EP0555302A1

EP0555302A1 - Method of treating demyelinating disease

Info

Publication number: EP0555302A1
Application number: EP91918867A
Authority: EP
Inventors: David Walter Barry; John Frederick Reinhard, Jr.
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1990-10-30
Filing date: 1991-10-29
Publication date: 1993-08-18
Also published as: WO1992007564A2; WO1992007564A3; JPH06502155A

Abstract

Antagoniste calcique, notamment la nimodipine, servant au traitement des maladies démyélinisantes telles que la sclérose en plaques, et pouvant s'associer à un composé antiviral, par exemple l'azidothymidine, dont l'activité est dirigée contre les rétrovirus.Calcium antagonist, in particular nimodipine, used for the treatment of demyelinating diseases such as multiple sclerosis, and which can be combined with an antiviral compound, for example azidothymidine, the activity of which is directed against retroviruses.

Description

564 - 1 - METHOD OF TREATING DEMYELINATING DISEASE

FIELD OF THE INVENTION

This invention relates to the use of a calcium antagonist, optionally in combination with an antiviral compound, for the treatment or prophylaxis of a demyelinating disease, especially multiple sclerosis.

BACKGROUND OF THE INVENTION

Nimodipine belongs to the class of pharmacological agents known as calcium antagonists or calcium channel blockers. Nimodipine is (+)-isopropyl-(2-methoxyethyl)-1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate(Bay e 9736) and is a mixture of the two iso ers of formulae I and II.

II

Nimodipine and its synthesis have been described in U.S. pkt.Nα. 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.) :

R43 1979, Kazda, S. et al. Arzneim. Forsch. 32: 331-338 (1982), Kazda, S. and Towart R. Acta. Neurochirug. 63: 259-265 (1982)). The registered drug "NIMOTOP" (approved name nimodipine) 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.

International patent publication O90/11761 proposes the treatment of myelopathy by using a calcium channel antagonist to reduce the death of central nervous system neurons in patients infected with AIDS. There is no mention of treating demyelinating diseases, such as multiple sclerosis.

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. 38: 4299(1973)) and its synthesis and use in the treatment of AIDS and AIDS-related complex has been disclosed in U.S. Patent No. 4,724,232 (1988) which is incorporated herein by reference. AZT is well known in the art. It has been suggested that antiviral compounds including AZT may have utility in multiple sclerosis (EP Patent Application No. 217580(1987)).

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) .

Multiple sclerosis(MS) is a disease of profound suffering and pervasive disability, the etiology of which remains unknown despite intensive investigation. It consists of patches or plaques of damaged myelin scattered throughout the central nervous system resulting from demyelination and subsequent scar formation. The name "multiple sclerosis" describes the fact that in this disease there are many damaged areas filled with sclerotic (scar) tissue. The result is progressive degeneration of the nervous system resulting in progressive debilitation of the afflicted individual. Disease progression is variable. with periods of exacerbations which may be followed by prolonged periods of quiescence. Pathologically, 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.

In the absence of a known cause for the disease, treatments have been empirical. The therapeutic efforts have been divided principally into anti-inflammatory, immunosupressive, anti-infective, and biological response modification. Although steroids or adrenal corticotropic hormone (ACTH) may provide some benefit in limiting acute exacerbations, many other attempted therapies have produced inconclusive benefits (Aronson, S.M., et al. Federation of Multiple Sclerosis Societies 1-297 (1981)). Since no satisfactory treatment of MS has been revealed, the main therapeutic modalities to date to treat this illness remain sympathetic and supportive care. There is a need for a safe, reliable, and effective method of treating MS and related diseases. It is an object of the present invention to address these problems.

DESCRIPTION OF THE INVENTION

The invention provides the use of a calcium antagonist, optionally in combination with an antiviral compound, for the manufacture of a new medicament for use in the treatment and prophylaxis of a demyelinating disease.

The present invention also provides a method for the treatment or prophylaxis of a demyelinating disease of a mammal by administering an effective amount of a calcium antagonist, optionally in combination with an antiviral compound, to said mammal, preferably a human.

The present invention further provides a method for the treatment of prophylaxis of a demyelinating disease of a mammal by administering an effective amount of a calcium antagonist, in combination with an antiviral compound to said mammal, preferably a human. The invention also relates to the use of a calcium antagonist in combination with an antiviral agent for the preparation of a pharmaceutical composition which is useful for treating a demyelinating disease.

The calcium antagonist is one which is preferably able to cross the blood/brain barrier and enter the central nervous system. The calcium antagonist (e.g. the compounds of formula I or II, or a mixture thereof) may be used in the form of its pharmaceutically acceptable acid addition salts. According to the present invention, it is preferable to administer a mixture of the compounds of formula I and II as defined herein. Nimodipine is defined herein as said mixture of the compounds of formula I and II (i.e.

(+)-isopropyl-(2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-3,5-pyridine dicarboxylate) .

The optically pure stereoisomers of formula I, (-)-(4S)- ispropyl-(2-methoxyethyl)-l,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-3,5-pyridine dicarboxylate, and formula II, (±)-(4-R)-ispropyl-(2-methoxyethyl)-1,4-dihydro-2,6-dimethyl -4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, can be prepared according to known methods (Towart, R. , Wehinger, E., Meyer, H. , and Kazda, S. Arzneim. -Forsch./Drug Res. 32: 338-346 (1982)).

