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WO2008118785A2 - Procédés de traitement de la dépression utilisant des traitements à effet immédiat et la d-cyclosérine - Google Patents

Procédés de traitement de la dépression utilisant des traitements à effet immédiat et la d-cyclosérine Download PDF

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Publication number
WO2008118785A2
WO2008118785A2 PCT/US2008/057844 US2008057844W WO2008118785A2 WO 2008118785 A2 WO2008118785 A2 WO 2008118785A2 US 2008057844 W US2008057844 W US 2008057844W WO 2008118785 A2 WO2008118785 A2 WO 2008118785A2
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Prior art keywords
immediate
depression
composition
impact
cycloserine
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Ceased
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PCT/US2008/057844
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WO2008118785A3 (fr
Inventor
Jason P. Mcdevitt
Michael Davis
Kerry J. Ressler
Nathan Andrew Shapira
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TIKVAH THERAPEUTICS
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TIKVAH THERAPEUTICS
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Publication of WO2008118785A2 publication Critical patent/WO2008118785A2/fr
Publication of WO2008118785A3 publication Critical patent/WO2008118785A3/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles

Definitions

  • This invention relates to methods and compositions for the treatment of depression in humans that include administering an immediate-impact treatment and D-cycloserine (DCS).
  • DCS D-cycloserine
  • Immediate-impact treatments for depression include acute administration of pharmacological agents such as ketamine, as well as non-pharmacologic treatments such as electroconvulsive shock therapy (ECT). These immediate-impact treatments are particularly useful for subjects with severe depression who need more immediate relief than is typically provided by standard pharmacological remedies, e.g. by administering selective serotonin reuptake inhibitors (SSRIs). Such pharmacological agents commonly take up to three weeks before positive effects are observed. ECT is also frequently performed on subjects for whom pharmacological agents has not been effective. [0004] While immediate-impact treatments can be quite effective in improving depression, maintaining these beneficial effects can be problematic.
  • N-methyl-D-aspartate (NMDA) receptor antagonists administered systemically or infused directly into the amygdala, have been shown to block extinction, e.g. block an action whereby a previously fear conditioned patient is exposed repeatedly to a fear-eliciting cue in the absence of any aversive event, and the fear conditioned response declines.
  • DCS has been shown to facilitate consolidation of a new learning that competes with a previously conditioned response. For example, DCS has been used together with psychotherapies that promote extinction, such as cognitive behavioral therapy.
  • Methods are provided for treating depression in humans.
  • Methods for treating depression in a subject disclosed herein include those methods comprising administering to a subject in need thereof: a) a composition comprising a therapeutically effective amount of D- cycloserine; and b) an immediate-impact depression treatment, wherein said immediate-impact depression treatment is administered within six hours of administering said D-cycloserine.
  • a sub-antimicrobial dose of D-cycloserine is administered and/or can be administered on an acute basis. For example, between about 10 mg and about 100 mg D- cycloserine can be administered.
  • the composition comprising a D-cycloserine may administered, for example, within about four hours of administering said immediate-impact depression treatment or within about two hours of administering said immediate-impact depression treatment.
  • the disclosed immediate-impact depression treatment may comprise a composition comprising a therapeutically effective amount of a second pharmacologic agent, for example, ketamine or a pharmaceutically acceptable salt thereof, or the immediate-impact depression treatment may comprise electroconvulsive shock therapy.
  • a second pharmacologic agent for example, ketamine or a pharmaceutically acceptable salt thereof
  • the immediate-impact depression treatment may comprise electroconvulsive shock therapy.
  • the methods may comprise D-cycloserine administered before, after, or substantially simultaneous with administration of said immediate-impact depression treatment.
  • the compositions may each be administered intravenously.
  • a subject treated by the disclosed methods has more improvement in depression symptoms as measured by a clinical assessment method as compared to improvement in depression symptoms by administration of an immediate depression treatment alone.
  • Methods are also provided for improving the efficacy of an immediate-impact treatment for depression, comprising administering to a subject in need thereof a composition comprising D-cycloserine within six hours of administering the immediate-impact treatment to said subject.
