MXPA01006895A - Composition and formulations and their use as nociceptic, anti-anxiolytic and anabolic agents - Google Patents

Abstract

Composition and formulations comprising a first agent such as folinic acid, pharmaceutically acceptable salts thereof or mixtures thereof, and a second agent(s) such as analgesics, muscle relaxants, mood disorder agents, anti-inflammatories, anti-migraine agents, anti-emetics, diuretics, high protein composites, and the like. The products are suitable as nociceptics and for the treatment of wasting disorders, bulimia, anorexia nervosa, anxiety, irritability and other symptoms associated with Pre Menstrual Syndrome, as well as for administration either in conjunction with steroids or to compensate adenosine depletion and/or bizarre behavior or aggression common in steroid users.

Description

COMPOSITIONS AND FORMULATIONS AND THEIR USE AS NOCICÉPTIC, ANTIANSIOLÍTICOS AND ANABÓLICOS AGENTS FIELD OF THE INVENTION This invention relates to a composition and formulations comprising folinic acid, pharmaceutically acceptable salts thereof and other agents such as analgesics, anti-inflammatories, muscle relaxants, antimigraine agents, antiemetics, diuretics and the like. The products are suitable as nociceptics, for the treatment of debilitating or wasting disorders, anxiety, irritability associated with premenstrual syndrome and for administration either combined with steroids or to compensate for the exhaustion of .denosine common in steroid users.

BACKGROUND OF THE INVENTION Folinic acid is an intermediate product of folic acid metabolism and is considered to be the active form in which folic acid is converted to the organism. It is also known that ascorbic acid or vitamin C is required as a necessary factor in the conversion of folic acid to folinic acid. Folinic acid has been used therapeutically as an antidote to folic acid antagonists, such as methotrexate. blocks the conversion of folic acid into folinic acid. In addition, folinic acid has been used as an antianemic, for its ability to combat folate deficiency. So far, folinic acid has never been used in patients who experience adenosine depletion or in a method to therapeutically elevate adenosine levels in the brain or in another organ. Adenosine is a purine involved in intermediate metabolism. Adenosine also participates in the regulation of physiological activity in a variety of mammalian tissues as well as in many local regulatory mechanisms, for example, those that occur at synapses in the central nervous system (CNS) and neuroeffector junctions in the peripheral nervous system. In the CNS, adenosine inhibits the release of a variety of neurotransmitters, eg, acetylcholine, noradrenaline, dopamine, serotonin, glutamate and GABA, depresses neurotransmission, induces spinal analgesia possibly by reducing the neuronal connection and has anxiolytic properties. In the heart, adenosine suppresses pacemaker activity, decreases AV conduction, has antiarrhythmic and arrhythmogenic effects, modulates autonomous control and triggers the synthesis and release of prostaglandins. In addition, adenosine has powerful vasodilatory effects and modulates the vascular tone. At present, adenosine is used clinically for the treatment of supraventricular tachycardia (SVT) and other cardiac abnormalities, as well as for testing cardiovascular function. Adenosine analogs are also investigated for use as anticonvulsant, anxiolytic and neuroprotective agents. Adenosine is also protective of tissues subject to ischemia (oxygen deprivation) and aids in the reperfusion of these tissues, for example, in the brain after a stroke or other conditions and diseases that cause chronic or acute cerebral ischemia, in the heart after a heart attack or other conditions and diseases that cause chronic or acute cardiac ischemia and in other organs with risk of ischemia associated with disease processes and conditions, acute and chronic physiological events and in organs that can be released during the collection and transport stages before the transplant, as well as in the organs already transplanted, among others. Adenosine analogs are also investigated for use as anticonvulsant, anxiolytic and neuroprotective agents. In addition, adenosine is a natural anti-inflammatory agent, which, for example, is known to mediate the anti-inflammatory effect of methotrexate. Adenosine also promotes and accelerates wound healing and regulates the Neutrophilic function by activating a serine / threonine phosphatase. Although adenosine has several therapeutic applications as previously described, has an extremely short half life (approximately one second). The short half-life of adenosine and its propensity to cause angina-like pain makes it a poor choice for therapeutic applications. By virtue of the foregoing, it is readily apparent that a significant reduction in adenosine levels or depletion of adenosine can result in a wide range of detrimental conditions and that the ability to treat, reverse and prevent adenosine depletion is a very useful means of therapeutic intervention. An agent with a longer half-life would provide a great advantage in its use as a nociceptic and for the therapeutic and prophylactic treatment of a variety of diseases and conditions such as anxiety, irritability associated with premenstrual syndrome (PMS) and debilitating disorders or wear and to counteract the effects of steroids, among others.

