WO2000028985A1 - Method of treating seizure disorders - Google Patents
Method of treating seizure disorders Download PDFInfo
- Publication number
- WO2000028985A1 WO2000028985A1 PCT/US1999/027384 US9927384W WO0028985A1 WO 2000028985 A1 WO2000028985 A1 WO 2000028985A1 US 9927384 W US9927384 W US 9927384W WO 0028985 A1 WO0028985 A1 WO 0028985A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- seizures
- treatment
- subject
- seizure disorders
- formulations
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
Definitions
- the present invention concerns methods, compounds and compositions useful for the treatment of seizure disorders in subjects in need thereof.
- the ketogenic diet has been described as a means for treating epilepsy in children.
- the ketogenic diet comprised of a high fat, low carbohydrate, and low protein diet, was initially devised in 1921, and is still being utilized. See, e.g., R. Schwartz, Dev. Med. Child. Neurol 31, , 141 (1989).
- the biochemical and physiological mechanism(s) by which the ketogenic diet functions has yet to be quantitatively elucidated.
- ketogenic diet Numerous deleterious physiological effects of the ketogenic diet have been noted. These effects include hyperuricemia, acidosis, hypocalcemia, he aturia, development of renal calculi, AED-associated toxicity in those individuals undergoing concomittant pharmacologic therapy, recurrent infections, refusal to eat, disordered mineral metabolism, optic neuropathy, and impaired neutrophil function.
- hyperuricemia acidosis
- hypocalcemia hypocalcemia
- he aturia development of renal calculi
- AED-associated toxicity in those individuals undergoing concomittant pharmacologic therapy
- refusal to eat disordered mineral metabolism
- optic neuropathy and impaired neutrophil function.
- impaired neutrophil function R. Woody, J. Pediatrics 115, 427 (1989).
- H. Keith, Arch. Neurol Psych. 29, 148-154 (1933) describes the treatment of experimentally produced convulsions in rabbits with intraveneous injection of aceto- acetic acid and sodium aceto-acetate.
- the convulsions were produced by an injection of a convulsing dose of thujone. Insofar as applicant is aware, this treatment has not been extended to a practical treatment for seizure disorders.
- the present invention concerns a method of treating seizures in a subject in need thereof.
- the method comprises administering ⁇ -hydroxybutyrate or an analog thereof (including pharmaceutically acceptable salts thereof) in an amount effective to treat the seizure disorder.
- a second aspect of the present invention is a pharmaceutical formulation comprising active compounds as described above in a pharmaceutically acceptable carrier.
- a third aspect of the present invention is the use of a compound as given above for the preparation of a medicament for the treatment of seizure disorders in a subject in need thereof.
- Figure 1 shows the incidence of pentylenetetrazol (PTZ) induced seizures in animals treated by the method of the present invention, as compared to various control groups.
- PTZ pentylenetetrazol
- Figure 2 shows the average seizure duration for animals treated by the method of the present invention, as compared to various control groups.
- Figure 3 shows the mortality rate outcome of PTZ-induced seizures in animals treated by the method of the present invention, as compared to various control groups.
- seizure disorder or seizures may be treated by the method of the present invention, including but not limited to chronic seizure disorders such as grand mal epileptic seizures (or primary generalized tonic-clonic epilepsy), petit mal seizures (or absence, typical epilepsy), myoclonic seizures, partial elementary seizures, partial (psychomotor) complex seizures or temporal lobe epilepsy, secondary generalized seizures, and other chronic unclassifiable seizures.
- chronic seizure disorders is particularly preferred.
- the treatment of generalized epilepsy and partial epilepsy are particularly preferred, with these terms having their conventional meaning in light of current medical usage. See, e.g., Principles of Neurology (5 th Ed. R. Adams & M. Victors Eds. 1993).
- treat and “treatment” as used herein are intended to encompass any clinically beneficial relief of symptoms, particularly a partial relief of symptoms and/or a reduction in frequency, duration and/or severity of seizure episodes.
- While the present invention is primarily concerned with the treatment of human subjects, it may also be employed for the treatment of animal subjects, such as dogs and cats, for veterinary purposes.
- ⁇ -hydroxybutyrate may be employed to carry out the present invention, along with analogs or derivatives thereof, preferably excluding acetoacetate.
- ⁇ - hydroxybutyrate has the formula:
- R is C ⁇ to C 6 alkyl, such as methyl, ethyl, propyl or butyl.
