WO2000029023A1 - Cox-2 inhibitors in combination with nmda-blockers for treating pain - Google Patents
Cox-2 inhibitors in combination with nmda-blockers for treating painInfo
- Publication number
- WO2000029023A1 WO2000029023A1 PCT/US1998/024317 US9824317W WO0029023A1 WO 2000029023 A1 WO2000029023 A1 WO 2000029023A1 US 9824317 W US9824317 W US 9824317W WO 0029023 A1 WO0029023 A1 WO 0029023A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- methylsulfonyl
- fluorophenyl
- group
- methyl
- Prior art date
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Classifications
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- 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
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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
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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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
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to a method for alleviating a pain state not associated with a cough condition, i.e., arthritic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache or migraine, by administering to a mammal in need of relief from a pain state not associated with a cough condition a cyclooxygenase-2 inhibitor (also referred to as a cyclooxygenase II, COX-2 or COX II inhibitor) together with a nontoxic antagonist, or blocker, for the N-methyl-D- aspartate (NMDA) receptor or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation.
- a cyclooxygenase-2 inhibitor also referred to as a cyclooxygenase II, COX-2 or COX II inhibitor
- NMDA N-methyl-D- aspartate
- Non-steroidal antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity in addition to inhibiting hormone- induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
- prostaglandin G/H synthase also known as cyclooxygenase.
- cyclooxygenase- 1 the constitutive enzyme, as originally identified in bovine seminal vehicles. This enzyme has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man.
- prostaglandins have both physiological and pathological roles
- cyclooxygenase- 1 is responsible for endogenous basal release of prostaglandins and is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow.
- cyclooxygenase-2 the gene for a second inducible form of cyclooxygenase, referred to as cyclooxygenase-2, has been cloned, sequenced and characterized initially from chicken, murine and human sources. Cyclooxygenase-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. In contrast to cyclooxygenase- 1, cyclooxygenase-2, the inducible form, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Therefore, a selective inhibitor of cyclooxygenase-2 can have similar antiinflammatory, analgesic and antipyretic properties to a conventional NSAID, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects.
- cyclooxygenase-2 inhibitors are known. See, e.g., U.S. Patent Nos. 5,393,790; 5,409,944; 5,418,254; 5,420,343; 5,436,265; 5,466,823; 5,474,995; 5,476,944; 5,486,534; 5,510,368; 5,521 ,213; 5,536,752; 5,547,975; 5,550, 142; 5,552,422; 5,565,482; 5,576,339; 5,580,985; 5,585,504; 5,593,994; 5,596,008; 5,604,253; 5,604,260; 5,639,780; 5,677,318; 5,691,374; 5,698584; 5,710,140; 5,733,909; 5,767,291 ; 5,789,413 and 5,817,700.
- Cyclooxygenase-2 inhibitors exhibit a diminished ability to induce some of the mechanism-based side effects that occur with the use of NSAIDs.
- such inhibitors can have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a diminished ability to induce asthma attacks in aspirin-sensitive aspirin-sensitive asthmatic subjects.
- Dextromethorphan is the d-isomer of the codeine analog of levorphanol.
- dextromethorphan is said to have no analgesic or addictive properties (Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", 8 th ed., McGraw-Hill, Inc. (1990), p. 518)
- a method of alleviating a pain state not associated with a cough condition comprises administering to a mammal exhibiting a pain state not associated with a cough condition (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected from the group consisting of nontoxic N-methyl-D-aspartate receptor antagonist and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.
- the method of this invention is applicable to the treatment of all varieties of pain other than one associated with a cough condition, e.g., arthritic pain and other forms of chronic pain such as neuropathic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, and the like.
- a cough condition e.g., arthritic pain and other forms of chronic pain such as neuropathic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, and the like.
- an enhanced level of analgesia for an equivalent dosage of at least one cyclooxygenase-2 inhibitor, or an equivalent level of analgesia for a reduced dosage of at least one cyclooxygenase-2 inhibitor can be achieved when at least one cyclooxygenase-2 inhibitor is administered prior to, with or following the administration of the analgesia-potentiator.
- N-methyl-D-aspartate receptor shall be understood to include all of the binding site subcategories associated with the NMDA receptor, e.g., the glycine-binding site, the phenylcyclidine (PCP)-binding site, etc., as well as the NMDA channel.