DESCRIPTION OF THE INVENTION The present invention relates to a composition, formulations and method for preventing and treating anxiety, nausea, irritability associated with premenstrual syndrome, debilitating disorders, including bulimia and anorexia nervosa, as well as to increase muscle mass (protein), which comprises administering to a subject in need of such treatment, a pharmaceutical composition comprising a first agent selected from the group consists of folinic acid, pharmaceutically acceptable salts thereof and mixtures thereof and a second agent, for example, other anti-anxiety agents, nociceptics, antidepressants, anti-inflammatory and analgesic agents, among others. The composition may also comprise formulation ingredients and a physiologically acceptable carrier. This method is thus applicable to prophylactic and therapeutic treatment and to the reduction of the severity of the diseases and conditions described above, regardless of their origin or whether or not they are accompanied by a decrease in adenosine levels (whether due to endogenous abnormalities or are the result of substances administered exogenously). Of particular importance is the application of the composition and formulations of the invention for the treatment and prevention of some diseases and conditions affecting the central nervous system (CNS) such as nausea, anxiety, symptoms of premenstrual syndrome, to treat CNS problems associated with Steroids, disease of weakening or wear, to induce weight gain in anorexia nervosa and bulimia and to increase body mass in general and in particular muscle mass. These agents can be provided as various pharmaceutical formulations in bulk or in unit form, as well as in the form of a food product with other edible ingredients, for example, energy bars, chewing gum, candies, beverages, cakes, salad dressings, pasta, etc.

PREFERRED FORM OF CARRYING OUT THE INVENTION The present invention is generated from the inventor's desire to improve prior technology for the prevention and treatment of debilitating disorders, anorexia nervosa or bulimia, anxiety irritability associated with premenstrual syndrome, nausea, anxiety and other related pathologies that are often associated with depletion of adenosine in the central nervous system (CNS). The present treatment is effective, whether or not there is a marked reduction or depletion of adenosine and whatever its cause, for example, due to the use of steroids and other drugs that deplete adenosine, deficient adenosine synthesis, elevated adenosine metabolism or any other another cause. It is known that adenosine is a natural agent provided with analgesic, anti-inflammatory, anti-ischemic, soporific and anxiolytic properties. The inventor of the present unexpectedly found that the first agent also exhibits sustainable activity as a nociceptic, anti-anxiety agent, to treat and prevent the harmful symptoms associated with steroid consumption, such as strange behavior, insanity and aggression. He also found through his research that the first agent has considerable activity to treat and prevent irritability and other abnormal behaviors related to mood, associated with premenstrual syndrome, weakening syndrome (the first agent acts as an anabolic ), bulimia and anorexia nervosa, among others. In the particular case of premenstrual syndrome, the inventor found that symptoms are often associated with cyclical alterations in adenosine levels, perhaps due to fluctuations in neuronal steroid levels. Because it has a very short half-life (approximately one second) and because it has a propensity to cause angina-like pain, adenosine itself is a poor choice for the treatment of anxiety, symptoms of premenstrual syndrome (PMS), Weakening disorders, anorexia nervosa and bulimia and to cope with the harmful side effects of Steroid consumption The inventor postulated that an agent such as folinic acid, which has the ability to induce adenosine synthesis, that has a significantly longer half-life than adenosine and that does not produce angina-like pain, is more suitable for administration in subjects than they suffer from these conditions. However, adenosine can not be administered reasonably as a therapeutic agent, because it has a very short half-life (approximately one second). This fact and its propensity to cause angina-like pain, makes adenosine itself a bad choice for the treatment of pain and inflammation. An agent such as folinic acid, which is capable of inducing the synthesis of adenosine, is more convenient for administration in subjects