  • a composition comprising D-cycloserine may be administered between about 1 hour and about 8 hours after, between about 1 hour and about 6 hours, or between 1 hour and about 4 hours after, for example, administration of ketamine or a pharmaceutically acceptable salt thereof.
  • a composition comprising D-cycloserine can be administered between about 5 minutes and about 1 hour, or between about 5 minutes and 2 hours, after administration of electroconvulsive shock therapy.
  • improved efficacy of an immediate impact treatment is measured by a clinical assessment test, for example, the disclosed methods may improve the efficacy of an immediate impact treatment in a subject over a longer period of time as compared to the efficacy of administering to a subject an immediate impact treatment alone, as measured by a clinical assessment test.
  • kits for use in treating a patient with depression comprises: a composition suitable for administration to a patient comprising D-cycloserine; a composition suitable for administration to a patient comprising ketamine or the pharmaceutically acceptable salts thereof; and instructions for use.
  • the present invention is directed to methods and compositions for treating depression.
  • the disclosed methods comprise administering to a subject in need thereof an effective amount of an agonist or partial agonist of N-methyl-D-aspartate and an immediate- impact depression treatment.
  • a disclosed method for treating depression in subject includes administering to a subject in need thereof a) an effective amount of D- cycloserine; and b) an immediate-impact depression treatment, wherein said immediate-impact depression treatment is administered before, during or after administering D-cycloserine, e.g. administered within six hours of administering said D-cycloserine.
  • Depression refers to the clinical condition known as major depressive disorder, and is characterized by a state of intense sadness, melancholia, or despair that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living.
  • This disclosure relates to treating a patient for depression, wherein "treat” or “treating” refers to an earnest attempt to alleviate depression.
  • such treatment alleviates depression in a subject or patient.
  • Depression is alleviated if either (or both) the severity or frequency of a symptom of the depression is reduced.
  • a subject can be treated for depression in accordance with the methods of the invention irrespective of whether the treatment actually was successful in alleviating the depression.
  • An immediate-impact treatment for depression is a non-chronic treatment for depression, other than psychotherapy, that can significantly alleviate depression in a subject within about 24 hours of administration of the treatment.
  • an immediate-impact treatment is not typically a chronic treatment for depression; rather, an immediate-impact treatment is undertaken with the intent of achieving a rapid alleviation of depression.
  • Exemplary immediate-impact treatments for depression include administration of ketamine and ECT.
  • D-cycloserine refers to the chemical D-cycloserine (CA Index Name: 3- Isoxazolidinone, 4-amino-, (4R)- (9CI); CAS Registry No. 68-41-7), or pharmaceutically acceptable salts thereof.
  • DCS is an FDA (United States Food and Drug Administration)- approved drug for treatment of tuberculosis, and is sold by Eli Lilly and Company under the trade name Seromycin®.
  • DCS is a structural analog of D-alanine, and is a broad-spectrum antibiotic produced by some strains of Streptomyces orchidaceus and S. garphalus.
  • DCS has antibiotic activity in vitro against growth phase Gram-negative bacteria such as Escherichia coli, some strains of Staphylococcus aureus, and Chlamydia species, among others.
  • the minimum inhibitory concentrations (MIC) in vitro for typical Mycobacterium tuberculosis strains range from about 6-25 ⁇ g/mL.
  • DCS is generally dosed at 500-1000 mg/day divided twice daily (PDR 1997) with chronic treatment. At a dose of 500 mg/day, serum concentrations of 25-30 ⁇ g/ml are generally maintained. The peak serum concentrations occur within 3-8 hours after dosing, and it is primarily renally excreted with a half-life of 10 hours.
  • DCS can give rise to significant neurological side effects in treated subjects. Typical side effects on chronic dosing schedules (who were generally chronically ill with tuberculosis) include drowsiness, depression, headache, confusion, tremor, vertigo, and memory difficulties, paresthesias, and seizure.
  • a therapeutically effective amount of DCS is lower than the amounts typically used for the treatment of tuberculosis.
  • a “therapeutically effective amount” or “therapeutically effective dose” of the pharmacologic agent is an amount of the pharmacologic agent that typically results in e.g. a greater therapeutic benefit, or a therapeutic benefit for a longer time, relative to that observed in the absence of administering the pharmacologic agent.
  • a therapeutically effective amount of DCS used in the disclosed methods of treating depression relates to a sub-antimicrobial dose of DCS.
