  • a continuous infusion of a compound or a salt thereof of the present disclosure can be used to maintain anesthesia or sedation following induction with another sedative hypnotic agent.
  • a bolus dose of a compound or a salt thereof of the current disclosure to induce anesthesia or sedation can be followed by infusion of a different sedative hypnotic agent.
  • the duration of action of a local anesthetic is proportional to the time during which it is present at effective concentrations in contact with the nerve, or, more precisely, the ion channel(s).
  • the effect of most currently used local anesthetics tends to be short-lived as a result of dissociation from and diffusion away from the intended site of action; therefore, repeated doses must be administered for a prolonged effect.
  • Undesired side effects of local anesthetics are largely a function of systemic concentrations of the drug resulting from such diffusion. These effects include paralysis of cardiac and smooth muscle systems, or undesired stimulation of the CNS. Because of these serious side effects, the quantity of drug administered must be carefully controlled.
  • Objectives of the present disclosure include methods of inducing anesthesia, inducing sedation, treating central nervous system disorders, peripheral nervous system disorders, psychiatric disorders, ischemia, insomnia, or treating with an anticonvulsant.
  • a compound or a salt thereof of the present disclosure can be used to induce anesthesia in a patient by administration of a therapeutically effective amount of compound or a salt thereof to a subject.
  • the compositions and methods disclosed herein can be utilized as an anesthetic.
  • a compound or a salt thereof of the present disclosure e.g., BHB, a derivative thereof, an ester thereof, or salt thereof
  • Conduction anesthesia blocks transmission of nerve impulses between a targeted part of the body and the spinal cord, and causes loss of sensation in the targeted body part.
  • a subject treated with a compound or a salt thereof of the current disclosure and under conduction anesthesia may remain fully conscious.
  • a compound or a salt thereof of the current disclosure may also be used within at least two categories of regional anesthesia.
  • a peripheral blockade inhibits sensory perception in a local body part, such as, for example, the numbing of a tooth area for dental work or administering a nerve block to stop sensation from an entire limb.
  • a central blockade administers the anesthetic around the spinal cord, suppressing all sensation below the block.
  • instances of local anesthetics include, but are not limited to, infiltration anesthesia, perisurgical tissue anesthesia, field block anesthesia, peripheral nerve block anesthesia, epidural anesthesia, spinal anesthesia, bier block anesthesia, and combinations thereof.
  • Sedation is the depression of a subject’s awareness to the environment and lowering of general responsiveness to external stimulation. A few levels of sedation include minimal sedation, moderate sedation, deep sedation, and general anesthesia.
  • Applications that may use a compound or a salt thereof of the current disclosure to induce anesthesia include, but are not limited to, local surgery, regional surgery, arm surgery, hand surgery, face, neck, head, torso, abdominal, lower abdominal pelvic, rectal, lower extremity surgery, minor operations in oral surgery and dental treatment, such as operations which can be completed in several to ten minutes such as tooth extraction in dental treatment.
  • oral surgery and dental treatment such as operations which can be completed in several to ten minutes such as tooth extraction in dental treatment.
  • applicable operations are not limited to the uses in the oral surgery and dental treatment, and the composition can be used for surgical local anesthesia such as for skin incision.
  • Applications that may use a compound or a salt thereof of the current disclosure to induce infiltration anesthesia include, but are not limited to, subcutaneous infiltration, including IV placement, superficial/shave biopsy, suturing; wound infiltration, including postoperative pain control at incision site; intraarticular injections, including postsurgical pain control, arthritic joint pain control; and infiltrative nerve blocks, including ankle block, scalp block, Bier block, wrist block, and digit block.
  • Types of surgeries that may need a method of inducing anesthesia with a compound or a salt thereof of the current disclosure includes, but is not limited to, dental surgery, oral surgery, cosmetic surgery, upper body surgery, lower body surgery, abdominal liposuction, adrenalectomy, alveolar cleft surgery, ankle replacement, aortic valve repair surgery, arm biopsy, arm liposuction, arthrocentesis, arthroscopic finger fusion, arthroscopic foot joint replacement, arthroscopic revision hip surgery, arthroscopic total knee replacement, back and neck surgery, back surgery, beating heart pulmonary artery valve replacement, bilateral salpingectomy, bone grafting, breast reconstruction, breast augmentation, brow lift, bunion surgery, buttock lift, calf augmentation, cardiopulmonary bipass, cataract surgery, central venous catheter placement, cerebral aneurysm repair, cervical spine fusion, Cesarean section delivery, cheek augmentation, chest wall resection, chin lift, cleft lip surgery, colectomy, cornea transplant, coronary artery bypass, elbow
  • a compound that may be used as an anesthetic may be a compound that binds to the cellular membrane, acts on the central nervous system, is able to achieve high concentration within the body, or a combination thereof.
  • the compositions and methods disclosed herein can be utilized to treat a neurological disease or disorder.
  • the neurological disease or disorder is pain. Pain can be acute pain or can be chronic pain. Pain can be nociceptive pain (i.e., pain caused by tissue damage), neuropathic pain or psychogenic pain.
  • the pain is caused by or associated with a disease (e.g., cancer, arthritis, diabetes). In other cases, the pain is caused by injury (e.g., sports injury, trauma).
  • Non-limiting examples of pain that are amenable to treatment with the compositions and methods herein include: neuropathic pain including peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, neuropathy associated with cancer, neuropathy associated with HIV/AIDS, phantom limb pain, carpal tunnel syndrome, central post-stroke pain, pain associated with chronic alcoholism, hypothyroidism, uremia, pain associated with multiple sclerosis, pain associated with spinal cord injury, pain associated with Parkinson’s disease, epilepsy, osteoarthritic pain, rheumatoid arthritic pain, visceral pain, and pain associated with vitamin deficiency; and nociceptive pain including pain associated with central nervous system trauma, strains/sprains, and burns; myocardial infarction, acute pancreatitis, post-operative pain, posttraumatic pain, renal colic, pain associated with cancer, pain associated with fibromyalgia, pain associated with carpal tunnel syndrome, and back pain
  • compositions of the current disclosure may also be used in personal care products.
  • Personal care products may include, but are not limited to, shave cream, toothpaste, creams, gels, lotions, ointments, wax, or combinations thereof.
  • the compositions and methods herein may be utilized to ameliorate a level of pain in a subject.
  • a level of pain in a subject is ameliorated by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100%.
  • a level of pain in a subject can be assessed by a variety of methods.
  • a level of pain is assessed by self-reporting (i.e., a human subject expresses a verbal report of the level of pain he/she is experiencing).
  • a level of pain is assessed by behavioral indicators of pain, for example, facial expressions, limb movements, vocalization, restlessness and guarding. These types of assessments may be useful for example when a subject is unable to self-report (e.g., an infant, an unconscious subject, a non-human subject).
  • a level of pain may be assessed after treatment with a composition of the disclosure as compared to the level of pain the subject was experiencing prior to treatment with the composition.
  • Anesthetic recovery can be categorized in at least four main classes. In stage 1, all functions are normal. In stage 2, the subject may be able to maintain itself in a desired position, or can stand and move about, but may still show some sedation effects.
  • stage 3 the subject may be conscious and all reflexes present, but may not be able to control its body position.
  • stage 4 the subject may be semi-conscious or unconscious and have minimal or absent reflexes.
  • local anesthetics include, but are not limited to, procaine, amethocaine, cocaine, lidocaine (lignocaine), prilocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, and dibucaine.
  • Examples of general anesthetics that are used include, but are not limited to, inhaled agents such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, and xenon, non-opioid intravenous agents such as amobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, and propofol, intravenous opioid analgesic agents, such as Alfentanil, Fentanyl, Remifentanil, Sufentanil, Buprenorphine, Butorphanol, diacetyl morphine (heroin), Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, and Pentazocine, and muscle relaxants,
  • Side effects may occur after a subject is dosed with anesthesia. Side effects may include, but are not limited to, nausea, vomiting, sore throat, confusion, muscle aches, itching, chills, shivering, postoperative delirium, cognitive dysfunction, malignant hyperthermia, headache, back pain, difficulty urinating, hematoma, pneumothorax, nerve damage, respiratory depression, hypotension, and any combinations thereof.
  • a compound or a salt thereof of the present disclosure may be induce fewer side effects in a subject when compared to other commonly used anesthetics.
  • a compound or a salt thereof of the present disclosure can be used to treat a central nervous system disorder by administration of a therapeutically effective amount of compound to a subject.
  • disorders of the central nervous system include, but are not limited to, schizophrenia, schizoaffective disorders, schizophreniform disorders, delusional syndromes and other psychotic conditions related and not related to taking psychoactive substances, affective disorder, bipolar disorder, mania, depression, anxiety disorders of various etiology, stress reactions, consciousness disorders, coma, delirium of alcoholic or other etiology, aggression, psychomotor agitation and other conduct disorders, sleep disorders of various etiology, withdrawal syndromes of various etiology, addiction, pain syndromes of various etiology, intoxication with psychoactive substances, cerebral circulatory disorders of various etiology, cerebral atrophy, cerebellar atrophy, senile tremor, essential tremor, psychosomatic disorders of various etiology, conversion disorders, dissociative disorders, urination disorders, autism and other developmental disorders, cognitive disorders of various types, including Alzheimer’s disease, a traumatic brain injury (TBI), Parkinson’s disease, attention deficit
  • a compound or a salt thereof of the present disclosure can be used to treat sleep disorders, such as insomnia.
  • a compound or a salt thereof of the present disclosure may be used to treat a tremor, tremors, involuntary muscle contractions, or twitching of muscles or body parts of a subject.
  • the tremor may be, for example, cerebellar tremor, dystonia and dystonic tremors, enhanced physiologic tremor, essential tremor, Holmes’ tremor, isolated chin tremor, isolated voice tremor, movement disorders, orthostatic tremor, palatal tremor, parkinsonian tremor, psychogenic tremor, Rubral tremor, task-specific tremors, writer's tremor, or any combination thereof.