- the active compounds are known, or can be made by variations of known techniques in light of the suggestion of the instant disclosure. Active compounds include salts such as sodium salts of the foregoing, which may be prepared by conventional techniques.
- the active compounds described above may be formulated for administration in single pharmaceutical carrier for the treatment of a variety of conditions.
- the active compounds including the physiologically acceptable salts thereof, or the acid derivatives of either thereof are typically admixed with, inter alia, an acceptable carrier.
- the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
- the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.5% to 95% by weight of the active compound.
- One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.
- the formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
- Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
- the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
- a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
- Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
- Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
- Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may be administered by means of subcutaneous, intravenous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood.
- Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include vaseline, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
- Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis ⁇ tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
- the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.
- the therapeutically effective dosage of any one active agent will vary somewhat from compound to compound, patient to patient, and will depend upon factors such as the condition of the patient and the route of delivery. Such dosages can be determined in accordance with routine pharmacological procedures known to those skilled in the art, particularly in light of the disclosure provided herein.
- the dosage is 10 or 20 to 150 or 200 mg active compound per Kg subject body weight.
- the total dosage may be given as one administration daily, or may be divided among multiple administrations (e.g., two or three) each day.
- the active agents described herein may be administered alone or in combination with one or more other anti-epileptic drugs.
- antiepileptic drugs include but are not limited to valproate, carbamazepine, clonazepam, phenytoin, primidone, acetazolamide, and ethosuximide . These compounds are administered at their known dosages in their known schedules, in the same or a separate pharmaceutical carrier from the active agents described above.
- BHB ⁇ -hydroxybutyrate
- PTZ pentylenetetrazol
- the rats were divided into a control group or one of theee experimental groups.
- one set of rats was fed a ketogenic diet in accordance with known techniques (Research Diet, New Jersey, USA) and another had BHB added to their water supply, in an amount of 50 mg per deciliter, both for three weeks prior to PTZ injection.
- BHB was injected intraperitoneally as a 100 mg/ml solution of sterile, isotonic saline at a dose of 150 mg/Kg, 45-60 minutes prior to PTZ injection.
- Figure 1 shows the response of these groups to PTZ injection. All of the rats in the control and diet groups had tonic-clonic seizures, while only 50% of the water group (i.e., the group that had BHB added to their water supply) had seizures. Eighty percent of the BHB injection group had seizures. The average seizure duration in all of the experimental groups was shorter than the controls, 93 vs. 37 seconds (p ⁇ 0.01, paired t-test) ( Figure 2). In addition, BHB significantly reduced the mortality rate from PTZ-induced seizures. Figure 3 shows that 67% of the control rats but none of the rats from the water group died after PTZ injection. The mortality rate was also reduced to 30% in the diet group and 12% in the injection group. This study demonstrated that BHB alone, given by either oral or parenteral route, can produce significant antiepileptic effects.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU17358/00A AU1735800A (en) | 1998-11-19 | 1999-11-18 | Method of treating seizure disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10905598P | 1998-11-19 | 1998-11-19 | |
US60/109,055 | 1998-11-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000028985A1 true WO2000028985A1 (en) | 2000-05-25 |
WO2000028985A9 WO2000028985A9 (en) | 2000-11-02 |
Family
ID=22325561
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/027384 WO2000028985A1 (en) | 1998-11-19 | 1999-11-18 | Method of treating seizure disorders |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU1735800A (en) |