  • a sub- antimicrobial dose refers to a dose of DCS that is less than or equal to 2 mg DCS per kg body weight of the subject (i.e., less than or equal to 2 mg/kg), and greater than about 0.4 mg/kg (this lower limit is needed to maintain efficacy for facilitation of extinction).
  • sub-antimicrobial doses of DCS achieve peak serum concentrations in the subject of less than or equal to about 5 ⁇ g/mL, although there is substantial variability between subjects.
  • DCS calcium sulfate
  • the drug no longer kills most microorganisms, including those that are ordinarily susceptible to higher DCS concentrations typically reached in the body when DCS is used to treat tuberculosis (i.e., 500 mg or 1000 mg per day).
  • the serum concentration levels of DCS in subjects administered DCS are a function of numerous factors, including body weight, metabolism, and the amount of drug ingested.
  • all microorganisms do not have the same susceptibility to DCS. Accordingly, while it is possible that a sub-antimicrobial dose of DCS can still kill a small subset of microorganisms, sub- antimicrobial doses of DCS generally will not have a significant antimicrobial effect in the body.
  • a sub-antimicrobial dose of DCS When administered to adult human subjects, a sub-antimicrobial dose of DCS generally comprises a drug formulation (e.g., pill, capsule, tablet) of DCS containing DCS in an amount equal to or less than 100 mg, preferably less than 80 mg DCS (e.g. about 5 mg to about 100 mg, or about 10 mg to about 100 mg, or even about 10 mg to about 80 mg) to provide a greater margin between the concentration of DCS and the minimum inhibitory concentration (MIC) of DCS against microorganisms active in a subject's body.
  • DCS minimum inhibitory concentration
  • Children being administered DCS for treatment of tuberculosis are normally dosed at a level between about 10-20 mg/kg.
  • a sub- antimicrobial dose of DCS when administered to a child subject according to the methods of the present invention, comprises less than or equal to 2 mg/kg, and generally achieves peak serum concentrations of DCS in the child subject of less than or equal to 5 ⁇ g/mL.
  • the dosages of DCS contemplated herein are lower than those used to treat tuberculosis, the side effects of DCS will be greatly reduced by infrequent dosing at concentrations five to twenty-fold lower than those routinely used for TB treatment.
  • the disclosed methods include administering DCS and an immediate-impact treatment for the treatment of depression.
  • the DCS may be administered within about six hours of the commencement or termination of an immediate-impact treatment for depression, e.g.
  • DCS may be administered before or after administering an immediate-impact treatment. Alternatively, the DCS may be administered substantially at the same time as an immediate impact treatment. [0025] In some embodiments, DCS is administered on an acute basis.
  • Acute administration of a pharmacological agent to a subject generally refers to a single exposure of the subject or patient to a therapeutically effective amount of the pharmacological agent within an extended time period, i.e. a time period of two, three, or four days or longer. For example, a once, twice or thrice-weekly administration of DCS constitutes acute administration.
  • Administering a single dose of DCS, wherein the dose is formulated to have both immediate release and delayed release characteristics, constitutes acute dosing provided that the peak blood level of DCS in the subject is achieved within 12 hours of the time the dose is administered.
  • the timing of administration and the therapeutically effective dose of DCS in a given subject will depend on the severity of symptoms, in addition to the age, sex, and size of the subject being treated, among other variables.
  • the serum concentration of DCS in a subject will be at least 1 ⁇ g/mL in order to facilitate consolidation of the immediate-impact treatment for depression.
  • the timing of administration of DCS according to the present invention will be within about six hours, more preferably within about three hours, prior to an immediate- impact treatment for depression, or within about six hours, more preferably within about three hours, following an immediate-impact treatment for depression.
  • a therapeutically effective dose of DCS is administered to a subject two hours prior to a non- pharmacological immediate-impact treatment for depression, then DCS will be present at therapeutically effective levels both before and after the immediate-impact treatment for depression.
  • a B vitamin such as one or more of the B-complex vitamins
  • a B-complex vitamin includes thiamine (Bl), riboflavin (B2), niacin (B3), pyridoxine (B6), folic acid (B9), cyanocobalamin (B 12), pantothenic acid and biotin.
  • pyridoxine can be additionally administered at up to ten times the dosage of DCS.
  • the DCS for administeriation as contemplated herein is provided in a composition that includes a B -complex vitamin, e.g. pyridoxine, for a example, as a tablet or other composition that includes for example 50 mg DCS and 50 mg pyridoxine.
  • DCS has been reported to reduce the levels of certain important chemicals in the blood of subjects, including calcium, folic acid, magnesium, vitamin K, and vitamin B6 and vitamin B 12.