  • Tremors may affect the hands, arms, eyes, head, and legs of a subject.
  • the compositions and methods disclosed herein can be utilized for cognitive enhancement.
  • the compositions disclosed herein can be a nootropic.
  • BHB, a derivative thereof, or a salt thereof can be administered alone or in combination with a therapy to enhance cognitive function of a subject.
  • cognitive enhancement can comprise an increase in: memory, focus, creativity, motivation, or any combination thereof.
  • an increase in: memory, focus, creativity, motivation, or any combination thereof can be measured in a subject before and after a treatment.
  • a subject after administration of a compound herein a subject can have an increase in their memory as compared to their memory prior to administration of the compound as measured by a cognitive test.
  • cognitive enhancement can be in a subject diagnosed with a central nervous system disorder.
  • the compounds herein can be used to increase the memory of a subject with Alzheimer’s disease.
  • the compositions and methods disclosed herein can be administered to treat a traumatic brain injury (TBI).
  • TBI traumatic brain injury
  • BHB, a derivative thereof, or a salt thereof can be administered alone or in combination with a therapy to treat a TBI in a subject.
  • a TBI can comprise a concussion, a contusion, a brain hemorrhage, a intracranial hematoma, a coup-contrecoup brain injury, a diffuse axonal injury, a penetrating brain injury, a second impact syndrome, or any combination thereof.
  • a TBI can comprise a mild concussion, a moderate TBI, a severe TBI, an uncomplicated TBI, a complicated TBI, a closed TBI, an open TBI, or a non-traumatic TBI.
  • a therapy to treat a TBI can comprise a speech therapy, a physical therapy, an occupational therapy, a cognitive training, an anti-seizure drug, a coma-inducing drug, a diuretic, a surgery, or any combination thereof.
  • an anti-seizure drug can comprise phenytoin, levetiracetam, valproic acid, gabapentin, topiramate, carbamazepine, a salt of any of these, or any combination thereof.
  • a coma-inducing drug can comprise propofol, a barbiturate, pentobarbital, thiopental, a salt of any of these, or any combination thereof.
  • a diuretic can comprise a mannitol or a salt thereof.
  • treatment of a TBI can comprise a reduction in the number of: headaches, convulsions, or both.
  • treatment of a TBI can comprise a reduction in: dizziness, confusion, slurred speech, personality changes, or any combination thereof.
  • treatment of a TBI can comprise increased coordination, increased memory, or both.
  • the reduction in: headaches, dizziness, confusion, convulsions, slurred speech, personality changes, or any combination thereof can be measured before and after a treatment.
  • increased coordination, increased memory, or both can be measured before and after a treatment.
  • a subject can have a cancer and the compositions and methods disclosed herein can be utilized to treat the cancer in the subject.
  • BHB, a derivative thereof, or a salt thereof can be administered alone or in combination with a therapy to treat a cancer in a subject.
  • a cancer can be a carcinoma, a sarcoma, a lymphoma, a leukemia, a myeloma, or any combination thereof.
  • a carcinoma can comprise an adenocarcinoma, a basal cell carcinoma, transitional cell carcinoma, or a squamous cell carcinoma.
  • a sarcoma can comprise a bone sarcoma, or a soft tissue sarcoma.
  • a cancer can comprise a brain and/or a spinal cord cancer.
  • a cancer can be a colorectal cancer.
  • a cancer can be a childhood cancer, an adolescent cancer, or an adult cancer.
  • a cancer can comprise an adenoid cystic carcinoma, an adrenal gland tumor, an amyloidosis, an anal cancer, an appendix cancer, an astrocytoma, an ataxia-telangiectasia, a Beckwith-Wiedemann syndrome, a bile duct cancer, a cholangiocarcinoma, a Birt-Hogg-Dubé syndrome, a bladder cancer, a bone cancer (sarcoma of bone), a brain stem glioma, a brain tumor, a breast cancer, a breast cancer, a breast cancer (metastatic), a metastatic cancer, a carney complex, a central nervous system tumors, a brain cancer, a spinal cord cancer, a cervical cancer, a childhood cancer, a colorectal cancer, a Cowden syndrome, a craniopharyngioma, a desmoid tumor, a desmoplastic infantile ganglioglioma, an ependym
  • treatment of a cancer can comprise reducing the size of a tumor as compared to the size of the tumor prior to the administration of a composition herein. In some cases, treatment of a cancer can comprise reducing the amount of a cancer as compared to the amount of the cancer prior to the administration of a composition herein. In some cases, treatment of a cancer can comprise substantially eliminating or eliminating a tumor and/or cancer. In some cases, treatment of a cancer can comprise reducing the spread of a cancer. In some cases, a subject can be diagnosed with a cancer.
  • a diagnosis can comprise an in vitro diagnostic test, an imagining diagnostic (for example, an X-ray, a CT Scan, an ultrasound, a mammogram, a PET-CT scan), a physical exam, a blood test, a metabolite screen, or any combination thereof.
  • an imagining diagnostic for example, an X-ray, a CT Scan, an ultrasound, a mammogram, a PET-CT scan
  • a physical exam for example, an X-ray, a CT Scan, an ultrasound, a mammogram, a PET-CT scan
  • disorders of the peripheral nervous system include, but are not limited to, traumatic nerve damage, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, spinobulbar muscular atrophy, spinal muscular atrophy, diabetic neuropathy, uremic neuropathy, peripheral neuropathy, peripheral neurodegenerative disease, peripheral nerve trauma, metabolic neuropathy, diabetic neuropathy, uremic neuropathy, toxic neuropathy, chemotherapy induced neuropathy, retroviral drug-induced neuropathy, motor neuron disease, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy or CIDP, multifocal motor neuropathies or MMN, neuropathy associated with monoclonal components, neuropathy associated with anti- MAG gammopathy, myasthenia gravis, Lambert-Eaton syndrome, restless leg syndrome, and Stiff Man Syndrome.
  • a compound or a salt thereof of the present disclosure can be used as an anticonvulsant by administration of a therapeutically effective amount of compound to a subject.
  • An anticonvulsant may be used to control and/or prevent seizures or to stop an ongoing series of seizures.
  • the seizure may be Absence Seizures, Atypical Absence Seizures, Atonic Seizures, Clonic Seizures, Myoclonic Seizures, Tonic Seizures, Tonic- Clonic Seizures, Simple Partial Seizures, Complex Partial Seizures, Secondarily Generalized Seizures, Febrile Seizures, Nonepileptic Seizures, or Refractory Seizures.
  • a compound or a salt thereof of the disclosure may be used to treat a seizure in a subject, wherein the subject is a human, a dog, a cat, a horse, or a mouse.
  • the methods and compositions of the disclosure are utilized to treat epilepsy.
  • the nervous system disorder is Angelman syndrome (including, for example, ubiquitin E3 ligase mutation), Benign Rolandic Epilepsy, CDKL5 Disorder, Childhood and Juvenile Absence Epilepsy, Dravet Syndrome, Frontal Lobe Epilepsy, Glut1 Deficiency Syndrome, Hypothalamic Hamartoma, Infantile Spasms/West’s Syndrome, Juvenile Myoclonic Epilepsy, Landau-kleffner Syndrome, Lennox-Gastaut Syndrome (LGS), Epilepsy with Myoclonic-Absences, Ohtahara Syndrome, Panayiotopoulos, PCDH19 Epilepsy, Progressive Myoclonic Epilepsies, benign myoclonic epilepsy of infancy, benign neonatal familial convulsions (including, for example, potassium voltage-gated channel subfamily Q (KCNQ) mutation), Rasmussen’s Syndrome, Ring Chromosome 20 Syndrome, Reflex Epilepsies, Temporal Lobe
  • the methods and compositions may be used to treat status epilepticus.
  • a patient may experience a seizure of one, two, three, four, five minutes or more. In some cases, a seizure may last about 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 10 seconds, 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, or longer.
  • a patient may experience one, two, three, four, five, or more seizures within a given time frame. In some cases, a patient may experience one, two, three, four, five, or more seizures within a five-minute period. A patient may or may not return to normal between seizures.
  • compositions described herein may be used to prevent or control epileptic seizures.
  • Epileptic seizures may be classified as tonic-clonic, tonic, clonic, myoclonic, absence or atonic seizures.
  • the severity of epilepsy may be measured with a known scale, such as, for example, the VA scale, the Chalfont National Hospital scale, the Liverpool scale, the Hague scale, or the Occupational Hazard scale.
  • compositions and methods herein may prevent or reduce the number of epileptic seizures experienced by a subject by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or 100%.
  • compositions and methods herein may prevent or reduce the severity of epileptic seizures experienced by a subject by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or 100%.
  • compositions and methods herein may increase the quality of life (QoL) of a subject by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or 100%.
  • QoL quality of life
  • a compound or a salt thereof of the present disclosure can be used to treat psychiatric disorders by administration of a therapeutically effective amount of compound to a subject.
  • Psychiatric disorders may also be known as mental disorders, mental illnesses, or psychological disorders.
  • Non-limiting examples of psychiatric disorders include acute stress disorder, adjustment disorder, adolescent antisocial behavior, alcohol abuse, amphetamine dependence, alcohol dependence, anorexia nervosa, antisocial personality disorder, attention deficit disorder, attention deficit hyperactivity disorder, binge eating disorder, bipolar disorder, bulimia nervosa, caffeine-related disorder, claustrophobia, cocaine dependence, depression, dyslexia, dissociative identity disorder, euphoria, Huntington’s disease, major depressive disorder, mean world syndrome, melancholia, minor depressive disorder, mixed episode, Munchausen’s syndrome, narcolepsy, nicotine withdrawal, nightmare disorder, obsessive- compulsive disorder (OCD), obsessive-compulsive personality disorder, pain disorder, panic disorder, paranoid personality disorder, Parkinson’s disease, perfectionism, physical abuse, posttraumatic stress disorder (PTSD), schizophrenia, seasonal affective disorder, sedative-related disorder, separation anxiety disorder, sleep disorder, and combinations thereof.