suffering from these conditions. The inventor has shown that the administration of folinic acid induces the de novo synthesis of adenosine. He demonstrated that the oral administration of folinic acid causes a dramatic increase in the cerebral levels of adenosine in an animal model. Since folinic acid has a much longer half-life than adenosine itself and is not associated with the induction of angina-like pain, the first agent represents an unexpected improvement over adenosine in the increase of cerebral levels of adenosine and for that reason it is suitable as an agent nociceptico, antiansiolítico and antibulímico, as well as for the treatment of anorexia nervosa, debilitating diseases, to increase body mass and counteract the side effects of steroids in the CNS. Folinic acid, its salts and its mixtures are effective for the prevention and treatment of these and other syndromes and conditions, in which an increase in the level of adenosine has therapeutic value. The agent of the invention is provided as a pharmaceutical composition in combination with agents which are currently used to treat the diseases, conditions, symptoms and syndromes, mentioned above and to address other concomitant symptoms encountered in these patients. The present technology is very useful in subjects in which in the best of cases, the existing treatments are partially effective or in which although the treatment may be effective at the beginning, its effectiveness decreases with time. The present method is effective to stimulate the synthesis of adenosine and, therefore, treat subjects, who for example, have used or have been administered steroids for therapeutic reasons, to treat or control anxiety, nausea and irritability (as is the case of premenstrual syndrome), to increase weight gain and treat debilitating disorders and to prevent extreme weight loss in anorexia nervosa and bulimia. The term "adenosine depletion" is intended to encompass both diseases and conditions, such as nausea, anxiety, weight loss and the like, which are associated with levels of adenosine that are significantly reduced or depleted in one or more tissues, compared to the levels previous adenosine in the same subject or with a standard average level for the species (discrimination point) and conditions where the adenosine levels are basically the same as the previous adenosine levels in that subject, but due to some other condition or alteration in that patient, a therapeutic benefit is achieved in the patient by increasing the levels of adenosine with respect to previous levels. The present method is preferably carried out in patients in which the levels of adenosine are reduced, for example, by more than about 5%, about 10%, about 15%, about 20%, about 30% and more , until the total exhaustion in comparison with the previous levels of adenosine in the subject. Although the present invention mainly relates to the treatment of human subjects, it is also used for the treatment of vertebrates in general, in particular mammals. Among the treated animals may be domestic and wild animals, large and small, for veterinary purposes, including domestic pets (cats, dogs and the like), zoo animals, racing horses, farm animals (cows, sheep, and the like) and many others. Folinic acid and its pharmaceutically acceptable salts, hereinafter referred to as "active compounds", are known and can be manufactured according to known procedures. See in general, The Merck Index, Monograph No. 4141 (llth Ed. 1989); U.S. Patent No. 2,741,608. The second agent of the present composition can be one or more of a variety of therapeutic and diagnostic agents that are suitable for administration in humans and / or animals. Some of the categories of agents suitable for incorporation into the present compositions and formulations are analgesics, premenstrual drugs, anti-menopausal agents such as hormones and the like, anti-aging agents, anti-anxiety agents, nociceptics, agents for mood disorders, antidepressants, agents for bipolar mood disorders, antischizophrenic agents, anticancer agents, alkaloids, agents for controlling blood pressure, hormones, anti-inflammatory agents, other agents suitable for the treatment and prophylaxis of diseases and conditions associated or accompanied by pain and inflammation, for example, arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, eg, Chron's disease and ulcerative colitis, autoimmune disease, muscle relaxants, steroids, soporific agents, anti-ischemic agents, antiarrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing and burns agents, antiangiogenic agents, cytokines, growth factors, antimetastatic agents, antacids, agents antihistamines, antibacterial agents, antiviral agents, antiflatulent agents, agents for reperfusion injuries, to counteract appetite suppressants, sunscreens, -elements, products to lower the temperature of the skin, fluorescent and phosphorescent contrast and fluorescent contrast agents it is radioactive, libido modifying agents, bile acids, laxatives, antidiarrheal agents, skin renewing agents, hair growth agents, etc. Among the hormones are the male and female sex hormones, such as premarin, progesterone, androsterones and their analogues, thyroxine and glucocorticoids, among the modifying agents of the libido are Viagra and other agents modulators of the level of NO, among the analgesics are the uncontrolled drugs such as ibuprofen, oruda, aleve and acetaminophen and controlled substances such as morphine and codeine, among the antidepressants are the tricyclics, inhibitors of MAO and epinephrine,? -amino butyric acid (GABA), agents that raise the level of dopamine and serotonin, for example, Prozac, amitriptyline, ellbutrin and Zoloft, among the skin regenerating agents are Retin-A, for hair growth, for example, Rogaine, among the anti-inflammatory agents are the non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, among the soporifics are melatonin and sleep-inducing agents, for example, diazepam, cytoprotectors, anti-ischemic agents and for brain injuries, such as enadoline and many others. Examples of agents in the different groups are provided in the following list. Examples of analgesics include acetaminophen, anilerdin, aspirin, buprenorphine, butabital, butorphanol, choline salicylate, codeine, dezocin, diclofenac, diflunisal, dihydrocodeine, elcatoninin, etodolac, fenophene, hydrocodone, hydromorphone, ibuprofen, ketoprofen, ketorolac, levorphanol. , magnesium salicylate, meclofenamate, mefenamic acid, meperidine, methadone, methotrimeprazine, morphine, nalbuphine, naproxen, opium, oxycodone, oxymorphone, pentazocine, phenobarbital, propoxyphene, salsalate, sodium salicylate, tramadol, and narcotic analgesics, in addition to those listed above. See, Mosby's Physician's GenRx. Examples of anti-anxiety agents include alprazolam, bromazepam, buspirone, chlordiazepoxide, chlormezanone, clorazepate, diazepam, halazepam, hydroxyzine, ketazolam, lorazepam, meprobamate, oxazepam and prazepam, among others. Examples of anti-anxiety agents associated with mental depression include chlordiazepoxide, amitriptyline, loxapine, maprotiline and perphenazine, among others. Examples of anti-inflammatory agents include non-rheumatics, aspirin, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen, floctafenin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, magnesium salicylate, meclofenamate, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, salsalate, sodium salicylate, sulindac, tenoxicam, thiaprofenic acid, tolmetin. Examples of anti-inflammatories for ocular treatment include diclofenac, flurbiprofen, indomethacin, ketorolac, rimexolone (generally for postoperative treatment). Examples of anti-inflammatories for non-infectious nasal applications include beclomethasone, budesonide, dexamethasone, flunisolide, triamcinolone and the like. Examples of soporifics (anti-insomnia / sleep-inducing agents) such as those used for the treatment of insomnia, include alprazolam, bromazepam, diazepam, diphenhydramine, doxylamine, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, prazepam, quazepam , temazepam, triazolam, zolpidem and sopiclona, among others. Examples of sedatives include diphenhydramine, hydroxyzine, methotrimeprazine, promethazine, propofol, melatonin, trimeprazine and the like. Examples of sedatives and agents used for the treatment of small ailments and tremors, among other conditions, include amitriptyline hydrochloride, chlordiazepoxide, amobarbital, secobarbital, aprobarbital, butabarbital, etclorvinol, glutethimide, L-tryptophan, mephobarbital, sodium methohexital, Midazolam hydrochloride, oxazepam, sodium pentobarbital, phenobarbital, secobarbital sodium, tiamilal sodium and many others. Agents used in the treatment of brain trauma (brain injury / ischemia) include enadoline hydrochloride (for example, for the treatment of severe brain injury, discontinued drug development, Warner Lambert). Examples of cytoprotective agents and agents for the treatment of menopause and menopausal symptoms include ergotamine alkaloids, belladonna and phenobarbiturics.