  • Co-administration of DCS with supplements of any of these ingredients is contemplated by the methods and compositions of this invention.
  • a subject undergoing treatment with the methods of the invention can experience significant improvements in depression. Relative to subjects treated only with immediate- impact treatments for depression, subjects treated according to the methods of the invention (i.e., subjects administered DCS in conjunction with the immediate-impact treatment for depression) will experience greater improvements, or more long-lasting improvements, as measured by any clinically recognized assessment method for depression (e.g., the 21 -item Hamilton Depression Rating Scale). It should be noted that not every subject will benefit from the methods of the invention, just as other pharmaceutical agents do not typically benefit every patient.
  • DCS chronic, non-pharmacological treatments for depression, including chronic deep brain therapy, vagus nerve stimulation, light therapy, and repetitive transcranial magnetic stimulation, many of which are performed on a daily basis.
  • DCS can be administered on a chronic basis in conjunction with these treatments, but it is likely that a tolerance to DCS would quickly be established, and the benefits of administering DCS in conjuction with these chronic treatments may be minimal.
  • DCS it is possible to administer DCS on an acute basis, in conjunction with a small subset of a series of these or other chronic treatments (e.g., DCS could administered on a once-weekly basis in conjunction with a daily treatment using vagus nerve stimulation), but with minimal benefit.
  • Electroconvulsive Shock Therapy contemplate treatment of depression in a subject by administering DCS and ECT.
  • DCS will be administered subsequent to administration of ECT.
  • ECT is a medical procedure wherein an electrical current is passed through the brain of a subject to induce a seizure.
  • the procedure is performed on an in-patient basis up to three times per week, although maintenance ECT may be performed less frequently on an outpatient basis.
  • the subject is anesthetized, and then the muscles are temporarily paralyzed, often via administration of succinylcholine.
  • bilateral ECT electrodes are placed above each temple.
  • unilateral ECT the electrodes are placed above the temple of one side of the brain and in the middle of the forehead.
  • An electric current is then applied, triggering a seizure, preferably of duration between about 30 seconds and about 60 seconds.
  • ECT works to improve depression, but the biochemistry of the brain is substantially altered during and after seizure activity.
  • DCS can be administered in conjunction with all of these ECT sessions, or, preferably, in conjunction with one or two ECT sessions per week.
  • an intravenous (IV) catheter is typically inserted into a subject undergoing ECT, it is preferable to administer DCS intravenously through the catheter, rather than via oral dosing or other forms of dosing.
  • DCS is administered subsequent to the termination of the induced seizure, preferably within thirty minutes.
  • a subject with depression may undergo ECT while being monitored by an electroencephalogram (EEG).
  • EEG electroencephalogram
  • 50 mg DCS is administered intravenously after the EEG levels off following the seizure and before the subject has awakened from anesthesia.
  • a subject with depression may undergo ECT three times per week for three weeks.
  • DCS may be administered intravenously to the subject within ten minutes of the conclusion of the induced seizure, as monitored by EEG.
  • 100 mg DCS can be administered intravenously to the subject within ten minutes of the conclusion of the induced seizure, as monitored by EEG.
  • Ketamine refers to the chemical ketamine (IUPAC name: 2-(2-chlorophenyl)-2- methylamino-cyclohexan-1-one, CAS Registry No. 6740-88-1), or pharmaceutically acceptable salts thereof, most typically the hydrochloride salt. Ketamine is a general dissociative anaesthetic for human and veterinary use.
  • the methods of the invention contemplate treatment of depression in a subject by administering DCS and administering ketamine to a subject in need thereof.
  • DCS is administered subsequently to administration of ketamine, preferably within about six hours after administration of ketamine, more preferably between about one hour and four hours after administration of ketamine.
  • a composition comprising ketamine and about 10-100 mg of DCS.
  • an intravenous (IV) catheter is inserted into a subject undergoing ketamine treatment for depression. It is preferable, according to the methods of the invention, preferable to administer DCS intravenously through the inserted catheter, rather than via oral dosing or other forms of dosing.
  • the ketamine concentration has an initial slope (known as the alpha phase) lasting about 45 minutes with a half-life of 10 to 15 minutes.
  • This first phase corresponds clinically to the anesthetic effect of the drug.
  • the anesthetic action is terminated by a combination of redistribution from the central nervous system to slower equilibrating peripheral tissues and by metabolic transformation.