WO (1) | WO2000028985A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001095739A2 (en) | 2000-06-13 | 2001-12-20 | Hill's Pet Nutrition, Inc. | Diet which induces ketosis in a canine or feline |
WO2005107724A1 (en) * | 2004-05-07 | 2005-11-17 | Ketocytonyx Inc. | Treatment of apoptosis |
US7262037B2 (en) | 2002-01-04 | 2007-08-28 | Guoqiang Chen | Method for the production of D-(-)-3-hydroxybutyric acid by recombinant Escherichia coli |
US7485743B2 (en) | 2004-07-20 | 2009-02-03 | Btg International Limited | Oligomeric ketone compounds |
FR2997302A1 (en) * | 2012-10-29 | 2014-05-02 | Assist Publ Hopitaux De Paris | New butan-1-ol compound combined with thiamine or ketogenic preparation, useful for preventing or treating pyruvate dehydrogenase deficiency in individual in which ketogenic diet is ineffective and neurological disorder e.g. Leigh syndrome |
EP3528802A4 (en) * | 2016-10-24 | 2020-05-13 | University Of South Florida | Delaying latency to seizure by combinations of ketone supplements |
EP3615084A4 (en) * | 2017-04-24 | 2021-04-14 | Branequest, Inc. | Membrane active molecules |
US11202790B2 (en) | 2017-03-10 | 2021-12-21 | Tecton Group, Llc | Composition comprising ketone body and nicotinamide adenine dinucleotide modulator and methyl donor |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4663166A (en) * | 1984-06-22 | 1987-05-05 | Veech Richard L | Electrolyte solutions and in vivo use thereof |
US5116868A (en) * | 1989-05-03 | 1992-05-26 | The Johns Hopkins University | Effective ophthalmic irrigation solution |
US5616092A (en) * | 1991-07-09 | 1997-04-01 | Hydro-Gear Limited Partnership | Transaxle having hydrostatic transmission with expansion chamber |
-
1999
- 1999-11-18 WO PCT/US1999/027384 patent/WO2000028985A1/en active Application Filing
- 1999-11-18 AU AU17358/00A patent/AU1735800A/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4663166A (en) * | 1984-06-22 | 1987-05-05 | Veech Richard L | Electrolyte solutions and in vivo use thereof |
US5116868A (en) * | 1989-05-03 | 1992-05-26 | The Johns Hopkins University | Effective ophthalmic irrigation solution |
US5616092A (en) * | 1991-07-09 | 1997-04-01 | Hydro-Gear Limited Partnership | Transaxle having hydrostatic transmission with expansion chamber |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001095739A3 (en) * | 2000-06-13 | 2002-05-02 | Hills Pet Nutrition Inc | Diet which induces ketosis in a canine or feline |
US6410063B1 (en) | 2000-06-13 | 2002-06-25 | Hill's Pet Nutrition, Inc. | Composition and method |
AU2001268321B2 (en) * | 2000-06-13 | 2006-07-13 | Hill's Pet Nutrition, Inc. | Diet which induces ketosis in a canine or feline |
WO2001095739A2 (en) | 2000-06-13 | 2001-12-20 | Hill's Pet Nutrition, Inc. | Diet which induces ketosis in a canine or feline |
US7262037B2 (en) | 2002-01-04 | 2007-08-28 | Guoqiang Chen | Method for the production of D-(-)-3-hydroxybutyric acid by recombinant Escherichia coli |
US20220347133A1 (en) * | 2004-05-07 | 2022-11-03 | Btg International Limited | Epilepsy treatment employing ketogenic compounds which arrest apoptosis |
WO2005107724A1 (en) * | 2004-05-07 | 2005-11-17 | Ketocytonyx Inc. | Treatment of apoptosis |
US7485743B2 (en) | 2004-07-20 | 2009-02-03 | Btg International Limited | Oligomeric ketone compounds |
FR2997302A1 (en) * | 2012-10-29 | 2014-05-02 | Assist Publ Hopitaux De Paris | New butan-1-ol compound combined with thiamine or ketogenic preparation, useful for preventing or treating pyruvate dehydrogenase deficiency in individual in which ketogenic diet is ineffective and neurological disorder e.g. Leigh syndrome |
EP3528802A4 (en) * | 2016-10-24 | 2020-05-13 | University Of South Florida | Delaying latency to seizure by combinations of ketone supplements |
US10945975B2 (en) | 2016-10-24 | 2021-03-16 | University Of South Florida | Delaying latency to seizure by combinations of ketone supplements |
US11202790B2 (en) | 2017-03-10 | 2021-12-21 | Tecton Group, Llc | Composition comprising ketone body and nicotinamide adenine dinucleotide modulator and methyl donor |
US11865127B2 (en) | 2017-03-10 | 2024-01-09 | Tecton Group, Llc | Composition comprising ketone body and nicotinamide adenine dinucleotide modulator and methyl donor |
EP3615084A4 (en) * | 2017-04-24 | 2021-04-14 | Branequest, Inc. | Membrane active molecules |
EP3973997A1 (en) * | 2017-04-24 | 2022-03-30 | Branequest, Inc. | Membrane active molecules |
Also Published As
Publication number | Publication date |
---|---|
AU1735800A (en) | 2000-06-05 |
WO2000028985A9 (en) | 2000-11-02 |
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