  • PTSD
  • a compound or a salt thereof of the present disclosure can be used to treat depression by administration of a therapeutically effective amount of compound to a subject.
  • Types of depression for example, include major depression, persistent depressive disorder, bipolar disorder, seasonal affective disorder, psychotic depression, postpartum depression, premenstrual dysphoric disorder, situational depression, and atypical depression.
  • depression screening measures can provide an indication of the severity of symptoms for a time period.
  • rating scales may be used for this purpose, including, but not limited to, the Hamilton depression rating scale, the Montgomery-Asberg depression rating scale, Beck depression inventory, Beck depression inventory PC, Amritsar depression inventory, Beck hopelessness scale, Caroll depression scales, Centre for epidemiological studies depression scale, clinical assessment of depression, depression anxiety stress scales, Edinburgh postnatal depression scale, major depression inventory, patient health questionarie (PHQ-9) screening instrument, Zung self-rating depression scale, and Zung depression inventory.
  • a compound or a salt thereof of the present disclosure can be used to affect a desirable change in a patient.
  • a patient’s score may decrease after treatment with a compound or a salt thereof of the current disclosure.
  • a compound or a salt thereof of the present disclosure can be used to treat ischemia by administration of a therapeutically effective amount of compound to a subject.
  • Ischemia is an inadequate blood supply to an organ or part of the body, and can be, for example, myocardial ischemia, cerebral ischemia, small or large intestine ischemia, brain ischemia, limb ischemia, cutaneous ischemia, or combinations thereof.
  • a compound or a salt thereof of the present disclosure can be used to treat disorders of the brain, such as, for example, lissencephaly.
  • the brain disorder may by the Lis-1 mutation or Lis-1 related lissencephaly.
  • a compound or a salt thereof of the present disclosure can be used to treat disorders of the ear, such as auditory neuropathy, by administration of a therapeutically effective amount of compound to a subject.
  • Auditory neuropathy is a type of hearing impairment and can be, for example, auditory neuropathy spectrum disorder (ANSD).
  • a compound or a salt thereof of the present disclosure can be used to treat disorders of the eye by administration of a therapeutically effective amount of compound to a subject.
  • Disorders of the eye can include, but are not limited to, blurred vision, macular degeneration, age-related macular degeneration (AMD or ARMD), retinal degeneration (rhodopsin mutation), eye floaters, eyelid inflammation, eye pain, and glaucoma.
  • AMD or ARMD age-related macular degeneration
  • rhodopsin mutation retinal degeneration
  • eye floaters eyelid inflammation, eye pain, and glaucoma.
  • a compound or a salt thereof of the present disclosure can be used to treat spasticity by administration of a therapeutically effective amount of compound to a subject.
  • Spasticity in a subject may be a result of other diseases, such as cerebral palsy, multiple sclerosis, traumatic brain injury, stroke, or spinal cord injury. Spasticity may be measured by the amount of muscle rigidity, and measurements may be done according to scales such as the Ashworth Scale, Modified Ashworth Scale, or Bohannon & Smith Scale.
  • the Modified Ashworth Scale consists of scores ranging from 0-4. Treatment with a compound or a salt thereof of the current disclosure may decrease a subject’s score by 0 points, 1 point, 2 points, 3 points, 4 points.
  • a compound or a salt thereof of the present disclosure can be used to treat symptoms of itching or pruritis by administration of a therapeutically effective amount of compound to a subject. Itching may be caused by other conditions, including, but not limited to, psychological problems, stress, anxiety, dry skin, sunburns, metabolic and hormone disorders such as liver or kidney diseases, cancers, reactions to drugs, diseases of the blood, allergic reactions, insect stings or bites, infections, infestation by lice or mites, or combinations thereof.
  • a compound or a salt thereof of the current disclosure can be used to treat b-12 deficiency, hyperthyroidism, hyperparathyroidism, hypocalcemia, hyponatremia, kidney disease, liver disease, or Wilson’s disease.
  • a compound or a salt thereof of the current disclosure can be used to treat alcohol related disorders, arsenic poisoning, caffeine related disorders, cocaine related disorders, dichlorodiphenyltrichloroethane (ddt), lead, or toluene poisoning, or nicotine related disorders, such as nicotine withdrawal.
  • a compound or a salt thereof of the present disclosure can be used for weight loss.
  • a compound or a salt thereof of the present disclosure can be used for treating obesity.
  • beta hydroxybutyric acid (BHB) or a salt thereof can be used alone or in combination with another drug for weight loss.
  • obesity can comprise normal weight obese; metabolically obese normal weight; metabolically healthy obese; and metabolically unhealthy obese.
  • a compound herein can be used alone or in combination with another drug to maintain a healthy weight.
  • a healthy weight comprises a body mass index (BMI) of 18.5 to ⁇ 25.
  • BMI body mass index
  • obesity can comprise sarcopenic obesity.
  • obesity can comprise overweight, obese (class I), obese (class II), or obese (class III).
  • overweight comprises a BMI of 25.0 to ⁇ 30.
  • obese class I comprises a BMI of 30 to ⁇ 35.
  • obese class II comprises a BMI of 35 to ⁇ 40.
  • obese class III comprises a BMI of 40 or higher.
  • obese comprises a BMI of 30.0 or higher.
  • a compound or a salt thereof of the present disclosure can reduce a BMI of a subject. In some cases, after administration of the compound or a salt thereof the subject can have a reduced BMI as compared to their BMI prior to administration of the compound or the salt thereof. A compound or a salt thereof of the present disclosure may suppress appetite, or cause a patient to lose interest in consuming food.
  • a compound or a salt thereof of the current disclosure may be part of a diet regiment, diet program, or diet supplement.
  • a level of BHB or any compound disclosed herein can be measured in a subject.
  • a level of BHB or any compound disclosed herein can be measured in a subject after the administration of a therapy described herein.
  • a level of BHB or any compound disclosed herein can be measured before administration of a therapy described herein.
  • the level of BHB can be measured before administration and after administration of BHB, a derivative thereof, or a salt thereof.
  • BHB or any compound disclosed herein can be given to a patients of different weights.
  • BHB (or any compound disclosed herein) levels can be measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times per day. In some cases, BHB (or any compound disclosed herein) levels can be measured for 1, 2, 3, 4, 5, 6, 7 days. In some cases, BHB levels (or any compound disclosed herein) can be measured for 1, 2, 3, 4, or more weeks. In some cases, BHB (or any compound disclosed herein) levels can be measured for 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, or more months. In some cases, BHB (or any compound disclosed herein) levels can be measured for 1, 2, 3 or more years.
  • BHB levels can be measured at random time points during the day and/or week. In some cases, BHB levels can be taken at specific time points during the day and/or week. In some cases, BHB levels can be used in a mathematical model or in machine learning to provide personalized pharmacokinetics for a subject. In some cases, the mathematical model or machine leaving can predict the amount of BHB to administer to a subject. In some cases, the BHB (or any compound disclosed herein) concentration can be measured in a biological sample of a subject. In some cases, the biological sample can comprise blood, saliva, urine, or any other biological substance.
  • a compound or a salt thereof of the current disclosure can be used to treat asthma or allergies, or symptoms thereof, such as shortness of breath, wheezing, coughing, and inhibition in breathing.
  • a compound may be a bronchodilator, or a substance that dilates bronchi and/or bronchioles.
  • a compound may decrease resistance in the respiratory airway and may increase airflow and oxygen to the lungs.
  • Action potentials are generated in nerve and muscle cells by ion currents that pass selectively across plasma membranes through transmembrane ion channels.
  • a compound or a salt thereof of the present disclosure may act on the cell membrane by adsorption or partitioning into the membrane.
  • the cell membrane may be a lipid bilayer. Physical properties of the membranes may be altered by a compound or a salt thereof of the current disclosure, including, but not limited to, distribution of lipids in the membrane (e.g. into rafts or domains), elastic constants of the membrane, electrostatic potentials of the membrane, fluidity, lateral pressure profiles, stress distributions, melting events, phase transitions or properties, thickness of the membrane, surface tension, or combinations thereof.
  • a compound or a salt thereof disclosed herein act on the cell membrane by altering the lateral pressure profile.
  • a method herein can comprise screening compounds of the present disclosure for drug development.
  • a method herein can comprise screening an anesthetic effect of a compound herein, such as BHB, a derivative thereof, an ester thereof, or salt thereof.
  • BHB a compound herein
  • the BHB compounds screened contain modifications.
  • the BHB compounds screened are BHB analogs.
  • the BHB analogs are generated by medicinal chemistry techniques.
  • a cancer drug can be derived from a BHB analog.
  • a cancer drug can be derived from BHB, a derivative thereof, an ester thereof, or salt thereof.
  • a cancer drug can be developed using an anesthetic screening assay.
  • a longer-acting and/or more potent BHB analog will act as an anesthetic at a higher dose. The increased anesthetic effect of a BHB analog compared to unmodified BHB can be used to determine longer-acting BHB-like compounds.
  • the increased anesthetic effect can comprise an increased potency of a compound, an increased duration of anesthesia, or both.
  • anesthetic screening studies can use a small number of animals and yield quick results as compared to screening in a cancer model.
  • the animals in the screen can be a mammal, such as a mouse, a rat, a dog, a cat, or any applicable animal model.
  • a method for screening for an anti-cancer compound can comprise: i) providing a beta hydroxybutyric acid (BHB) analog; ii) administering the BHB analog to an animal at a predetermined dose; iii) measuring a duration of the anesthesia; and iv) selecting the BHB analog with a threshold duration of anesthesia as a candidate for an anti-cancer compound.
