MXPA97006404A - Method for dealing adenos - Google Patents

Abstract

A method for treating adenosine depletion in a subject in need of such treatment is described. The method comprises administering to the subject folic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat adenosine depletion. A method for treating asthma in a subject in need of such treatment is also described. The method comprises administering to the subject dehydroepiandrosterone, its analogues, or a pharmaceutically acceptable salt thereof in an amount effective to treat the ace

Description

METHOD OF DEALING WITH OEN ADENOSINE D E S C R I P C I N Field of the invention.

This invention relates to methods for treating adenosine depletion by the administration of folinic acid or a pharmaceutically acceptable salt thereof. This invention further relates to methods for treating asthma by administration of dehydroepiandrosterone, its analogues, or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION Adenosine is a purine that contributes to intermediate metabolism and participates in the regulation of physiological activity in a variety of mammalian tissues. Adenosine participates in many local regulatory mechanisms, particularly synapses in the central nervous system (CNS) and neuroeffector junctions in the peripheral nervous system (PNS). In the CNS, adenosine: inhibits the release of a variety of neurotransmitters, such as acetylcholine, noradrenaline, dopamine, serotonin, glutamate and GABA; depressant neurotransmission; reduces neuronal firing to induce spinal analgesia; and has anxiolytic properties. Cf. A. Pelleg and R. Porter, Pharmacothera and (2), 157 (1990); J. Daval et al., Life Sciences 49: 1435 (1991). In the heart, adenosine suppresses the activity that establishes the pace or gait, lowers AV conduction, has antiarrhythmic and arrhythmogenic effects, modulates autonomic control and triggers the synthesis and release of prostaglandins. Cf. K. Mullane and M. Wiilliam, Adenosine and Adenosine Receptors p. 289 (M. Williams, de Humana Press, 1990).

Adenosine has powerful vasodilatory effects and modulates vascular tone. Cf. A.Deiseen et al; J. Pflugrers Arch. 406: 608 (1986). Adenosine is typically used clinically for the treatment of superventricular tachycardia and other cardiac abnormalities. Cf. Chronister, American Journal of Critical Care 2 (1) 41-47 (1993). Adenosine analogs are being investigated for use as anticonvulsant, anxiolytic and neuroprotective agents. Cf. M. Higgins et al., Pharmacy World & Science 16 (2): 62-68 (1994).

Adenosine has also been implicated as a primary determinant underlying the symptoms of bronchial asthma. This induces bronchoconstriction and smooth muscle contraction of the airways. Cf. J. Thorne and K.Broadley, American Journal of Respiratory & Critical Care 149 (2 pt.l): 392-399 (1994); Ali et al., Agents & Actions 37 (3-4): 165-167 (1992). Adenosine causes bronchoconstriction in asthmatics but not in non-asthmatics. Cf. Bjorc et al., American Review of Respiratory Disease 145 (5): 1087-1091 (1992); S. Holgate et al., Annals of the New York Academy of Sciences 629: 227-236 (1991).

In view of the foregoing, it will be readily apparent that: (i) depletion of adenosine can lead to a wide variety of detrimental conditions and that methods for treating adenosine depletion can be extremely useful means of therapeutic intervention; and (i) methods for inducing adenosine depletion may also be useful for treating conditions such as asthma.

The invention In accordance with the foregoing, a first aspect of the present invention is a method for treating adenosine depletion in a subject in need of such treatment. The method comprises administering to the subject folinic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat adenosine depletion. The method can be carried out on afflicted subjects suffering from adenosine depletion induced by steroids, subjects suffering from anxiety, subjects suffering from exhaustion, or subjects suffering from any other disorder attributable to adenosine depletion, or when an increase in Adenosine levels are therapeutically beneficial. A second aspect of the present invention is the use of folinic acid or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating adenosine depletion in a subject in need of such treatment, as indicated above.

