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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61K31/435—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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K31/70—Carbohydrates; Sugars; 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals

Definitions

• Nimodipine and its synthesis have been described in U.S. pkt.N ⁇ . 3,799,934 (1947), and its pharmaceutical formulations have been described in U.S. Pat. No. 3,932,645 (1976), both of which U.S. patents are incorporated herein by reference.
• Pharmacological studies characterize nimodipine as a potent cerebral vasodilator (Kazda, S. and Hoffmeister, F. Arch. Pharmacol. 307(Suppl.) :
• NIMOTOP approved name nimodipine
• the registered drug "NIMOTOP” is indicated for the improvement of neurological deficits due to spasm following subarachnoid hemorrhage from ruptured congenital intracranial spasyms.
• the pharmacology of nimodipine has been reviewed (Scriabine A. and Van Deri Kerckhoff . Annals New York Acad. Sci. 522: 698-706 (1988)).
• Nimodipine has long been known as a therapeutic agent for humans particularly as a cerebral vasodilator which may be safely administered both orally and parentally, it is available at reasonable cost and its activity in the body has been extensively studied.
• Azidothymidine(AZT) is 3'-azido-3'-deoxythymidine(BW A509U) which has the registered trade name "RETROVIR” (approved name zidovudine) . It is an antiviral compound active against human immunodeficiency virus (HIV) and is a currently marketed product which is approved for the treatment of HIV infection in both children and adults.
• the preparation of AZT has been disclosed (Horowitz J.P. et al., J. Org. Chem.29: 2076(1964) and Glinski R.P. et al., ibid.
• Myelin is a substance composed mainly of fats and proteins which is wrapped in numerous thin layers around nerve fibers forming the myelin sheath.
• the function of the myelin sheath is to speed the transmission of messages along the nerve fibers.
• Demyelination is the process of destroying or removing the myelin sheath of a nerve or nerves.
• Demyelinating diseases of central or peripheral origin are diseases which destroy myelin. Demyelinating diseases include, for example, multiple sclerosis, Guillain Barre syndrome, tropical spastic paraparesis(TSP) , and a yotrophic lateral sclerosis(ALS) .
• the disease is characterized by scattered areas of demyelination and, during acute disease, perivascular ly phocytic cuffing and diffuse gliosis (Hauser, S.L. , et al. Ann. Neurol. 19:578(1986)).
• a typical MS plaque or lesion is an area of grossly visible, well demarcated, demyelinated white matter.
• the disease occurs more commonly in certain geographic areas, as well as in family members of those already afflicted. Many victims are confined to wheelchairs or bed after ten years. It has been reported that the prevalence ranges from 50/100,000 in the United States to 200/100,000 in Canada, Northern Great Britain, parts of France, Scandinavia and Russia with close to a million victims in the United States alone.
• the present invention also pertains to the physiologically acceptable non-toxic acid addition salts of the basic compounds of formula I or II or a mixture thereof.
• Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicyclic acid, phthalic acid, embonic acid, enanthic acid, p-toluenesulfonic acid, and the like.
• the compound of formula I or II or a mixture thereof is administered in the form of the free base.
• calcium antagonists or calcium channel blocking agents which may be used in accordance with the present invention include, for example; other dihydropyridines (e.g. nifedipine, nicardipine) , phenylalkylamines (e.g. verapamil) , benzothiazapines (e.g. diltiazam) and diphenylpiperazines.
• dihydropyridines e.g. nifedipine, nicardipine
• phenylalkylamines e.g. verapamil
• benzothiazapines e.g. diltiazam
• diphenylpiperazines e.g. diltiazam
• the antiviral compound is preferably a compound active against retroviruses (such as HIV) .
• AZT is preferred. It should be non-neurotoxic.
• AZT may be administered per se or in the form of a pharmaceutically acceptable salt, e.g. an alkali metal salt such as sodium or potassium, an alkaline earth salt or ammonium salt.
• a pharmaceutically acceptable salt e.g. an alkali metal salt such as sodium or potassium, an alkaline earth salt or ammonium salt.
• the mono-, di-, or triphosphates ⁇ f AZT or their pharmaceutically acceptable base salts i.e. alkali metal, alkaline earth or ammonium salt
• Antiviral compounds which may be used in accordance with the present invention should preferably be active against HIV-I, cross the blood-brain barrier, and be non-toxic to the host at the doses needed to achieve the desired effect.