  • a threshold duration of anesthesia can be more than about, or equal to about: 1 min, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 90 min, 120 min, 3 hours, 4 hours, 5 hours, or 6 hours.
  • a threshold duration of anesthesia can be from about: 1 min to about 12 hours, 10 min to about 1 hour, 30 min to about 1 hour, 30 min to about 2 hours, 1 hour to about 6 hours, or 40 min to about 3 hours.
  • the animal can be a mouse or a rat.
  • the measuring can further comprise measuring the potency of the BHB analog.
  • the BHB analog with the threshold duration of anesthesia can be compared to an unmodified BHB (e.g., BHB) threshold duration of anesthesia.
  • a compound or a salt thereof of the present disclosure may be interfacially-active, have interfacial active properties, surface active properties, or combinations thereof.
  • neurotransmitters in the GABA family may bind to the corresponding receptor and elicit currents through the reception or the neurotransmitters may elicit adsorption onto membranes, modulating currents through the receptor that the neurotransmitter elicited by binding.
  • a compound or a salt thereof of the present disclosure may bind to gamma-aminobutyric acid (GABA), GABA-A receptors, glycine receptors, acetylcholine receptors, serotonin receptors, glutamate receptors, or combinations thereof.
  • GABA gamma-aminobutyric acid
  • Kits with unit doses of one or more of the compounds described herein, usually in oral or injectable doses, are provided.
  • kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating the disease, and optionally an appliance or device for delivery of the composition.
  • the kit may further comprise any device suitable for administration of the composition.
  • a kit comprising an injectable formulation of pharmaceutical compositions may comprise a needle suitable for subcutaneous administration and an alcohol wipe for sterilization of the injection site.
  • kits may be provided with instructions.
  • the instructions may be provided in the kit or they may be accessed electronically (e.g., on the World Wide Web).
  • the instructions may provide information on how to use the compositions of the present disclosure.
  • the instructions may further provide information on how to use the devices of the present disclosure.
  • the instructions may provide information on how to perform the methods of the disclosure.
  • the instructions may provide dosing information.
  • the instructions may provide drug information such as the mechanism of action, the formulation of the drug, adverse risks, contraindications, and the like.
  • the kit is purchased by a physician or health care provider for administration at a clinic or hospital. In some cases, the kit is purchased by a laboratory and used for screening candidate compounds.
  • the computer system 100 illustrated in FIG.1 may be understood as a logical apparatus that can read instructions from media 111 and/or a network port 105, which can optionally be connected to server 109 having fixed media 112.
  • the system, such as shown in FIG.1 can include a CPU 101, disk drives 103, optional input devices such as keyboard 115 and/or mouse 116 and optional monitor 107.
  • Data communication can be achieved through the indicated communication medium to a server at a local or a remote location.
  • the communication medium can include any means of transmitting and/or receiving data.
  • the communication medium can be a network connection, a wireless connection or an internet connection. Such a connection can provide for communication over the World Wide Web. It is envisioned that data relating to the present disclosure can be transmitted over such networks or connections for reception and/or review by a party 122 as illustrated in FIG.1.
  • Numbered Embodiments [239] A number of compositions, and methods are disclosed herein. Specific exemplary embodiments of these compositions and methods are disclosed below. The following embodiments recite non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated.
  • Embodiment 1 A method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each
  • Embodiment 2 The method of embodiment 1, wherein said compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • Embodiment 3. A method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, wherein the method is selected from inducing sedation, sedating, treating a central nervous system disorder, treating a peripheral nervous system disorder, treating a convulsing disorder, treating a psychiatric disorder, treating ischemia, treating pain, treating spasticity, treating itching, and any combination thereof.
  • Embodiment 4. The method of embodiment 1, wherein said compound or a salt thereof is a racemic mixture.
  • Embodiment 1 The method of embodiment 1, wherein said compound or a salt thereof has an enantiomeric excess of greater than 80%.
  • Embodiment 6. The method of embodiment 1, wherein said compound or a salt thereof has a diastereomeric excess of greater than 80%.
  • Embodiment 7. The method of embodiment 1, wherein said compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry.
  • Embodiment 8. The method of embodiment 1, wherein said compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry.
  • Embodiment 9. The method of embodiment 1, wherein said compound or a salt thereof is administered in a formulation.
  • a pharmaceutical composition comprising a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 al
  • Embodiment 18 The pharmaceutical composition of embodiment 17, wherein said compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • Embodiment 19 A pharmaceutical composition comprising a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, and a pharmaceutically-acceptable excipient.
  • Embodiment 20 The pharmaceutical composition of embodiment 17, wherein said compound or salt thereof is butyric acid.
  • Embodiment 21 The pharmaceutical composition of embodiment 17, wherein said compound or salt thereof is 3-hydroxybutyric acid.
  • Embodiment 22 The pharmaceutical composition of embodiment 17, wherein said compound or salt thereof is 3-hydroxybutyric acid.
  • R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -X-R 4 , - N(R 4 )2, -C(X)R 4 , -C(X)YR
  • Embodiment 23 The compound of embodiment 22, wherein said compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • Embodiment 24 A compound or a salt thereof listed in Table 1 or Table 2.
  • Embodiment 25 A method of combining a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 )2, -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 )2, -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one
  • Embodiment 28 A method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of Formula (I): or a salt thereof, wherein: R 1 , R 2 , R 3 are independently selected at each occurrence from hydrogen, halogen, -X-R 4 , -N(R 4 ) 2 , -N(R 4 )C(X)R 4 , -C(X)R 4 , -C(X)YR 4 , -C(X)N(R 4 ) 2 , -CN, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 carbocycle, C 5-10 aryl, 3- to 10-membered heterocycle, and 3- to 10-membered heteroaryl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, -X
  • Embodiment 29 The method of embodiment 28, wherein said compound is represented by Formula (I-A): (I-A), or a salt thereof.
  • Embodiment 30 A method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or a salt thereof listed in Table 1 or Table 2, wherein the method is selected from inducing sedation, sedating, treating a central nervous system disorder, treating a peripheral nervous system disorder, treating a convulsing disorder, treating a psychiatric disorder, treating ischemia, treating pain, treating spasticity, treating itching, and any combination thereof.
  • Embodiment 31 The method of embodiment 28, wherein said compound or a salt thereof is a racemic mixture.
  • Embodiment 32 The method of embodiment 28, wherein said compound or a salt thereof is a racemic mixture.
  • Embodiment 28 wherein said compound or a salt thereof has an enantiomeric excess of greater than 80%.
  • Embodiment 33 The method of embodiment 28, wherein said compound or a salt thereof has a diastereomeric excess of greater than 80%.
  • Embodiment 34 The method of embodiment 28, wherein said compound or a salt thereof has an alkene group, and wherein said alkene group has a cis geometry.
  • Embodiment 35 The method of embodiment 28, wherein said compound or a salt thereof has an alkene group, and wherein said alkene group has a trans geometry.
  • Embodiment 36 The method of embodiment 28, wherein said compound or a salt thereof is administered in a formulation.
  • Embodiment 37 The method of embodiment 28, wherein said compound or a salt thereof is administered in a formulation.
  • Embodiment 28 wherein said administering of a compound or a salt thereof alters distribution of lipids in a cell membrane.
  • Embodiment 38 The method of embodiment 28, wherein said administering of a compound or a salt thereof alters cell membrane thickness.
  • Embodiment 39 The method of embodiment 28, wherein said compound or salt thereof is selected from the group consisting of: (S)-3-hydroxybutanoic acid, (R)-3-hydroxybutanoic acid, 3,3-dimethylbutanoic acid, 2-benzamido-2-hydroxyacetic acid, butyric acid, 2-ethylmalonic acid, glutamine, and a salt of any one thereof.
  • Embodiment 40 Embodiment 40.
  • Embodiment 42 The method of embodiment 28, wherein said compound or salt thereof is butyric acid.
  • Embodiment 43 The method of embodiment 28, wherein said compound or salt thereof is 3- hydroxybutyric acid.
  • Embodiment 44 A method for screening for an anti-cancer compound, the method comprising: i) providing a beta hydroxybutyric acid (BHB) analog; ii) administering the BHB analog to an animal at a predetermined dose; iii) measuring a duration of anesthesia; and iv) selecting the BHB analog with a threshold duration of anesthesia as a candidate for an anti-cancer compound.
  • Embodiment 45 The method of embodiment 44, wherein the animal is a mouse or a rat.
  • Embodiment 46 The method of embodiment 44, wherein the animal is a mouse or a rat.
  • Embodiment 44 wherein the measuring further comprises measuring a potency of the BHB analog.
  • Embodiment 47 The method of embodiment 44, wherein the BHB analog with the threshold duration of anesthesia is compared to a BHB threshold duration of anesthesia.
  • Embodiment 48 A method for treating a cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB or a salt thereof, thereby treating the cancer in the subject in need thereof.
  • Embodiment 49 The method of embodiment 48, wherein the cancer comprises a solid tumor, and wherein after administering, the subject in need thereof has a decreased solid tumor volume as compared to a solid tumor volume prior to the administering.
  • Embodiment 50 Embodiment 50.
  • Embodiment 51 The method of any one of embodiments 48-50, wherein the BHB, the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • Embodiment 52 The method of embodiment 51, wherein the administration of BHB comprises intravesical administration.
  • Embodiment 53 The method of embodiment 51, wherein the administration of BHB comprises intravesical administration.
  • Embodiment 56 The method of any one of embodiments 48-52, wherein the BHB, the salt thereof, or the derivative thereof is administered as needed.
  • Embodiment 57 The method of any one of embodiments 48-56, wherein the BHB or a salt thereof is administered as an aqueous solution that is pH adjusted to a pH range ranging from 5.2-7.6, and wherein optionally the aqueous solution is heated.