A third aspect of the present invention is a method for treating asthma in a subject in need of such treatment by administering to the subject dehydroepiandrosterone, one of its analogs or a pharmaceutically acceptable salt thereof, in an amount effective to treat asthma . A fourth aspect of the present invention is the use of dehydroepiandrosterone, one of its analogs, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating asthma in a subject in need of such treatment. Folinic acid is an intermediate product of folic acid metabolism; The active form in which that acid is converted into the body, ascorbic acid is a necessary factor in the conversion process. Folinic acid has been used therapeutically as an antidote for folic acid antagonists such as methotrexate which blocks the conversion of folic acid to folinic acid. Additionally, folinic acid has been used as an antianemic (fights folate deficiency). Cf. The Merck Index, Monograph No.4141 (llth De. 1989). The use of folinic acid in patients suffering from adenosine depletion, or in a method to therapeutically elevate « the levels of adenosine in the brain or other organs, to date has not been suggested or described Detailed description of the invention: The method for treating adenosine depletion described above can be used to treat steroid-induced adenosine depletion; to stimulate the synthesis of adenosine and thereby treat or control anxiety (for example, in the treatment of pre-menstrual syndrome); to increase weight gain or treat anxiety disorders; and to treat other pathologies related to adenosine by the administration of folinic acid. Therefore, the term "adenosine depletion" is intended to encompass both conditions where adenosine levels are decreased in the subject compared to previous adenosine levels in that subject and conditions where adenosine levels are essentially the same as the previous levels of adenosine in that subject, but, because of some other conditions or alterations in that patient, a therapeutic benefit in the patient will be achieved by increased adenosine levels compared to previous levels. Preferably, the method is carried out on patients in which adenosine levels are reduced compared to the previous levels of adenosine in that subject. The present invention relates mainly to the treatment of human subjects but can also be used for the treatment of other mammalian subjects, such as dogs and cats, for veterinary purposes.

Folinic acid and its pharmaceutically acceptable salts (hereinafter sometimes referred to as the "active compounds") are known and can be made according to known procedures. See in general The Merck Index, Monograph no. 4141 (lia 1989 edition); patent of the E..U.A. no. 2 '741, 608.

The pharmaceutically acceptable salts will be both pharmacologically and pharmaceutically acceptable. These pharmacologically and pharmaceutically acceptable salts can be prepared as alkali metal salts or alkaline earth metal salts, such as sodium, potassium or calcium salts, of the folinic acid carboxylic acid group. The calcium salt of folinic acid is a preferred pharmaceutically acceptable salt.

The active compounds are preferably administered to the subject as a pharmaceutical composition.

Pharmaceutical compositions for use in the present invention include those suitable for inhalation, oral, topical (including buccal, sub-lingual, dermal and intraocular), parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and to "administration". transdermal Conveniently the compositions may be present in unit dosage form and may be prepared by any of the methods well known in the art. Compositions suitable for oral administration may be present in discrete units, such as capsules, dragees or tablets, each containing a predetermined amount of the active compound.; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil in water or water in oil emulsion. These compositions can be prepared by any suitable pharmacy method including the step of bringing into association the active compound and a suitable carrier. In general, the compositions of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier or carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with an agglutinating agent or agents, lubricants, inert diluents and / or active surface / dispersants. The molded tablets can be made by molding, in a suitable machine, the powder compound moistened with an inert liquid binder. Compositions for oral administration may optionally include enteric coatings known in the art to prevent degradation of the compositions in the stomach and provide release of the drug in the small intestine.

Compositions suitable for buccal (sub-lingual) administration include pellets comprising the active compound in a flavor base, usually sucrose and acacia or tragacanth; and tablets comprising the compound in an inert base, such as gelatin and glycerin or sucrose and acacia.

Compositions suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain antioxidants, buffers, bacteriostats and solutes that return the isotonic compositions to the blood of the intended recipient. Aqueous and non-aqueous sterile solutions may include suspending agents and thickening agents. The compositions may be present in single dose or multiple dose containers, for example sealed vials and vials and may be stored in a dry frozen condition (lyophilized) which requires only the addition of the sterile liquid carrier, for example, saline or water for injection immediately before use. Extemporaneous suspensions and solutions for injection can be prepared from sterile powders, granules or tablets of the kind previously described.

Compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gelatin, aerosol or oil. Vehicles or carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal improvers and combinations of two or more thereof.

Compositions suitable for transdermal administration, may be presented as discrete patches, adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.

Compositions suitable for transdermal administration can also be delivered by iontophoresis (Cf., for example Pharmaceutical Research 3, 318 (1986)) and typically take the form of an aqueous solution of the optionally damped active compound.