• DDC dideoxycytidine
• the components of the combination namely, a calcium antagonist (e.g. nimodipine) and an antiviral compound (e.g. AZT)
• a calcium antagonist e.g. nimodipine
• an antiviral compound e.g. AZT
• the components are administered within a sufficient time interval to ensure that the advantageous therapeutic effects of the combination are achieved in the treatment of a demyelinating disease such as MS.
• a preferred combination according to the present invention is a combination of nimodipine with AZT.
• the invention is particularly concerned with the treatment of multiple sclerosis.
• demyelinating diseases which may be treated in accordance with the present invention include: For example, Guillain Barre syndrome, acute disseminated encephalomyelitis, amyotrophic lateral sclerosis (ALS) , progressive multifocal leuko-encephalopathy (PML) , AIDS dementia complex (ADC) , subacute yelo-optico neuropathy, HTLV-associated myelopathy(HAM) , tropical spastic paraperisis (TSP) visna and caprine arthritis encephalitis (CAE) .
• ALS amyotrophic lateral sclerosis
• PML progressive multifocal leuko-encephalopathy
• ADC AIDS dementia complex
• HAM HTLV-associated myelopathy
• TSP tropical spastic paraperisis
• CAE caprine arthritis encephalitis
• Demyelination can also occur secondary to other infections, intoxications, or injuries, and thus, demyelinating complications resulting, directly or indirectly, from bacterial infections, viral infections, or interferon therapy, for example, may also be treated in accordance with the present invention.
• a further aspect of the present invention provides a method of inhibiting demyelination which comprises administering to a host (e.g. cells) , that has been diagnosed as having demyelination, an effective demyelinating inhibition amount of a calcium antagonist, optionally in combination with an antiviral compound.
• a host e.g. cells
• an effective demyelinating inhibition amount of a calcium antagonist optionally in combination with an antiviral compound.
• the active ingredients may be administered to the subject concerned in a conventional manner.
• the calcium antagonist and optional antiviral compound may be administered for therapy according to the present invention by any suitable route including oral, rectal, nasal, topical (including buccal and sublingual) , vaginal, and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) .
• suitable route including oral, rectal, nasal, topical (including buccal and sublingual) , vaginal, and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) .
• the preferred route will vary with the condition, eight, and age of the recipients, the nature and status of the disease and other clinical factors. It is most convenient to administer the therapeutic agents orally.
• An effective dose of a calcium antagonist and optional antiviral compound for the treatment or prophylaxis of a demyelinating disease will vary with a number of factors well known and understood by the physician. These include, for example, the condition, age and weight of the patients and the nature and status of the disease.
• a suitable dose of a calcium antagonist will be in the range of about 0.01 to 100 mg per kilogram bodyweight of the recipient per day, preferably in the range of 0.1 to 10 mg per kilogram bodyweight of the recipient per day, and most preferably in the range of 0.5 to 1.5 mg per kilogram of body weight per day.
• a suitable dose of an antiviral compound will be in the range of about 3.0 to 120 mg per kilogram bodyweight of the recipient per day, preferably in the range of 15 to 60 mg per kilogram bodyweight of the recipient per day. These dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• the desired dose of an antiviral compound is preferably presented as two, three, four, five,. six, or more sub-doses administered at appropriate intervals throughout the- day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 100 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
• the ratio of calcium antagonist to antiviral compound in the pharmaceutical composition will vary depending on the exact components chosen but will preferably be in the range of 1 to 30, more preferably 1 to 20.
• a calcium antagonist in combination with an antiviral compound is usually administered in a pharmaceutical composition containing the active compounds.
• a calcium antagonist e.g. a compound of formula I or II, or a mixture thereof
• an antiviral compound e.g. AZT
• a calcium antagonist e.g. a compound of formula I or II, or a mixture thereof
• an antiviral compound e.g. AZT
• the active ingredients can be administered in pharmaceutical composition form.
• the present invention further provides a pharmaceutical composition comprising a calcium antagonist, (for example, nimodipine). and an antiviral compound, (for example, AZT) usually together with at least one pharmaceutical carrier or exipient.
• a calcium antagonist for example, nimodipine
• an antiviral compound for example, AZT
• compositions include those adapted for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration.
• the compoisitions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association other active ingredient with the carrier which constitutes one or more accessory ingredients.
• the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
• compositions according to the present invention adapted for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredients; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredients may also be presented, as a bolus, electuary or paste.