  • Embodiment 58. The method of embodiment 57, wherein the aqueous solution is heated to a temperature ranging from about 23 degrees C to about 37 degrees C.
  • Embodiment 59 The method of any one of embodiments 48-54, further comprising diagnosing the subject with a cancer.
  • any one of embodiments 48-58, wherein the BHB, the salt thereof, or the derivative thereof is administered as an aqueous solution which is optionally pH adjusted, and wherein a concentration of the BHB, the salt thereof, or the derivative thereof in the aqueous solution ranges from about: 0.01 nM – 1 M.
  • the method of embodiment 59, wherein the concentration of the BHB, the salt thereof, or the derivative thereof in the aqueous solution is about: 0.01 nM, 0.1 nM, 1.0 nM, 10 nM, 100 nM, 1000 nM, 0.01 mM, 0.1 mM, 1.0 mM, 10 mM, 100 mM, 1000 mM.
  • Embodiment 61 The method of any one of embodiments 48-60, wherein the aqueous solution containing the BHB or salt thereof, after intravesical administration, is allowed to reside in the bladder for about: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 hours.
  • Embodiments section 2 Embodiment 1.
  • a method for treating a cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof, and a second therapeutic wherein the second therapeutic is selected from the group consisting of: a surgery, a chemotherapy, a hormone therapy, a hyperthermia therapy, an immunotherapy, a photodynamic therapy, a radiation therapy, a stem cell transplant therapy, a targeted therapy, and any combination thereof and wherein upon administration the subject in need thereof has a decreased number of cancer cells as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • the second therapeutic is selected from the group consisting of: a surgery, a chemotherapy, a hormone therapy, a hyperthermia therapy, an immunotherapy, a photodynamic therapy, a radiation therapy, a stem cell transplant therapy, a targeted therapy, and any combination thereof and wherein upon administration the subject in need thereof has a decreased number of cancer cells as compared to administration of the BHB, the salt thereof, or the derivative thereof alone
  • Embodiment 1 wherein upon administration the subject in need thereof has a decreased tumor size as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • Embodiment 3. The method of embodiment 1, wherein the second therapeutic is a chemotherapy.
  • Embodiment 4. The method of embodiment 1, wherein the second therapeutic is an immunotherapy.
  • Embodiment 5. The method of embodiment 4, wherein immunotherapy comprises Bacillus Calmette-Guérin (BCG) or a mutated BCG.
  • BCG Bacillus Calmette-Guérin
  • Embodiment 6 The method of embodiment 1, wherein the second therapeutic is a radiation therapy.
  • Embodiment 7. The method of any one of embodiments 1-6, wherein the subject is a human.
  • Embodiment 9 The method of any one of embodiments 1-7, wherein the second therapeutic is administered concurrently or consecutively.
  • Embodiment 9. The method of any one of embodiments 1-8, wherein the BHB, the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • Embodiment 10. The method of embodiment 9, wherein the BHB, the salt thereof, or the derivative thereof is administered orally.
  • a method for treating obesity or overweight comprising administering to a subject in need thereof a therapeutically-effective amount of beta hydroxybutyric acid (BHB), a salt thereof, or a derivative thereof, and a second therapeutic wherein the second therapeutic is selected from the group consisting of: orlistat, topiramate, naltrexone, semaglutide, tirzepatide, a derivative of any of these, and a salt of any of these, and wherein upon administration the subject in need thereof has increased weight loss as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • BHB beta hydroxybutyric acid
  • Embodiment 18 The method of embodiment 17, wherein the second therapeutic is orlistat, a derivative thereof, or a salt thereof.
  • Embodiment 17 wherein the second therapeutic is semaglutide, a derivative thereof, or a salt thereof.
  • Embodiment 20 The method of embodiment 17, wherein the second therapeutic is tirzepatide, a derivative thereof, or a salt thereof.
  • Embodiment 21 The method of any one of embodiments 17-20, wherein the subject is a human.
  • Embodiment 22 The method of any one of embodiments 17-21, wherein the second therapeutic is administered concurrently or consecutively.
  • Embodiment 23 is
  • beta hydroxybutyric acid (BHB), the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • Embodiment 24 The method of embodiment 23, wherein the BHB, the salt thereof, or the derivative thereof is administered orally.
  • Embodiment 25 The method of embodiment 23, wherein the BHB, the salt thereof, or the derivative thereof is administered by a device and wherein the device is a pump.
  • Embodiment 26 The method of any one of embodiments 17-22, wherein the beta hydroxybutyric acid (BHB), the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, nasally, ophthalmically, or
  • Embodiment 30 The method of any one of embodiments 17-28, further comprising administering a surgery, wherein the surgery is a bariatric surgery.
  • Embodiment 30 The method of any one of embodiments 17-29, wherein the BHB, the salt thereof, or the derivative thereof, and the second therapeutic are administered as needed, or for about a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, or chronically.
  • Embodiment 31 The method of any one of embodiments 17-30, further comprising diagnosing the subject with obesity or overweight.
  • Embodiment 32 The method of any one of embodiments 17-31, further comprising administering a third therapeutic.
  • Embodiment 33 The method of embodiment 32, wherein the third therapeutic is selected from the group consisting of: orlistat, phentermine, topiramate, naltrexone, bupropion, liraglutide, and a salt of any of these.
  • Embodiment 34 The method of any one of embodiments 17-33, further comprising measuring a level of the BHB, the salt thereof, or the derivative thereof in the subject.
  • Embodiment 35 The method of embodiment 34, wherein the level of the BHB, the salt thereof, or the derivative thereof is measured after the administration of the BHB, the salt thereof, or the derivative thereof, before the administration of the BHB, the salt thereof, or the derivative thereof, or both.
  • Embodiment 36 Embodiment 36.
  • a kit comprising BHB, a salt thereof, or a derivative thereof, and a second therapeutic wherein the second therapeutic is selected from the group consisting of: orlistat, topiramate, naltrexone, semaglutide, tirzepatide, a derivative of any of these, and a salt of any of these and a container.
  • Embodiment 37 A kit comprising BHB, a salt thereof, or a derivative thereof, and a second therapeutic or a salt thereof.
  • Embodiment 38 A kit comprising BHB, a salt thereof, or a derivative thereof, and a second therapeutic or a salt thereof.
  • a pharmaceutical composition comprising BHB, a salt thereof, or a derivative thereof, and a second therapeutic wherein the second therapeutic is selected from the group consisting of: orlistat, topiramate, naltrexone, semaglutide, tirzepatide, a derivative of any of these, and a salt of any of these.
  • Embodiment 39 A pharmaceutical composition comprising BHB, a salt thereof, or a derivative thereof, and a second therapeutic or a salt thereof.
  • Embodiment 40 The pharmaceutical composition of embodiment 39, wherein the second therapeutic comprises Bacillus Calmette-Guérin (BCG) or a mutated BCG.
  • BCG Bacillus Calmette-Guérin
  • a method for enhancing cognitive function in a subject comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof, and wherein upon administration the subject in need thereof has increased memory as compared to the subject’s memory prior to administration.
  • a method for treating a traumatic brain injury comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB, a salt thereof, or a derivative thereof, and a second therapeutic wherein the second therapeutic is selected from the group consisting of: a speech therapy, a physical therapy, an occupational therapy, a cognitive training, an anti-seizure drug, a coma-inducing drug, a diuretic, a surgery, and any combination thereof and wherein upon administration the subject in need thereof has a reduction in a number of headaches as compared to administration of the BHB, the salt thereof, or the derivative thereof alone.
  • TBI traumatic brain injury
  • a method for screening for an anti-cancer compound comprising: i) providing a beta hydroxybutyric acid (BHB) analog; ii) administering the BHB analog to an animal at a predetermined dose; iii) measuring a duration of anesthesia; and iv) selecting the BHB analog with a threshold duration of anesthesia as a candidate for an anti-cancer compound.
  • BHB beta hydroxybutyric acid
  • Embodiment 44 The method of embodiment 43, wherein the animal is a mouse or a rat.
  • the method of embodiment 43, wherein the measuring further comprises measuring a potency of the BHB analog.
  • Embodiment 47 A method for treating a cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a BHB or a salt thereof, thereby treating the cancer in the subject in need thereof.
  • Embodiment 48 The method of embodiment 47, wherein the cancer comprises a solid tumor, and wherein after administering, the subject in need thereof has a decreased solid tumor volume as compared to a solid tumor volume prior to the administering.
  • Embodiment 49. The method of embodiment 47 or embodiment 48, wherein the subject is a human.
  • Embodiment 50 The method of embodiment 47 or embodiment 48, wherein the subject is a human.
  • any one of embodiments 47-49, wherein the BHB, the salt thereof, or the derivative thereof is administered: buccally, enterally, by inhalation administration, by infusion administration, intramuscularly, intrathecally, intravenously, by intravesical administration, nasally, ophthalmically, orally, otically, by rectal administration, subcutaneously, sublingually, topically, by a device, or transdermally.
  • Embodiment 51 The method of embodiment 50, wherein the administration of BHB comprises intravesical administration.
  • Embodiment 55 The method of any one of embodiments 47-51, wherein the BHB, the salt thereof, or the derivative thereof, and a second therapeutic are independently administered as needed, or for about: a week, two weeks, three weeks, a month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, a year, weekly, biweekly, once every other week, for about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, a period from about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 to 12 weeks, or chronically.
  • Embodiment 56 Embodiment 56.
  • Embodiment 60 The method of any one of embodiments 47-59, wherein the aqueous solution containing the BHB or salt thereof, after intravesical administration, is allowed to reside in the bladder for about: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12 hours.
  • Tadpoles were placed in a petri dish containing aquarium water. Four to eight tadpoles were placed in each petri dish. The aquarium water contained the specified test compound at the listed concentration. When the tadpoles stopped moving, a plastic rod was used to elicit motion once again by contact between the rod and tadpole. The number of tadpoles that did not move when contacted by the rod was recorded. From this and the number of subjects, the percent of tadpoles in which movement was suppressed were calculated. [242] The tadpoles that did not move when contacted by a rod was then transferred to a petri dish containing aquarium water that did not have a test compound.