The dosage will vary depending on the age, weight and condition of the subject. Treatment can be started with small doses lower than the optimal dose and be increased until the optimal effect is reached under the circumstances. In general, the dosage will be of 1,5,10 or 20 mg / kg by weight of the body of the subject, up to 100, 200, 500 or 1,000 mg / kg by body weight of the subject. Commonly preferred are doses of 5 to 500 mg / kg, and doses of 10 to 200 mg / kg and doses of 20 to 100 mg / kg are most preferred. In general, the active compounds are preferably administered at a concentration which will achieve effective results without causing any undue harm or deleterious side effects and can be administered either as a single unit dose or, if desired, in convenient subunits administered at appropriate times to Throughout the day.

A method for treating asthma, in particular non-steroid-dependent asthma, is also described herein by administration to a subject in need of such dehydroepiandosterone (DHEA) treatment, one of its analogues, or a pharmaceutically acceptable salt. of it, in an amount effective to inhibit or control asthma in that subject.

Examples of DHEA and its analogues that can be used to carry out this method are represented by the formula (i): where. the interrupted line represents an optional double link; R is hydrogen or a halogen; Ri is a halogen or a group S020M wherein M is hydrogen, M is sodium, M is a sulfatide group: SO2O-CH, CHCH, OCORj OCOF ^ M is a phosphatide group: wherein each of R2 and R3"which may be the same or different, is a straight or branched chain alkyl radical with 1 to 14 carbon atoms, or a glucuronide group: The hydrogen atom in position 5 of formula I is present in the alpha or beta configuration or the compound comprises a mixture of both configurations. Exemplary compounds of formula (I) above include: DHEA, wherein R and Ri are each hydrogen and the double bond is present; 16-alpha bromoepiandrosterone, where R is Br, Ri is H and the double bond is present; 16-alpha fluoroepiandrosterone, where R is F and Ri is H and the double bond is present; etiocolanolone, wherein R and Rx are each hydrogen and the double bond is absent; dehydroepiandrosterone sulfate, wherein R is H, Ri is S02OM and M is the sulfatide group as defined above and the double bond is absent.

Preferably, in the compound of the formula I, R is halogen (for example, bromine, chlorine or fluorine), Ri is hydrogen and the double bond is present.

More preferably, the compound of the formula I is 16-alpha-fluoroepiandrosterone.