• compositions adapted for oral- administration employ- such ingredients as diluents and carriers, excipients and lubricants, as glucose, lactose, sucrose, corn and potato starch, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, powdered gum tragacanth, gelatin, alginic acid, agar, stearic acid, sodium, calcium, and magnesium stearates,. sodium lauryl- sulfate, polyvinylpyrrolidone, sodium citrate, calcium carbonate, and dicalcium phosphate.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. Sweetening, flavouring, preservative, dispersing and colouring agents car. also be present.
• a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch.
• Sweetening, flavouring, preservative, dispersing and colouring agents car. also be present.
• Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths.
• a lubricant such as talc, magnesium stearate and calcium stearate can be added to the powder mixture as an adjuvant before the filling operation;
• a glidant such as colloidal silica may be added to improve flow properties;
• a disintergrating or solubilizing agent may be added to improve the availability of the medicament when the capsule is ingested.
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethylcellulose) , lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or dispersing agents.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying, proportions to provide the desired release profile.
• the composition may be a controlled release composition.
• compositions for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid, carrier.
• compositions-for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
• Composition for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray compositions containing-in addition to the active ingredient such carriers as are known in the art to be appropriate.
• compositions for parenteral administration include aqueous and non-aqueous isotonic sterlile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• compositions of this invention may further include one or more accessory ingredient(s) selected from diluents. buffers, flavouring agents, binders, disintegrants, surface active agents, emulsifiers such as nonionic and anionic emulsifiers as, for example, polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylsulfonates and arysulfonates, or dispersing agents as, for example, lignin, sulfite waste lyes, ethylcellulose, starch and polyvinyl pyrrolidone, or thickeners, lubricants, preservatives (including antioxidants) and the like.
• diluents buffers, flavouring agents, binders, disintegrants, surface active agents, emulsifiers such as nonionic and anionic emulsifiers as, for example, polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylsulfonates
• the following tablet composition is prepared by wet granulation of the ingredients (except the magnesium stearate) with a solution of the polyvinylpyrrolidone (in Polysorbate 80 USP ("TWEEN 80”) and water) followed by drying of the granules, addition of the magnesium stearate and compression.
• a solution of the polyvinylpyrrolidone in Polysorbate 80 USP ("TWEEN 80" and water
• composition is prepared by filling a solution of the ingredients into a soft gelatine capsule.
• the following tablet composition is prepared by wet granulation of the ingredients (except the magnesium stearate) with a solution of the polyvinylpyrrolidone (in Polysorbate 80 USP ("TWEEN 80”) and water) followed by drying of the granules, addition of the magnesium stearate and compression.
• a solution of the polyvinylpyrrolidone in Polysorbate 80 USP ("TWEEN 80" and water
• composition is prepared by filling a solution of the ingredients into a soft gelatine capsule.
• Quinolinic acid is a neurotoxin formed in vivo from tryptophan, which accumulates in the cerebrospinal fluid of patients with multiple sclerosis and produces oligodendrocyte damage. Oligodendrocytes are the primary lesion site in multiple sclerosis.
• Oligodendrocyte cell cultures were established as described by McCarthy and DeVellis (J.Cell Biol. 85: 890-902, 1980) and were used after 2 weeks in culture. The cultures examined by phase-contrast, light-microscopy, were comprised of a nearly homogeneous population of process-bearing glia and, thus, were considered to be oligodendrocytes. Cells were exposed to increasing concentrations of quinolinic acid (QA) in the absence or presence of nimodipine (10 uM) for three days. The experiments were terminated by aspirating the media and assaying it, spectrophotometrically, for lactate dehydrogenase (LDH) activity.
• QA quinolinic acid
• nimodipine 10 uM
• the data in figure 1 reveal dose-dependent increases in media LDH activity which, at the highest concentrations of QA reached approximately 20% of the total cellular content of LDH. Since the release of LDH occurs when cells die, the data indicate that QA is toxic to oligodendrocytes in vitro. Treatment with nimodipine reduced the apparent toxicity of QA.
• the data are presented in Figure 1 where LDH activity is in mlU and the data are as means + their standard errors of the mean.

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• 1991
  • 1991-10-29 JP JP3517138A patent/JPH06502155A/ja active Pending
  • 1991-10-29 WO PCT/GB1991/001890 patent/WO1992007564A2/en not_active Application Discontinuation
  • 1991-10-29 EP EP91918867A patent/EP0555302A1/de not_active Withdrawn

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