- the invention herein contemplates the use of nontoxic substances that block an NMDA receptor binding site, e.g. , dextromethorphan, or that block the NMDA channel, e.g., a source of magnesium such as magnesium sulfate.
- nontoxic as used herein shall be understood in a relative sense and is intended to designate any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to humans or, in keeping with established regulatory criteria and practice, is susceptible to approval by the FDA for administration to humans.
- FDA United States Food and Drug Administration
- nontoxic is also used herein to distinguish the NMDA receptor antagonists, or blockers, that are useful in the practice of the present invention from NMDA receptor antagonists such as MK 801 (the compound 5-methyl-10,l l-dihydro-SH-dibenze[a,d] cyclohepten-5, 10-imine), CPP (the compound 3-[2-carboxypiperazin-4-yl] propyl-1-phosphonic acid) and PCP (the compound l-(l-phenylcyclohexyl)piperidine) whose toxicities effectively preclude their therapeutic use.
- MK 801 the compound 5-methyl-10,l l-dihydro-SH-dibenze[a,d] cyclohepten-5, 10-imine
- CPP the compound 3-[2-carboxypiperazin-4-yl] propyl-1-phosphonic acid
- PCP the compound l-(l-phenylcyclohexyl)piperidine
- potentiate and “potentiating” are used herein in their art- recognized sense, i.e., as referring to a significant increase in the level of pain- alleviating activity for the combination of cyclooxygenase-2 inhibitor and nontoxic
- NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation compared with that which could have been expected based on the activities of the cyclooxygenase-2 inhibitor administered alone and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation administered alone.
- the term "pain-alleviating” shall be understood herein to include the expressions "pain-suppressing" and "pain-inhibiting” as the invention is applicable to the alleviation of existing pain as well as the suppression or inhibition of pain which would otherwise ensue from an imminent pain-causing event.
- analgesia-inducing amount as applied to the cyclooxygenase-2 inhibitor employed in the method of this invention shall be understood to mean an amount of cyclooxygenase-2 inhibitor which when administered by itself or in combination with the nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation provides significant analgesic activity.
- any of the cyclooxygenase-2 inhibitors heretofore used to alleviate pain can be used herein.
- Specific cyclooxygenase-2 inhibitors that can be used in this invention are disclosed in aforementioned U.S. Patent Nos. 5,393,790; 5,418,254;
- the useful cyclooxygenase-2 inhibitors include the substituted spiro compounds of U.S. Patent No. 5,393,790, e.g. , 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene, 4-[6-(4- fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide, 6-(4-fluorophenyl)-7-[4-
- Patent No. 5,409,944 e.g., 5-methanesulfonamido-6-(2-thienylthio)-l-indanone, 5- methanesulfonamido-6-(2-(4-methyl-l ,3-diazinylthio))-l-indanone, 5- methanesulfonamido-6-(2-thiazolylthio)-l-indanone, and the like; the 2, 3 -substituted cyclopentadienyl compounds of U.S. Patent No.
- 5,476,944 e.g., 3,5-bis(l ,l- dimethylethyl)benzenethiol, trans-2-[[3 ,5-bis(l , 1 -dimethylethyl)henyl] hiOjCyclohexanol, 3,6-dioxabicyclo-[3.1.0]hexane, and the like; the 3,4-substituted pyrazoles of U.S. Patent No.
- Patent No. 5,576,339 e.g. , l-methylsulfonyl-4-[l ,l- dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene, 4-[4-(4-fluoropyhenyl)- l ,l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide, and the like; the substituted pyrazoles of U.S. Patent No.
- 5,585,504 e.g., 3- ⁇ henyl-4-(4-methylsulfonyl)phenyl-2-(5H)- furanone, 3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, and the like; the ortho substituted phenyl compounds of U.S. Patent No.
- 5,639,780 e.g., [4-(l-(4-Bromobenzyl)-5-methoxy-2- methyl-l-H-indol-3-yl)-3-(ethane-l ,2-diyl)]butanoic acid, 4-(l-(4-Bromobenzyl)-5- methoxy-2-methyl-l-H-indol-3-yl)-2-methylbutanoic acid and the like; the diphenyl- 1,2-3-thiadiazoles of U.S. Patent No.