As indicated, 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.

Preferably, the compound of formula I or II or a mixture thereof is administered in the form of the free base.

Other 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.

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. The mono-, di-, or triphosphates σf AZT or their pharmaceutically acceptable base salts (i.e. alkali metal, alkaline earth or ammonium salt) can also be substituted for AZT in the combination described by this invention.

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. For example dideoxycytidine (DDC) may also be used.

Where a combination is to be administered, the components of the combination, namely, a calcium antagonist (e.g. nimodipine) and an antiviral compound (e.g. AZT) , may be administered simultaneously (e.g. in a unitary pharmaceutical composition) or sequentially (e.g. in separate pharmaceutical compositions) . In the latter case, however, 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. Other 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) . 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.

It will be appreciated by one of ordinary skill in the art that 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.

The active ingredients may be administered to the subject concerned in a conventional manner. In general, 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) . It will be appreciated that 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. In general 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 a calcium antagonist 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 1.0 to 250 g, preferably 10 to 180mg, more preferably 20 to 90 mg of active ingredient per unit dosage form, and most preferably 30 to 60 mg of active ingredient per unit dosage form.

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) , in combination with an antiviral compound (e.g. AZT) , may be formulated as a single pharmaceutical composition or formulated separately.

For convenience, 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.

Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the patient. 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. In general, 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. The pharmaceutical 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.

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.

In addition to the aforementioned ingredients, the 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.

DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate pharmaceutical compositions in which the calcium antagonist is nimodipine and the antiviral compound is AZT. These examples serve to illustrate the invention and should not be construed as limiting thereof.

Example 1

Tablet Composition

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.

Calcium antagonist Lactose, B.P. Sodium starch glycollate Macrocrystalline cellulose Polyvinylpyrrolidone

Example 2

Capsule Composition

The following composition is prepared by filling a solution of the ingredients into a soft gelatine capsule.

2350 1175 Example 3

Tablet Composition

Calcium antagonist

Antiviral compound

Lactose, B.P.

Sodium starch glycollate

Microcrystalline cellulose

Polyvinylpyrrolidone

Example 4

Capsule Composition

2450 1425 The following experimental test was carried out.

Experiment 1 (nimodipine)

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.

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.

The data, evaluated by one-way ANOVA reveal statistically significant differences at the 100 and 300 uM concentrations of QA.

Claims

1) The use of a pharmaceutically acceptable calcium antagonist for the manufacture of a medicament for the treatment or prophylaxis of a demyelinating disease.

2) Use according to claim 1 wherein the calcium antagonist has a substantial ability to cross the blood/brain barrier.

3) Use according to claim 1 wherein the calcium antagonist is effective against quinolinic acid toxicity.

4) Use according to claim 1 wherein the calcium antagonist is selected from the group of calcium antagonists which consists of dihydropyridines, phenylalkylamines, benzothiazapines, and diphenylpiperazines.

5) Use according to claim 1 wherein the calcium antagonist is nimodipine.

6) Use according to claim 1 wherein the calcium antagonist is selected from the group consisting of nifedipine, nicardipine, verapamil, and diltiazam. 7) Use according to claim 1 wherein the medicament is in unit dosage form and comprises 1.0 to 250 mg of calcium antagonist per unit dose.

8) Use according to claim 1 for the treatment or prophylaxis of multiple sclerosis.

9) Use according to claim 1 for the treatment or prophylaxis of Guillain Barre Syndrome, tropical spastic paraperisis, or amyotrophic lateral sclerosis.

lb) Use in accordance with claim 1 of the calcium antagonist in combination with an antiviral compound which is non-neurotoxic.

11) Use according to claim 10 wherein the antiviral compound is active against retroviruses.

12) Use according to claim 11 wherein the antiviral compound is active against HIV-I.

13) Use according to claim 10 wherein the antiviral compound has a substantial ability to cross the blood/brain barrier.

14) Use according to claim 10 wherein the antiviral compound is azidothymidine (AZT) . 15) Use according to claim 10 wherein the antiviral compound is dideoxycytidine (DDC) .

16) Use according to claim 10 wherein the medicament is in unit dosage form and comprises 10 to 1500 mg per unit dose.

17) A method for the treatment or prophylaxis of a demyelinating disease of a mammal which comprises administering an effective amount of a pharmaceutically acceptable calcium antagonist to the mammal.

18) A method according to claim 17 wherein the calcium antagonist is administered at a dose of 0.01 to 100 mg per kilogram bodyweight per day.

19) A method according to claim 17 which further -comprises the administration of an effective amount of a pharmaceutically acceptable antiviral compound.

20) A method according to claim 19 wherein the antiviral compound is administered at a dose of 3.0 to 120 mg per kilogram bodyweight per day.

21) A pharmaceutical composition which comprises a calcium antagonist and an antiviral compound. 22) A composition according to claim 21 comprising nimodipine and azidothymidine.

23) A composition according to claim 21 which further comprises a pharmaceutically acceptable carrier.