  • EXAMPLE 2 Efficacy of a Compound of Formula I as an Anesthetic in mice [245] Solutions of varying molarity of a compound of Formula I were prepared. [246] Butyric acid was dissolved in water to form an 8 M solution.0.5 mL of the 8 M solution of butyric acid was injected subcutaneously (at the back of the neck) into the mouse. The mouse became anesthetized or lost consciousness after 10-15 minutes, and woke up several hours later.0.2 mL of the 8 M solution of butyric acid injected intravenously through the mouse tail vein was lethal to the mouse.
  • EXAMPLE 3 Efficacy of a Compound of Formula I as an Anesthetic in mice [247] Solutions of varying molarity of a compound of Formula I were prepared. [248] 3-hydroxybutyric acid was dissolved in water to form 1 M, 1.5 M, and 2 M solutions. 0.2 mL of a 1.5 M solution of 3-hydroxybutyric acid was injected into a tail vein of a CD-1 mouse. The mouse became unconscious or anesthetic for a certain period of time, which was recorded. The mouse eventually woke up and became conscious once again. This was repeated for at least 2 more times on subsequent days. A concentration of 2 M was lethal to the mouse. A concentration of 1 M did not have any observable effect on the mouse.
  • EXAMPLE 4 Efficacy of a Compound of Formula I as an Anesthetic in mice [249] Solutions of varying molarity of a compound of Formula I were prepared. [250] Ethylmalonic acid was dissolved in water to form 2 M, 3 M, and 4 M solutions.0.2 mL of a 3 M solution of ethylmalonic acid was injected into a tail vein of a mouse. The mouse became unconscious for a certain period of time, which was recorded. The mouse eventually woke up and became conscious once again. This was repeated for at least 2 more times on subsequent days. A concentration of 4 M was lethal to the mouse. A concentration of 2 M did not have any observable effect on the mouse.
  • EXAMPLE 5 Efficacy of a Compound of Formula I as an Anesthetic in mice [251] Solutions of varying molarity of a compound of Formula I were prepared. [252] Diethyl ethyl malonate, ethyl (S)-(+)-mandelate, ethyl isovaleric acid, ethyl butyrate, and diethyl ethylphenylmalonate were dissolved in intralipid to form 62.5 mM, 250 mM, and 1 M solutions.
  • EXAMPLE 6 Efficacy of a Compound of Formula I as an Anesthetic in mice [254] Solutions of varying molarity of a compound of Formula I were prepared. [255] Ethylmalonic acid was dissolved in water to form a 4 M solution.0.5 mL of the 4 M solution of ethylmalonic acid was injected subcutaneously into the mouse. The mouse became sedated, anesthetized, or lose consciousness.
  • EXAMPLE 7 Efficacy of a Compound of Formula I as an Anticonvulsant in mice [256] CF-1 mice were used in this study. Number 20 PE tubing to cannulate a mouse tail vein was used.
  • Pentylenetetrazol is used as a control to study seizure phenomena in and to identify compounds that may control seizure susceptibility. Solutions of 8 M butyric acid and 1.5 M 3- hydroxybutyric acid were made. [259] The time to twitch and time to seizure of the mouse in seconds is recorded in Tables 3-5, below. Table 3. Metrazol alone
  • the average time to twitch was increased when a mouse was also given either butyric acid or 3-hydroxybutyric acid.
  • the average time to twitch for a mouse when dosed only with metrazol was 37.3 seconds.
  • the average time to seizure was increased when a mouse was also given either butyric acid or 3-hydroxybutyric acid.
  • the average time to seizure for a mouse when dosed only with metrazol was 45.7 seconds.
  • EXAMPLE 8 Acute Intravenous Toxicity in Mice [262] Male mice, weighing 20 grams to 22 grams, are used after a stabilization period of at least ten days at the testing facility and at least one hour in the laboratory. Food but not water is withheld from all animals for 16 hours before the test. The animals are again given free access to food starting two hours after the drug administration. All animals are observed daily for 7 days post dosing.
  • EXAMPLE 9 Efficacy of Compound of Formula I as a Topical Anesthetic [263] Aliquots (0.25 ml) of solutions with varying amounts of a compound or salt disclosed herein are applied into the conjunctival sac of conscious rabbits (either sex; 2-4 kg) and the eye-lids are kept closed for approximately 20 sec. The corneal reflex is checked before application of the test solution and every 5 min thereafter. To test the corneal reflex, the cornea is touched six times with a stalked elastic bristle. The duration of anesthesia is calculated as the period from the time-point when the animal does not feel any of the six touches by the bristle to the time point when the animal again reacts to three of the six touches.
  • EXAMPLE 10 Efficacy of Compound of Formula I as a Dermal Topical Anesthetic [264] Approximately 18-24 hours before each experiment, the skin on the back of male guinea pigs is shaved and depilated with a commercially available hair remover. The anesthetic action of each agent following dermal application is determined using a “pin-prick” method.
  • the areas of the skin are tested for the presence or absence of a skin twitch in response to six standardized dermal probings with a pointed metal “algesimeter” at a predetermined maximum load of 10 grams.
  • the average number of probings not producing a skin twitch response is designated as the “anesthetic score”.
  • six responses to six stimuli represents “no anesthetic activity” and no response to six stimuli represents a “maximal anesthetic activity”.
  • a single area of skin 1 inch square is marked off on the back of each animal.
  • This area is covered by a 1 inch square, 16 layer thick gauze pad onto which was deposited 0.45 ml of a 10% solution of the test agent in water with DMSO. The entire area is then covered by wrapping an elastic bandage around the trunk of the animal. After a predetermined duration of treatment, the coverings are removed and the skin is assessed for the presence of anesthesia as described above. Dermal anesthesia is assessed at ten minute intervals to measure onset time and duration of dermal anesthetic activity; comparisons are made with reference compounds and vehicle.
  • EXAMPLE 11 Inducing Anesthesia in a Patient Undergoing Oral Surgery with a Compound of Formula I
  • patients are induced with a compound of Formula I or a salt thereof via intravenous injection (5 mg/kg dosing). All patients are allowed to breathe spontaneously with manual assistance when needed throughout the procedure. No further muscle relaxant or opioid analgesic is used. Anesthesia is maintained by inhaling 60% nitrous oxide in oxygen via a circle anesthesia breathing system.
  • Patient characteristics, neurobehavioral and sympathetic responses are monitored by the anesthesiology team and, in addition, by an extra observer.
  • EXAMPLE 12 Treatment of Pain Relief for a Patient after Surgery with a Compound of Formula I [267] A patient that has undergone surgery (1 day – 4 weeks) that does not respond to conventional treatment is treated with a compound of Formula I or a salt thereof. Dosage regimens depend on the level of pain the patient experiences. Patients are dosed with an amount of compound of Formula I or a salt thereof, and then evaluated 1 hour, 4 hours, and 8 hours after treatment. After evaluation, the dosage is increased, decreased, or kept the same depending on the change in the symptoms of pain. The treatment is maintained for as long as necessary to affect a stable resolution of the symptoms.
  • EXAMPLE 13 Treatment of Pain Relief for a Patient with Chronic Pain with a Compound of Formula I
  • Patients that are suffering from chronic pain have their pain levels assessed and evaluated. Patients are prescribed 10 mg/day of a compound of Formula I or a salt thereof, and then evaluated again after two weeks to determine if symptoms have improved. After evaluation, the dosage is increased, decreased, or kept the same depending on the change in the level of pain. The treatment is maintained for as long as necessary to affect a stable resolution of the symptoms of chronic pain.
  • EXAMPLE 14 Efficacy of Compound of Formula I in Treating Cerebrovascular Disorders such as Cerebral Ischemia
  • Seven-week-old male rats are housed in polymethylpentene cages in an animal room controlled for room temperature, relative humidity, ventilation rate, and light-dark cycle for at least 6 days. The animals are allowed free access to pellet diet and water from water bottles. Animals judged to be in good health are used.
  • the animals are monitored for rectal temperature using a temperature probe during the period of the surgical operation.
  • an incandescent lamp is used to maintain the temperature at around 37° C.
  • the right common carotid artery, external carotid artery, and internal carotid artery are exposed for occluding the middle cerebral artery (MCA).
  • MCA middle cerebral artery
  • the right common carotid artery and the external carotid artery are ligatured using sutures (5-0), and a 19 mm-long segment of No.4-0 nylon suture which are precoated with silicone was inserted into the MCA through the bifurcation of the external and internal carotid arteries to occlude the MCA.
  • a compound or a salt thereof of the current disclosure is dissolved in a vehicle and administered intravenously to the animals at a volume of 2 mL/kg immediately after the MCA occlusion-reperfusion and 30 minutes after the MCA occlusion-reperfusion.
  • the control group receives an equal volume of the vehicle in the same manner.
  • the animals are decapitated and the brains are immediately isolated. Sequential brain sections with a thickness of 2 mm are prepared.
  • the brain tissue sections are positioned to include the coronal plane at 4 mm anterior to the bregma, at 2 mm anterior to the bregma, at the bregma, at 2 mm posterior to the bregma, at 4 mm posterior to the bregma, and at 6 mm posterior to the bregma.
  • the brain sections are stained in 1% TTC solution and photographed, and the infarct area was measured. Based on these results, the infarct volume (4 mm anterior to the bregma—6 mm posterior to the bregma) is calculated.
  • EXAMPLE 15 Efficacy of Compound of Formula I in Treating Central Nervous System Disorders, such as Alzheimer’s Disease [273] Alzheimer's disease model animals are prepared by bilateral ibotenic acid lesions of basal ganglia in rats. Briefly, rats are anesthetized with pentobarbital sodium and placed in a small animal stereotaxic apparatus.