The compounds of formula I are prepared according to known procedures or variants thereof which will be apparent to those skilled in the art. See patent E.U.A. no. 4 '956, 355, United Kingdom Patent, no. 2 '240, 472, EPO patent application no. 429.187, PCT patent application no. 91/04030; see also M. Abou-Gharbia et al., J. Pharm. Sci. 70,1154-1157 (1981), Merck Index Monograph no. 7710 (lia 1989 edition). The compounds used to treat asthma may be administered per se or in the form of pharmaceutically acceptable salts, as discussed above, (the two together again are referred to as "active compounds"). Salts of the active compounds can be administered, either systemically as discussed above, or to the lungs of the subject as discussed below. In general, the salts of the active compounds are administered in a dose of 1 to 3,600 mg / kg per body weight, more preferably from 5 to 1,800 mg / kg and more preferably from 20 to 100 mg / kg approximately. The active compounds can be administered once or several times a day. The active compounds described herein can be administered to the lungs of a subject by any suitable means, but it is preferred to administer by generating an aerosol consisting of respirable particles and the respirable particles comprise the active compound, these particles inhale the subject (ie, by administration by inhalation). The respirable particles can be liquid or solid. The particles containing the active compound, for the practice of the present invention, will include particles of resspirable size: that is, particles of a size small enough to pass through the mouth and larynx upon inhalation and into the interior of the bronchi and albeoles of the lungs. In general, particles that are in the scale of a size of 0.5 to 10 microns (more particularly, less than a size of about 5 microns) are respirable. Particles of non-respirable size that are included in the aerosol tend to deposit in the throat and be swallowed and the amount of non-respirable particles in the aerosol are preferably reduced to a minimum. For nasal administration, a particle size in the scale of 10-500 microns is preferred in order to ensure retention in the nasal cavity. Liquid pharmaceutical compositions of the active compound for producing an aerosol can be prepared by combining the active compound with a suitable vehicle, such as sterile, pyrogen-free water. Compositions of solid particles containing respirable dry particles of the micronized active compound can be prepared by grinding the active compound dry with a mortar and pestle and then passing the micronized composition through a 400 mesh screen to break up or separate the large agglomerates. . A solid particulate composition comprising the active compound may optionally contain a dispersant which serves to facilitate the formation of an aerosol. A suitable dispersant is lactose, which can be mixed with the active compound in any suitable ratio (for example at a ratio of 1: 1 by weight). Aerosols of liquid particles comprising the active compound can be produced by any suitable means, such as with a nebulizer. See, for example, the US patent. no. 4 '501, 729. Nebulizers are commercially available devices that transform the solutions or suspensions of the active ingredient into a therapeutic aerosol mist, either by accelerating a compressed gas, typically air or oxygen, through a narrow venturi orifice. or by means of ultrasonic agitation. Compositions suitable for use in nebulizers consist of an active ingredient in a liquid carrier, the active ingredient, comprising up to 40% w / w of the compositions, but preferably less than 20% w / w. The carrier is typically water or a dilute alcoholic aqueous solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives, if the compositions are not compared sterile, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants. Aerosols of solid particles comprising the active compound can also be produced with any solid particle aerosol drug generator. Aerosol generators for administering drugs in solid particles to a subject produce particles that are respirable, as explained above, and generate an aerosol volume containing a predetermined metered dose of a drug at a regimen suitable for human administration. Examples of such aerosol generators include insufflators and metered dose inhalers. Ubiquinone can be administered concurrently with DHEA or its analogs in the asthma treatment methods described above. The phrase "administer concurrently" as used herein, means that, DHEA or the DHEA analogue are administered either (a) simultaneously over time (preferably by formulating the two together in a common pharmaceutical carrier), or (b) ) at different times during the course of a common treatment program. In the latter case, the two compounds are administered at sufficiently close times for ubiquinone to deplete ubiquinone in the lungs (and heart) of the subject and thereby counterbalance any deterioration of lung function (and heart) that may result from the administration of DHEA or its analogue. The term "ubiquinone" as used herein, refers to a family of compounds, which have structures based on a core of 2,3-dimethoxy-5-methylbenzoquinone with a variable terpenoid acid chain containing from one to twelve mono-unsaturated trans-isoprenoid units. Those compounds are known in the art, as "coenzyme Qn", where n is equal to 1-12. These compounds can be referred to herein as compounds represented by the formula: wherein n = 1 to 10. Preferably in the method of the present invention, ubiquinone is a compound according to the formula given above, wherein n = 6 to 10 (e.g., coenzymes Q6-? o) and more preferably where n = 10 (ie, coenzyme Q? 0). When the ubiquinone is formulated with a pharmaceutically acceptable carrier separately from DHEA, an analogue thereof or a salt thereof (for example, when DHEA, its analog or its salt is administered to the subject's lungs and ubiquinone is administered systemically) can be formulated by any of the previously indicated techniques. In general, ubiquinone is administered in an amount effective to displace the depletion of ubiquinone, depletion in the lungs and in the heart of the subject induced by DHEA, its analog or its salt and the dose will vary depending on the condition of the subject and the route of administration. Preferably the ubiquinone is administered in a total amount per day of about 1 to 1200 mg / kg per body weight, more preferably about 30 to 600 mg / kg and more preferably at about 50b to 150 mg / kg. Ubiquinone can be administered once or several times a day. The following examples are provided to more fully illustrate the present invention and are not constructed as restrictives thereof. In the examples that follow, DHEA stands for dehydroepiandrosterone, s means seconds, mg means milligrams, kg means kilograms, kW means kilowatts, Mhz means megahertz and nmol means nanomoles.

EXAMPLES 1 ¥ 2 Effects of Folinic Acid and DHEA on the Levels of In vivo Adenosine A 344 young male Fischer rats (120 g) were administered dehydroepiandrosterone (DHEA) (3 mg / kg) or methyltestosterone (40 mg / kg) in carboxymethylcellulose per tube once a day for 14 days. Folinic acid (50 mg / kg) was administered intraperitoneally once a day for 14 days. The 15th. day, the animals were sacrificed by microwave pulse (1.33 kW, 2450 Mhz, 6.5 s) to the skull, which instantly denatured the entire brain protein and prevented the additional metabolism of adenosine. The hearts of the animals were removed and instantly frozen in liquid nitrogen after 10 seconds of death. The liver and lungs were removed en bloc and were frozen instantaneously after 30 s of dying. The brain tissue was subsequently dissected. Adenosine was extracted from the tissue, derived from N6-ethenoadenosine and analyzed by high performance liquid chromatography (CLAF) using a spectrofluorometric detection according to the method of Clark and Dar (J. of Neuroscience Methods 25: 243 (1988)). . The results of these experiments are summarized in Table 1 below. The results are expressed as the mean ± SEM, with p < 0.05 compared to the control group and p < 0.05 compared to the groups treated with DHEA or I iltestosterone.