  • the later half-life of ketamine (beta phase) is about 2.5 hours.
  • Subsequent administration of DCS, a partial NMDA receptor agonist changes the dynamics at the NMDA receptor, and the transformation of the effects on the receptor to a net agonist is important in order to consolidate the benefits of the ketamine treatment.
  • a subject with depression is administered an intravenous infusion of ketamine hydrochloride with a dosing of, for example, 0.5 mg/kg.
  • ketamine hydrochloride with a dosing of, for example, 0.5 mg/kg.
  • 50 mg DCS is administered intravenously to the subject.
  • 80 mg DCS is administered intravenously to the subject.
  • compositions contemplated by the methods of the invention may be formulated and administered to a subject for treatment of depression as described below.
  • the invention encompasses the preparation and use of pharmaceutical compositions comprising DCS as an active ingredient useful for treatment of depression.
  • Such pharmaceutical compositions may consist of DCS alone, in any form suitable for administration to a subject, or the pharmaceutical composition may comprise DCS and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
  • the active ingredient(s) may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.
  • pharmaceutically acceptable carrier means a chemical composition with which the active ingredient may be combined and which, following the combination, can be used to administer the active ingredient to a subject.
  • physiologically acceptable ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered.
  • Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.
  • the relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention may vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents
  • parenteral administration and “administered parenterally” are art- recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac,
  • compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for oral, rectal, vaginal, intravenous, parenteral, topical, pulmonary, intranasal, buccal, sub-lingual, ophthalmic, intrathecal or another route of administration.
  • a first composition comprising ketamine and a second composition comprising DCS may be packaged in kit form to facilitate use in the disclosed methods.
  • Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.
  • a formulation of a pharmaceutical composition of the invention suitable for oral administration may be prepared, packaged, or sold in the form of a discrete solid dose unit including, but not limited to, a tablet, a hard or soft capsule, a cachet, a troche, or a lozenge, each containing a predetermined amount of the active ingredient.
  • Other formulations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion.
  • an "oily" liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water.
  • a tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent.
  • Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.
  • compositions used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.
  • Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate.
  • Known surface active agents include, but are not limited to, sodium lauryl sulphate.
  • Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate.
  • Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid.
  • binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
  • Known lubricating agents include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.
  • Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Soft gelatin capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • a pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
  • Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle.
  • Aqueous vehicles include, for example, water and isotonic saline.
  • Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
  • Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent.
  • suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, and hydroxypropylmethylcellulose.
  • Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, as well as condensation products of an alkylene oxide with either: a fatty acid, a long chain aliphatic alcohol, a partial ester derived from a fatty acid and a hexitol, or a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively).
  • Known emulsifying agents include, but are not limited to, lecithin and acacia.
  • Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl-para- hydroxybenzoates, ascorbic acid, and sorbic acid.
  • Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
  • Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.
  • Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent.
  • Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent.
  • Aqueous solvents include, for example, water and isotonic saline.
  • Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
  • Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.
  • a pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion.
  • the oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these.
  • compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology.
  • preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