  • Bilateral infusions of 5 ⁇ g/0.5 ⁇ L of ibotenic acid into the basal ganglia are made at a rate of 0.1 ⁇ L/min via a syringe pump and a stainless steel cannula.
  • Stereotaxic coordinates are as follows: ⁇ 0.8 mm posterior from bregma, 2.6 mm lateral (both sides) from midline, and 7.4 mm depth from the bone surface. Animals in sham group receive only anesthesia. Animals are then housed with free access to food and water for the rest of the study.
  • a compound or a salt thereof of the current disclosure is administered orally for 14 days after surgery to the model animals.
  • a control group receives the same amount of the vehicle.
  • the water maze is a circular pool. During testing in the water maze, a platform, 12 cm in diameter, is located 2 cm below the water in one of four locations (zone 4) in the pool, approximately 38 cm from the sidewall. A light bulb is placed around the pool as a cue external to the maze. The animals receive 2 trials per day from 10 days after the initiation of the administration with a compound or a salt thereof of the current disclosure or the vehicle. The rats are trained to locate the hidden escape platform, which remain in a fixed location throughout testing. Trials last a maximum of 90 sec. The latency to find the submerged platform is recorded and used as a measure of acquisition of the task.
  • EXAMPLE 16 Treatment of a Patient that has been Diagnosed with Alzheimer’s Disease [276] Patients that are diagnosed clinically with Alzheimer’s disease are evaluated for common symptoms such as memory loss and confusion.
  • motor strength of the patient is rated on a traditional 0-5 scale: i. absent motor strength ii. trace motor strength iii. can move the specified joint but only with gravity eliminated iv. can move the joint against gravity but not against any opposing force v. can move the joint against opposing force but the strength is not normal for the person or symmetrical vi. normal motor strength [279]
  • This scale is employed to measure the following motor strength for each of these joint motions on both the right and the left sides: hip flexion, hip adduction, hip abduction, knee flexion, knee extension, ankle dorsi-flexion, ankle plantar flexion, shoulder abduction, elbow extension, elbow flexion, wrist flexion, and wrist extension.
  • Hand grip strength was measured on a hand dynamometer that had been calibrated. Each patient is given three trials separated by thirty second rest periods and the strongest of the three measurements is recorded for each hand.
  • serum laboratories are drawn at the beginning of the study and every week of the study. The serum laboratories include glucose, blood urea nitrogen, creatinine, uric acid, calcium, total protein, albumin, phosphate, total bilirubin, cholesterol, LDH, SGOT/AST, alkaline phosphatase, hematocrit, hemoglobin, red blood cell count, platelet count, and white blood cell count with differential.
  • the motor strength of the two groups, administration with a compound of Formula I or control, are compared.
  • EXAMPLE 18 Anticonvulsant and Antiepileptic Effects of a Compound of Formula I
  • Adult male Sprague-Dawley rats are anesthetized with ketamine (80 mg/kg intramuscularly) and xylazine (10 mg/kg intramuscularly), and are stereotactically implanted with an insulated stainless steel bipolar electrode for stimulation and recording.
  • the electrode is implanted in the perforant path (8.1 mm posterior, 4.4 mm lateral, 3.5 mm ventral with respect to bregma), and is fixed to the skull with acrylic.
  • unrestrained, awake, implanted rats receive twice-daily kindling stimulation (5 days per week) with a one-second train of 62-Hertz (Hz) biphasic constant current 1.0- millisecond (ms) square wave pulses to induce kindled seizures.
  • the electroencephalogram is recorded from the bipolar electrode, which is switched
  • unrestrained, awake, implanted rats receive twice-daily kindling stimulation (5 days per week) with a one-second train of 62-Hertz (Hz) biphasic constant current 1.0-millisecond (ms) square wave pulses to induce kindled seizures.
  • the stimulator for the delivery of kindling stimulation.
  • each rat receives a stimulus train of 500 microAmperes ( ⁇ A). If a seizure is evoked, this intensity is used in subsequent stimulations. If no seizure is evoked, the stimulation intensity is increased in a sequence of 500, 700, 900, 1000, 1100, 1200, 1300 and 1400 ⁇ A until a seizure is evoked. The intensity that initially evoked seizure is used for subsequent stimulations.
  • the anticonvulsant and antiepileptic effects of a compound of Formula I or a salt thereof are determined by comparing the rats that require a larger number of seizures to reach more severe classes of seizures than saline treated controls.
  • EXAMPLE 19 Efficacy of Compound of Formula I in Preventing Seizure Spread
  • MES Maximal Electroshock Seizure
  • an animal receives an electrical stimulus, 0.2 seconds in duration, via corneal electrodes primed with an electrolyte solution containing an anesthetic agent.
  • the 0.2 second stimulation is generated with 150 mA in rats and 50 mA in mice at 60 Hz.
  • Rats, weighing from 105 g and 130 g, and mice, weighing from 18 g and 25.5 g receive an electrical stimulus 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours after administration of the test compound.
  • mice In rats, the compound is administered orally, while mice receive the agent via intraperitoneal injection.
  • the test endpoint, electrogenic seizure is manifested as hindlimb tonic extension. Inhibition of hindlimb tonic extension indicates that the test compound is able to inhibit MES-induced seizure spread and therefore has antiseizure activity.
  • Example 20 Efficacy of Compound of Formula I in Preventing and/or Treating Epilepsy [286] Mice and littermate controls are treated with a compound of Formula I or vehicle starting at postnatal day 14 (early treatment) or six weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities. Mice are monitored for seizures by serial video-EEG and for long-term survival.
  • Example 21 Efficacy of Compound of Formula I as an Anticonvulsant with a Maximal Electroshock Test (MES) [287] CF-1 male albino mice (25-35 g) were randomly selected into control and test groups, with the animals dosed with vehicle or test compound, at varying time-points and concentrations, respectively. On the study date, the mice are dosed by intraperitoneal injection with vehicle (30% polyoxyethylated 12-hydroxystearic acid) or test compound (50-250 mg/kg).
  • vehicle 30% polyoxyethylated 12-hydroxystearic acid
  • test compound 50-250 mg/kg
  • Seizures were induced by trans-corneal electric shock using a 60-Hz alternating current, 50 mA, delivered for 0.2 sec.
  • the mice in the test groups are subjected to electrical stimulus at time intervals from 15 minutes and 4 hours following administration of test compound.
  • the shock resulted in an immediate full body tonic extension.
  • the test was complete when the entire course of the convulsion has been observed (typically, less than 1 minute after electrical stimulation).
  • the ED50 value of the test compounds is calculated, and is the dose required to block the hind limb tonic-extensor component of the MES-induced seizure in 50% of the rodents tested.
  • EXAMPLE 22 Efficacy of Compound of Formula I on Social Behavior
  • BALB/cByJ hereafter BALB/c
  • BALB/c BALB/c
  • This example is used to examine the effects of a compound of Formula I or a salt thereof on the social behavior in BALB/c mice compared control mice.
  • the social investigatory behavior of mice is measured by the amount of time before the “test” mouse engages in social contact with the control, “stimulus” mouse.
  • All male mice are housed in temperature-controlled rooms. Food and water remained freely available.
  • Test mice Individual housing was provided firstly to permit resident male mice an opportunity to scent mark and habituate to their home cage and, secondly to heighten the motivation of “test” mice for social interaction. All the animals were allowed to acclimate to the test room (natural lighting) for at least 1 h prior to testing which was conducted from 9 a.m. and 3 p.m.
  • Two sets of “test” mice are treated, one with a compound of Formula I or a salt thereof, and the other with saline solution, as a control, at doses of 100, 200 and 300 mg/kg once daily for 5 consecutive days. The last dose was administered 60 min before testing.
  • the BALB/c mouse is then placed into the mouse cage with a “stimulus” mouse.
  • Example 23 Treatment of a Patient that has been Diagnosed with Inattention, Hyperactivity, or Schizophrenia
  • Patients with symptoms such as delusions, hallucinations, and disorganized or altered speech are evaluated with conventional testing used by mental health professionals to evaluate schizophrenia.
  • Patients are prescribed 10 mg/day of a compound of Formula I or a salt thereof, and then evaluated again after two weeks to determine if symptoms have improved. After evaluation, the dosage is increased, decreased, or kept the same depending on the change in the symptoms of schizophrenia. The treatment is maintained for as long as necessary to affect a stable resolution of the symptoms of schizophrenia.
  • Example 24 Treatment of a Patient that has been Diagnosed with Depression
  • Patients with clinical symptoms of depression are evaluated with conventional testing used by mental health professionals to evaluate depression.
  • EXAMPLE 27 Treatment of a Patient that has been Diagnosed with an Anxiety Disorder
  • Patients with clinical symptoms of anxiety disorders such as slowing of fear, specific phobias, panic attacks, are evaluated with conventional testing used by mental health professionals to evaluate the type and degree of the anxiety disorder.
  • Patients are prescribed 10 mg/day of a compound of Formula I or a salt thereof, and then evaluated again after two weeks to determine if symptoms have improved.
  • the dosage is increased, decreased, or kept the same depending on the change in the symptoms of anxiety.
  • EXAMPLE 28 Efficacy of a Compound of Formula I for Treatment of Attention Disorders
  • the timing/peak procedure test is an operant test in which mice are trained to respond to a food reward at a fixed time interval of 30 sec. Mice learn to increase their responding around the 30 sec time period. This test assesses impulsivity, attention and timing perception. A high peak of responding at the 30 sec interval and narrow spread are signatures of the animal's improved attention and time perception.
  • Mice are placed in a chamber and trained to lever press for food. After training, animals learn to respond after a fixed interval of 30 sec has elapsed as only this fixed interval response produces a reward.