- 5,691,374 e.g., 5-hydroxy-3-(3,4-difluorophenyl)-4-(4- (methylsulfonyl)phenyl)-2-(5H)-furanone, 5-hydroxy-5-methyl-,4-(4- (methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone, 5-hydroxy-4-(4-
- Patent No. 5,733,909 e.g. , (E)-3-(4-methylsulfonyl)phenyl-2-phenylbut-2-enoic acid methyl ester, (E)-3-(methylsulfonyl)phenyl-2-phenylbut-2-enoic acid, (E)-3-(4- methylsulfonyl)phenyl-l-morpholin-4-yl-2-phenylbut-2en-l-one and the like; the alkylated styrenes of U.S. Patent No.
- 5,817,700 e.g., 4,4-dichloro-3-(4-methylthiophenyl)-2-phenyl-2-cyclobuten-l-one, 4,4-dichloro-3-(4- methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l-one, 4-chloro-3-(4- methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l-one and the like and MK-966 (which is also referred to by Merk & Co. as "VIOXX").
- nontoxic substances that block the NMDA receptor and as such are useful for enhancing the analgesic activity of a cyclooxygenase-2 inhibitor in accordance with this invention are dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), their mixtures and their pharmaceutically acceptable salts.
- Other useful nontoxic substances that block the NMDA receptor include amantadine (1- aminoadamantine), memantine (3,5-dimethylaminoadamantone), pyrroloquinoline quinone and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid.
- dextromethorphan in the form of its hydrobromide salt is preferred for use herein due to its ready availability and its established use in over- the-counter medications where it functions as a cough suppressant. While dextrorphan and its pharmaceutically acceptable salts will also provide excellent results, it is not known to be in commercial manufacture at this time.
- a blocker for the NMDA receptor at least one nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation can also be used.
- NMDA receptor a subtype of excitatory amino acid receptors
- the major consequences of NMDA receptor activation include the following sequences, or cascades, of events occurring within nerve cells: a) translocation and activation of protein kinases such as protein kinase C ⁇ phosphorylation of substrate proteins such as cytosolic enzymes, channel proteins, receptor proteins, etc.
- ⁇ changes in functional activity b) initiation of early gene (c-fos, c-jun, zif-268, etc.) expression by either increased intracellular Ca+ + or Ca+ + -activated protein kinases ⁇ expression of functional genes responsible for production of cellular enzymes (such as protein kinases), receptor proteins (such as the NMDA receptor), ion channel proteins (such as K + , Na+, Ca+ + channels), neuropeptides (such as dynorphin), etc.
- cellular enzymes such as protein kinases
- receptor proteins such as the NMDA receptor
- ion channel proteins such as K + , Na+, Ca+ + channels
- neuropeptides such as dynorphin
- a substance that blocks the NMDA receptor will effectively prevent all of the foregoing major intracellular sequences of events from taking place.
- a substance that interferes with translocation and activation of protein kinase C or with calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase is also useful for the practice of this invention.
- Nontoxic substances that block a major intracellular consequence of NMDA receptor activation and are therefore useful in the practice of the invention include inhibitors of protein kinase C, e.g. , gangliosides such as ganglioside GM, (monosialoganglioside) and ganglioside GT, b (trisialoganglioside); amphipathic long chain bases such as sphingosine, N,N,N-trimethylsphingosine, sphinganine and psychosine; quinolyloxazole-2-ones such as 4-methyl-5-(3-quinolinyl)-2-(3H)- oxazolone and phenyl-5-(2-quinolinyl)-2-3(3H)-oxazolone; 1 ,4-bis-(amino- hydroxyalkylamino)-anthraquinones such as 1 ,4-bis-(3-propylamino-2- hydroxypropylamin
- Additional nontoxic substances that block a major intracellular consequence of NMDA receptor activation and as such are useful in the practice of the invention include inhibitors of calmodulin such as the phenothiazines, in particular, chlorpromazine, chlorpromazine sulfoxide, prochlorperazine dimaleate, perphenazine, trifluoperazine, fluphenazine, fluphenazine enanthate, fluphenazine decanoate, thioridazine, mesoridazine besylate, piperacetazine, acetophenazine dimaleate, carphenazine dimaleate, butaperazine dimaleate and phenothiazine sulfoxide; naphthalenesulfonamides such as N-(6-aminohexyl)-5-chloro-l- naphthalenesulfonamide, N-(6-aminohexyl)-5-chloro-2-
- the cyclooxygenase-2 inhibitor must be present in an analgesia-inducing amount, e.g., at a level corresponding to the generally recommended adult human dosages for a particular cyclooxygenase-2 inhibitor, and the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA activation must be present at a level that potentiates the analgesia-inducing effectiveness of the cyclooxygenase-2 inhibitor.
- cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation need not be administered together, they must both be present in the patient at effective levels at the same time. While it is within the scope of the invention to administer the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation separately, as a matter of convenience, it is preferred that they be coadministered as a single therapeutic composition.
- All modes of administrations are contemplated, e.g., orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation.
- the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.
- analgesic composition containing the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation will ordinarily be formulated with one or more pharmaceutically acceptable ingredients in accordance with known and established practice.
- the composition can be formulated as a liquid, powder, elixir, injectable solution, etc.
- Formulations for oral use can be provided as tablets or hard capsules wherein the pharmacologically active ingredients are mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.
- an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
- water or miscible solvents such as propylene glycol; PEG's and ethanol
- an oleaginous medium e.g., peanut oil, liquid paraffin or olive oil.
- the analgesic compositions can take the form of buccal or sublingual tablet, drops or lozenges formulated in conventional manner.
- compositions can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending, and/or coloring agents.
- the compounds of the invention can also be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.
- suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
- ion exchange resins for example as sparingly soluble derivatives, for example as a sparingly soluble salt.
- the compounds of the invention can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
- Formulations for injection can be presented in unit dosage from e.g. in ampoules or in multi-dose containers, with an added preservative.
- compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- a suitable vehicle e.g. sterile pyrogen-free water
- the compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.
- the compounds of the invention can be used, for example, as a liquid spray, as a powder or in the form of drops.
- the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlo- rodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
- a suitable propellant e.g. dichlo- rodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
- a suitable propellant e.g. dichlo- rodifluoromethane, trichlorofluoromethane
- Aqueous suspensions can include pharmaceutically acceptable excipients such as suspending agents, e.g. , sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g.
- suspending agents e.g. , sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia
- dispersing or wetting agents such as naturally occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g.
- polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, e.g. , polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g. , polyoxyethylene sorbitan monoleate.
- the aqueous suspensions can also contain one or more preservatives, e.g.
- ethyl-or-n-propyl-p-hydroxy benzoate one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
- at least one other pharmacologically active substance e.g.
- a non-narcotic analgesic such as tramadol, acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and the like, or a narcotic analgesic such as codeine, oxycodone, dihydrocodeine, hydrocodone, levorphanol, morphine, and the like can be administrered with the cylooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular
- the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide significantly potentiates the pain-alleviating activity of the cyclooxygenase-2 inhibitor.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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JP2000582069A JP2002538078A (en) | 1998-11-12 | 1998-11-12 | COX-2 inhibitor combined with NMDA-blocker to treat pain |
AU14086/99A AU1408699A (en) | 1998-11-12 | 1998-11-12 | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
CA002351224A CA2351224A1 (en) | 1998-11-12 | 1998-11-12 | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
PCT/US1998/024317 WO2000029023A1 (en) | 1998-11-12 | 1998-11-12 | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
EP98957950A EP1146905A1 (en) | 1998-11-12 | 1998-11-12 | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
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PCT/US1998/024317 WO2000029023A1 (en) | 1998-11-12 | 1998-11-12 | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
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WO2000029023A1 true WO2000029023A1 (en) | 2000-05-25 |
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PCT/US1998/024317 WO2000029023A1 (en) | 1998-11-12 | 1998-11-12 | Cox-2 inhibitors in combination with nmda-blockers for treating pain |
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Country | Link |
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EP (1) | EP1146905A1 (en) |
JP (1) | JP2002538078A (en) |
AU (1) | AU1408699A (en) |
CA (1) | CA2351224A1 (en) |
WO (1) | WO2000029023A1 (en) |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10059020A1 (en) * | 2000-11-28 | 2002-05-29 | Gruenenthal Gmbh | Dosage forms that can be administered parenterally |
WO2004039371A2 (en) * | 2002-10-29 | 2004-05-13 | Pharmacia Corporation | Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain |
WO2006024018A2 (en) * | 2004-08-24 | 2006-03-02 | Neuromolecular Pharmaceuticals, Inc. | Compositions for treating nociceptive pain |
WO2008055945A1 (en) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
WO2008065141A1 (en) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
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Also Published As
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JP2002538078A (en) | 2002-11-12 |
CA2351224A1 (en) | 2000-05-25 |
EP1146905A1 (en) | 2001-10-24 |
AU1408699A (en) | 2000-06-05 |
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