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Abstract

La présente invention concerne des procédés de traitement de la dépression chez l'homme. Les procédés comprennent l'administration de D-cyclosérine à un sujet et l'administration d'un traitement pour la dépression à effet immédiat. Des exemples de traitements à effet immédiat pour la dépression comprennent l'administration de kétamine, ainsi que des traitements non pharmacologiques tels que le traitement convulsivant à l'électrochoc.
PCT/US2008/057844 2007-03-23 2008-03-21 Procédés de traitement de la dépression utilisant des traitements à effet immédiat et la d-cyclosérine Ceased WO2008118785A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US89655607P 2007-03-23 2007-03-23
US60/896,556 2007-03-23

Publications (2)

Publication Number Publication Date
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WO2008118785A3 WO2008118785A3 (fr) 2008-12-24

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WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
WO2011104298A1 (fr) * 2010-02-24 2011-09-01 Universität Zürich Prévention et traitement de maladies provoquées par des niveaux élevés de désoxysphingolipides
CN105377371A (zh) * 2013-04-12 2016-03-02 西奈山伊坎医学院 创伤后应激障碍的治疗方法
CN105476976A (zh) * 2015-12-22 2016-04-13 广州瑞尔医药科技有限公司 药物组合物及其制备方法和应用
EP3035918A4 (fr) * 2013-08-26 2017-03-29 Amorsa Therapeutics, Inc. Dose orale à couche unique de kétamine neuro-atténuante
WO2021107690A1 (fr) * 2019-11-27 2021-06-03 Neurorive Inc Polythérapie de cyclosérine et de lithium pour le traitement de la dépression
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US20050222270A1 (en) * 2004-02-26 2005-10-06 Olney John W Prolonged administration of NMDA antagonist drug and safener drug to create improved stable neural homeostasis

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WO2011104298A1 (fr) * 2010-02-24 2011-09-01 Universität Zürich Prévention et traitement de maladies provoquées par des niveaux élevés de désoxysphingolipides
US11700840B2 (en) 2011-11-21 2023-07-18 The Institute For Ethnomedicine L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders
US12295353B2 (en) 2011-11-21 2025-05-13 The Institute For Ethnomedicine L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders
US11974551B2 (en) 2011-11-21 2024-05-07 The Institute For Ethnomedicine L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders
US11917986B2 (en) 2011-11-21 2024-03-05 The Institute For Ethnomedicine L-serine compositions, methods and uses for treating neurodegenerative diseases and disorders
CN105377371A (zh) * 2013-04-12 2016-03-02 西奈山伊坎医学院 创伤后应激障碍的治疗方法
US12403101B2 (en) 2013-04-12 2025-09-02 Icahn School Of Medicine At Mount Sinai Method of treating post-traumatic stress disorder
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US9913803B2 (en) 2013-08-26 2018-03-13 Amorsa Therapeutics, Inc. Single-layer oral dose of neuro-attenuating ketamine
EP3035918A4 (fr) * 2013-08-26 2017-03-29 Amorsa Therapeutics, Inc. Dose orale à couche unique de kétamine neuro-atténuante
US10653629B2 (en) 2013-08-26 2020-05-19 Amorsa Therapeutics, Inc. Single layer oral dose of neuro-attenuating ketamine
EP3960162A1 (fr) * 2013-08-26 2022-03-02 Amorsa Therapeutics, Inc. Dose orale à couche unique de kétamine neuro-atténuante
US11554100B2 (en) 2013-08-26 2023-01-17 Amorsa Therapeutics, Inc. Single-layer oral dose of neuro-attenuating ketamine
US11110070B2 (en) 2015-11-17 2021-09-07 The Trustees Of Columbia University In The City Of New York Pharmacological prophylactics against stress-induced affective disorders and their associated symptoms
CN105476976B (zh) * 2015-12-22 2018-09-25 广州瑞尔医药科技有限公司 药物组合物及其制备方法和应用
WO2017107242A1 (fr) * 2015-12-22 2017-06-29 广州瑞尔医药科技有限公司 Composition pharmaceutique, procédé de préparation associé et application associée
CN105476976A (zh) * 2015-12-22 2016-04-13 广州瑞尔医药科技有限公司 药物组合物及其制备方法和应用
US11622948B2 (en) 2017-11-09 2023-04-11 The Trustees Of Columbia University In The City Of New York Biomarkers for efficacy of prophylactic treatments against stress-induced affective disorders
US12239614B2 (en) 2017-11-09 2025-03-04 The Trustees Of Columbia University In The City Of New York Pharmacological prophylactics against stress-induced affective disorders in females
US12329726B2 (en) 2017-11-09 2025-06-17 The Trustees Of Columbia University In The City Of New York Biomarkers for efficacy of prophylactic treatments against stress-induced affective disorders
US20220387481A1 (en) * 2019-11-27 2022-12-08 Neurorive Inc Combination therapy of cycloserine and lithium for the treatment of depression
WO2021107690A1 (fr) * 2019-11-27 2021-06-03 Neurorive Inc Polythérapie de cyclosérine et de lithium pour le traitement de la dépression
AU2020391291B2 (en) * 2019-11-27 2024-04-18 Neurorive Inc Combination therapy of cycloserine and lithium for the treatment of depression
KR20210065892A (ko) * 2019-11-27 2021-06-04 주식회사 뉴로라이브 우울증 치료를 위한 사이클로세린 및 리튬 병용 요법
US12303530B2 (en) * 2019-11-27 2025-05-20 Neurorive Inc Combination therapy of cycloserine and lithium for the treatment of depression

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