  • mice To perform well on this task, animals need to learn an association between a response (lever pressing) and the delivery of reinforcement (condensed milk), they need to perceive and remember time, they need to act on the remembered time by responding or by inhibiting a response and finally they need to compare the elapsed time during a trial with their memory for the time for reinforcement.
  • Mice are dosed with a compound of Formula I or a salt thereof, and the response times are recorded and compared to control mice.
  • EXAMPLE 29 Treatment of a Patient that has been Diagnosed with Spasticity [305] A compound of Formula I or a salt thereof or a control is given to patients that have been previously diagnosed with muscle spasticity.
  • muscle contraction of the patient is rated on a traditional 0-4 scale: 0 – No increase in tone 1 – Slight increase in muscle tone, manifested by a catch and release or minimal resistance at the end of the ROM when the affected part(s) is moved in flexion or extension 1+ – Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM 2 – More marked increase in muscle tone through most of the ROM, but affected part(s) easily moved 3 – Considerable increase in muscle tone, passive movement difficult 4 – Affected part(s) rigid in flexion or extension
  • the muscle contraction of the two groups of patients, administration with a compound of Formula I or a salt thereof or control, are compared.
  • EXAMPLE 30 Treatment of a Patient that has Symptoms of Itching (Pruritus) [306] A compound of Formula I or a salt thereof or a control is given to patients that show symptoms of itching. After administration of a compound of Formula I or a salt thereof, prutitis of the patient is rated on a traditional 1-5 scale: 1 – Pruritus without the need to scratch 2 – Pruritus with the need to scratch but without excoriation 3 – Pruritus unrelieved by scratching but without excoriation 4 – Pruritus accompanied by excoriation 5 – Totally restless [307] The prutitis levels of the two groups of patients, administration with a compound of Formula I or a salt thereof or control, are compared.
  • EXAMPLE 31 Liquid formulation [308] A compound of Formula I or a salt thereof may be formulated as a liquid for intravenous administration with the composition listed in Table 6. Table 6.
  • Liquid formulation EXAMPLE 32 Paste formulation [309] A compound of Formula I or a salt thereof may be formulated as a paste for topical administration with the composition listed in Table 7. Table 7.
  • Paste formulation EXAMPLE 33 Ointment formulation [310] A compound of Formula I or a salt thereof may be formulated as an ointment for topical administration with the composition listed in Table 8. Table 8.
  • EXAMPLE 35 Gel formulation [312] A compound of Formula I or a salt thereof may be formulated as a gel for topical administration with the composition listed in Table 10. Table 10.
  • Gel formulation EXAMPLE 36 Administration of a Compound of Formula (I) via a Patch [313] A compound of Formula I or a salt thereof is administered to a subject via a transdermal patch.
  • the transdermal patch consists of a compound of Formula I on porous material such as gauze or sponge and a backing layer that holds the porous material.
  • the patch can alternatively consist of microneedles.
  • the backing layer is attached to the skin of a subject so that the porous material is in contact with the skin of a subject.
  • EXAMPLE 37 Measurement of Cell Membrane Physical Properties after Dosage with a Compound of Formula (I) [314] A compound of formula (I) is administered to a subject. Physical properties change after dosage, and various measurements are used to quantify the changes in cell membrane structure. A small sample of cells are harvested from the subject, and the sample is analyzed via transmission electron microscopy.
  • EXAMPLE 38 Synthesis of a Compound of Formula I [315] A compound of Formula I or a salt thereof is synthesized according to Scheme I: Scheme I: [316] The variable R in Scheme I is selected from substituents known to one skilled in the art.
  • Non-limiting examples of substituents include independently alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy, carboxylic acid, ester, amine, amide, carbonate, carbamate, nitro, thioether, thioester, cycloalkyl, heteroalkyl, aryl, and heteroaryl, any of which is substituted or unsubstituted, halogen, hydroxyl, sulfhydryl, nitro, nitroso, cyano, azido, and H.
  • An aldehyde is condensed with a cyanide to form a nitrile. The nitrile is then hydrolyzed to from the substituted amino acid.
  • EXAMPLE 39 Esterification of a Compound of Formula I [318] A compound of Formula I or a salt thereof is esterified according to Scheme II: Scheme II: [319]
  • the variable R’ in Scheme II is selected from substituents known to one skilled in the art. Non-limiting examples of substituents include independently alkyl, alkenyl, alkynyl, carboxylic acid, ester, amide, carbonate, carbamate, thioester, cycloalkyl, heteroalkyl, aryl, and heteroaryl, any of which is substituted or unsubstituted, and H.
  • An acid is heated in the presence of an alcohol and an acid, with or without solvent.
  • Reaction times vary on substrates, and can be from 1 minute to 100 hours. Reaction temperatures vary on substrates, and can be from 0 °C to 200 °C.
  • EXAMPLE 40 Resolution of a Compound of Formula I [321] A compound of Formula I or a salt thereof is resolved according to Scheme III: Scheme III: [322] A chiral resolving agent (CRA), or chiral auxiliary, is used to separate a racemic mixture into the enantiomers. Chiral resolving agents are selected from compounds known to one skilled in the art. Non-limiting examples of chiral resolving agents include chiral oxazolidinones and chiral sulfoxides.
  • a compound of formula I is resolved using a chiral silica gel column.
  • EXAMPLE 41 Formation of a Salt of a Compound of Formula I
  • a salt of a compound of formula I is made according to methods known to those skilled in the art.
  • a salt is formed according to Scheme IV: Scheme IV:
  • EXAMPLE 42 Method of treating obesity [325]
  • Beta hydroxybutyric acid (BHB) is administered to a subject with obesity in a therapeutically effective amount.
  • a second therapeutic, orlistat is administered with the BHB in a therapeutically effective amount. The combination of the orlistat and BHB increases the weight loss of the subject as comparted to administration of orlistat or BHB alone.
  • EXAMPLE 43 Method of treating cancer [326] Beta hydroxybutyric acid (BHB) is administered to a subject with colorectal cancer in a therapeutically effective amount. Additionally, a second therapeutic, 5-fluorouracil, is administered with the BHB in a therapeutically effective amount. The combination of the 5- fluorouracil and BHB decreases the tumor size of the colorectal cancer as compared to administration of 5-fluorouracil or BHB alone.
  • EXAMPLE 44 Method of screening for cancer drugs [327] Modified Beta hydroxybutyric acid (BHB) compounds are generated by medicinal chemistry techniques. The modified BHB compounds are screened in an animal anesthetic assay. Briefly, the modified BHB compounds are administered to the animals at doses that induce anesthesia.
  • BHB Beta hydroxybutyric acid
  • the duration and potency of the administered modified BHB compounds as anesthesia inducing compounds are determined and compared to unmodified BHB.
  • the longer- acting and/or more potent compounds are selected as potential anti-cancer compounds.
  • EXAMPLE 45 Method of screening for cancer drugs [328]
  • the modified Beta hydroxybutyric acid (BHB) compounds from Example 44 are tested in a carcinogenic animal model. Briefly, the modified BHB compounds are supplemented to the diet of mice that have been exposed to a carcinogen. The mice consuming the modified BHB compounds are compared to mice fed with a normal diet, which have also been exposed to the carcinogen. The size, number, and spread of tumors are determined and compared between the mice consuming the modified BHB compounds and the mice fed a normal diet.
  • EXAMPLE 46 Method of treating cancer in a mouse [329] Beta hydroxybutyric acid (BHB) is administered to mice with bladder cancer in a therapeutically effective amount. Additionally, a second therapeutic, Bacillus Calmette-Guérin (BCG), is administered concurrently or consecutively with the BHB in a therapeutically effective amount. The combination of the BCG and BHB decreases the tumor size of the bladder cancer as compared to administration of BCG or BHB alone.
  • BHB Bacillus Calmette-Guérin
  • EXAMPLE 47 Method of treating cancer in a human Beta hydroxybutyric acid (BHB) is administered by intravesical administration to a human subject with a bladder cancer in a therapeutically effective amount. Additionally, a second therapeutic, Bacillus Calmette-Guérin (BCG), is administered by intravesical administration concurrently or consecutively with the BHB in a therapeutically effective amount. The combination of the BCG and BHB decreases the tumor size of the bladder cancer as compared to administration of BCG or BHB alone.
  • BCG Bacillus Calmette-Guérin
  • the combination of the BCG and BHB decreases the tumor size of the bladder cancer as compared to administration of BCG or BHB alone.
  • EXAMPLE 48 Method of treating bladder cancer in a murine subject Beta hydroxybutyric acid (BHB) is administered by intravesical administration to a murine subject with a bladder cancer tumor in a therapeutically effective amount.
  • Murine subjects were induced with bladder tumors prior to administration of BHB.
  • murine subjects are anesthetized and maintained at 1- 3% isoflurane during treatment.
  • One or two doses of BHB are given to the female murine subjects after bladder evacuation using a 24G angiocatheter. Double the concentration and half the volume of BHB in solution are given to male murine subjects after partial bladder evacuation.
  • Control groups of male and female murine subjects are also treated with phosphate buffered saline (PBS) solution alone. Doses of BHB and/or PBS solutions are given at 24 hour interval(s).
  • PBS phosphate buffered saline

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Abstract

La divulgation concerne, entre autres, des méthodes d'induction d'anesthésie et de sédation et des méthodes de traitement de maladies et de troubles comprenant des troubles du système nerveux central, des lésions cérébrales traumatiques, des troubles du système nerveux périphérique, l'obésité, le cancer, la dépression et l'ischémie. La divulgation concerne également des traitements à l'aide d'un anticonvulsivant contre des maladies et des troubles. Des traitements peuvent consister à administrer une dose efficace d'un composé ou d'une formulation selon la divulgation à un sujet en ayant besoin. La divulgation concerne également des compositions comprenant de l'acide bêta-hydroxybutyrique (BHB) pour le traitement de cancers et de l'obésité.
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