TABLE 1. Effects of DHEA-1-methyltestosterone and folinic acid on adenosine levels in various tissues of the rat.

The results of these experiments indicate that rats administered with DHEA or methyltestosterone daily for two weeks showed adenosine depletion in multiorganos. The depletion was dramatic in the brain (60% depletion for DHEA, 34% for high dose of methyltestosterone) and heart (37% depletion for DHEA, 22% depletion for high dose of methyltestosterone). Coadministration of folinic acid completely abolished adenosine depletion mediated by steroids. The administration alone of folinic acid induces increases in adenosine levels for all the organs studied.

The above examples are illustrative of the present invention and are not constructed as limiting thereof. The invention is defined by the following clauses, with equivalents of the clauses to be included there.

Claims (18)

1. R E I V I N D I C A C I O N S 1. A method for treating adenosine depletion in a subject in need of such treatment, which comprises administering to the subject folinic acid or a pharmaceutically acceptable salt thereof, in an amount effective to treat adenosine depletion.
2. 2. Method according to claim 1, wherein the subject suffers from adenosine depletion induced by steroids.
3. 3. Method according to claim 1, wherein the subject suffers from anxiety, and folinic acid or its pharmaceutically acceptable salt is administered in an amount effective to treat anxiety.
4. 4. Method according to claim 1, wherein the subject suffers from premenstrual syndrome and folinic acid its pharmaceutically acceptable salt is administered in an amount effective to treat premenstrual syndrome.
5. 5. Method according to claim 1, wherein the subject suffers from depletion and the folinic acid or its pharmaceutically acceptable salt is administered in an amount effective to cause the subject to gain weight.
6. 6. - Method according to claim 1, wherein the step of administering is carried out by oral administration.
7. 7. Method according to claim 1, wherein the step of administering is carried out by parenteral injection.
8. 8. Method according to claim 1, wherein the step of administering is carried out by subcutaneous injection.
9. 9. Method according to claim 1, wherein the step of administering is carried out by transdermal administration.
10. 10. Method according to claim 1, wherein the step of administering is carried out by administration by inhalation.
11. 11. A method for treating asthma in a subject in need of such treatment, comprising administering to the subject, in an amount effective to treat asthma, a compound according to formula I or a pharmaceutically acceptable salt thereof. where: the interrupted line represents an optional double link; R is hydrogen or a halogen; Ri is hydrogen or an SO M group where M is hydrogen, M is sodium, M is a sulfatide group -SO2O-CHj CHCH, OCORj OCOR, M is a phosphatide group wherein each of R2 and R, which may be the same or different, is a straight or branched chain alkyl radical having 1 to 14 carbon atoms, or a gluculonide group:
12. 12. - The method according to claim 11, wherein R is halogen, R is hydrogen and the double bond is present.
13. 13. The method according to claim 11, wherein the compound of formula I is selected from the group consisting of: dehydroepiandrosterone, 16-alpha-bromoepiandrosterone, 16-alpha-fluoroepiandrosterone, ethiocholanolone, dehydroepiandrosterone sulfate and pharmaceutically acceptable salts of the same.
14. 14. Method according to claim 11, wherein the compound of the formula I is: 16-alpha-fluoroepiandrosterone or a pharmaceutically acceptable salt thereof.
15. 15. Method according to claim 11, wherein the step of administering is a step of systemic administration.
16. 16. Method according to claim 11, wherein the administration step is a step of administration by inhalation.
17. 17. Method according to claim 11, further comprising the step of concurrently administering ubiquinone to the subject in an amount effective to inhibit the depletion of ubiquinone in the lungs of the subject.
18. 18. Method according to claim 11, wherein the asthma is an asthma that does not depend on steroids. SUMMARY A method for treating adenosine depletion in a subject in need of such treatment is described. The method comprises administering to the subject folinic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat adenosine depletion. A method for treating asthma in a subject in need of such treatment is also described. The method comprises administering to the subject dehydroepiandrosterone, its analogs, or a pharmaceutically acceptable salt thereof in an amount effective to treat asthma.