Examples of agents for the treatment of menopausal vasomotor symptoms are clonidine, conjugated estrogens and medroxyprogesterone, estradiol, estradiol cypionate, estradiol valerate, estrogens, conjugated estrogens, esterified estrone, estropipate and ethinyl estradiol. Examples of agents for the treatment of premenstrual syndrome (PMS) symptoms are progesterone, progestin, gonadotropin-releasing hormone, oral contraceptives, danazol, luprolide acetate and vitamin B6. Examples of agents for the treatment of emotional / psychiatric disorders are the tricyclic antidepressants which include amitriptyline hydrochloride (Elavil), amitriptyline hydrochloride, perphenazine (Triavil) and doxepin hydrochloride (Sinequan). Examples of tranquillizers, antidepressants and anti-anxiety agents are diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), SSRI's (selective serotonin uptake inhibitors), fluoxetine hydrochloride (Prozac), sertalin hydrochloride (Zoloft), paroxetine hydrochloride (Paxil), fluvoxamine maleate (Luvox), venlafaxine hydrochloride (Effexor), serotonin, serotonin agonists (fenfluramine) and other uncontrolled medications (OTC). Examples of antimigraine agents are Imitrex and the like. Pharmaceutically acceptable salts must be both pharmacologically and pharmaceutically acceptable. These pharmacologically and pharmaceutically acceptable salts can be prepared as alkali or alkaline earth metal salts, for example, sodium, potassium or calcium salts or the carboxylic acid group of folinic acid. The calcium salt of folinic acid is a preferred pharmaceutically acceptable salt. Organic salts and esters are also suitable for use with this invention. The active compounds are preferably administered to the subject as a pharmaceutical composition. The pharmaceutical compositions used in the present invention include systemic and topical formulations and among these are preferred formulations suitable for inhalation, oral, rectal, vaginal nasal, ophthalmic, otic, intracavitary, intraoral, topical (including buccal, sublingual, dermal, intraocular), parenteral (which includes subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and transdermal, among others. The compositions may conveniently be presented in single or multiple unit dosage forms, as well as in bulk and may be prepared by any of the methods well known in the pharmaceutical art. The composition of the invention can also be provided in the form of a kit, either formulated or with instructions for its formulation and regimen of administration. The kit can also contain other agents, such as those described above and for example, in the case of parenteral administration, it can be provided with a vehicle in a separate container, in which case the vehicle is sterile. The present composition can also be provided in a separate container that can be sterile for the addition of a liquid carrier prior to administration. See, for example, U.S. Patent No. 4,956,355; U.S. Patent No. 2,240,472; Patent Application EPO Series No. 429,187; PCT Patent Application Series No. 91/04030, which is considered part of the present, as reference. See, also Mortensen, S.A., et al., Int. J. Tiss. Reac. XII (3): 155-162 (1990); Greenberg, S., et al., J. Clin. Pharm. 30: 596-608 (1990); Folkers, K., et al., Proc. Nat'l. Acad. Sci. 87: 8931-8934 (1990), which is considered part of the present, as a reference. Formulations suitable for oral and parenteral administration and also inhalable preparations are preferred. All methods include the step of associating or mixing the active compound with a vehicle consisting of one or more additional ingredients. In general, the formulations are prepared by mixing the active ingredient uniformly and intimately with a liquid carrier, a finely divided solid or with both and then, if necessary, the product is converted into the desired formulations. Compositions suitable for oral administration may be presented in discrete units, such as capsules, pills, troches or tablets, each with a predetermined amount of the active compound; as 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. Said compositions can be prepared by any suitable pharmaceutical method which includes the step of combining the active compound with a suitable vehicle. In general, the compositions of the invention are prepared by uniformly and intimately mixing the active compound with a liquid carrier or a finely divided solid 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 additional ingredients. Compressed tablets can be prepared by compressing, in a suitable equipment, the compound in a fluid form, for example, a powder or granules optionally mixed with a binder, lubricant, inert diluent and / or surfactants / delivery agents. Molded tablets can be made by molding in a team suitable, of the pulverized 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 allow release of the drug in the small intestine. Compositions suitable for buccal (sublingual) administration include troches comprising the active compound in a flavor base, usually sucrose and acacia or tragacanth and lozenges comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia. Compositions suitable for parenteral administration comprise sterile injectable solutions of the active compound, both aqueous and non-aqueous, these preparations are preferably isotonic with the blood of the recipient to which they are intended. These preparations may contain antioxidants, buffers, bacteriostats and solutes which make the compositions isotonic with the blood of the recipient to which they are intended. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The compositions can be presented in unit dose or multiple dose containers, for example, sealed ampoules and vials and can be stored under freeze-drying (lyophilized) conditions, which it only requires the addition of the sterile liquid vehicle, for example, saline solution or injectable water, immediately before use. Extemporaneous injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the type already described. Compositions suitable for topical application to the skin, preferably have the form of ointment, cream, lotion, paste, gel, spray, aerosol or oil. Vehicles that can be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers 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 (see, for example, Pharmaceutical Research 3, 318 (1986)) and generally in the form of an aqueous solution of the active compound optionally with buffer. The active compound of this invention (first agent) is supplied in a wide range of amounts in the composition. For example, folinic acid, its salts "and their mixtures may be contained in the composition in amounts of about 0.001%, about 1%, about 2%, about 5% to about 99.999%, about 98%, about 90%, about 40%, about 20%, about 10%, about 5% of the composition, preferably about 1% to 99%, more preferably about 2% to 40% and even more preferably between about 2% and 10% of the composition. These amounts can be adjusted when additional agents with overlapping activities are included, as discussed above. The dosage of the active compound may vary depending on the age, weight, and condition of the subject. The treatment can be started with a small dosage that is less than the optimum dose of the first agent of the invention, which is folinic acid or one of its salts. The dose can be increased until in the circumstances a desired and / or optimal effect is achieved. In general, the dosage is from about 1, about 5, about 10, about 20, about 50 mg / kg of body weight and up to about 100, about 200, about 500 or about 1000 mg / kg of body weight. At present, the preferred doses are approximately between 5 and 500 mg / kg of body weight of the subject, the most preferred doses are of approximately between 10 and 200 mg / kg and even more preferably, doses of approximately between 50 and 100 mg / kg of body weight of the subject. However, the higher or lower doses are also considered and therefore are included within the limits of this patent. In general, the active agent is preferably administered at a concentration that will allow effective results without causing harmful or unduly harmful side effects and can be administered either as a unit dose or, if desired, in convenient subunits, administered at appropriate time intervals, as required. long day The second therapeutic or diagnostic agent is administered in amounts known to the art to be effective for the intended application. In cases where the second agent has an activity that overlaps with the principal agent, ie, folinic acid and its salts, the dose of one or both agents can be adjusted to achieve a convenient effect. without exceeding the dose range that avoids adverse side effects. Thus, for example, when other analgesic and anti-inflammatory agents are added to the composition, these may be in amounts known in the art for the intended application or in slightly lower doses than when administered alone. In general, the present composition is provides in a variety of systemic and topical formulations. The systemic or topical formulations of the invention are selected from the group consisting of oral, intrabuccal, intrapulmonary, rectal, intrauterine, intradermal, topical, dermal, parenteral, intratumoral, intracranial, buccal, sublingual, nasal, intramuscular, subcutaneous, intravascular, intrathecal formulations , inhalable, transdermal, intraarticular, intracavitary, implantable, transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otic, intravenous, intramuscular, intraglandular, intraorganic, intralymphatic, implantable, slow release and enteric layer. The preparation and preparation of these different formulations is known in the art and does not need to be detailed here. The active compounds can be administered once or several times a day. The active compounds set forth herein can be administered to the lungs of a subject by any suitable means, but are preferably administered by generating an aerosol consisting of respirable particles, the respirable particles are constituted by the active compound, these particles are inhaled by the subject, for example, by administration by inhalation. The respirable particles can be liquid or solid. The particles formed for the active compound, to practice the present invention should include particles of respirable size, ie, particles of a size small enough to pass through the mouth and larynx during inhalation and to the bronchi and alveoli of the lungs. In general, the particle size varies from approximately 0.5 to 10 microns, more particularly, particles with a size smaller than 5 microns are respirable. Particles of non-respirable size that are included in the aerosol, tend to deposit in the throat and swallow, preferably the amount of non-respirable particles in the aerosol, is minimized. For nasal administration, a particle size in the range of 10 to 500 μm is preferred to ensure retention in the nasal cavity. Liquid pharmaceutical compositions of the active compound, to produce an aerosol, can be prepared by combining the active compound with a stable carrier, eg, sterile, pyrogen-free water. Solid particulate compositions containing respirable dry particles of micronized active compound can be prepared by grinding the active compound with a mortar and pestle and then passing the micronized composition through a 400 mesh screen to disintegrate or separate the large agglomerates. A solid particulate composition constituted by the active compound, optionally it may 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 a suitable ratio, for example, a ratio of 1 to 1 by weight. The aerosols of liquid particles comprising the active compound can be produced by any suitable means, for example, with a nebulizer. See, for example, U.S. Patent No. 4,501,729. Nebulizers are devices that are commercially available, which transform solutions or suspensions of the active ingredient into a mist of therapeutic aerosol, either by accelerating a compressed gas, usually air or oxygen, through a venturi orifice. narrow or by means of ultrasonic agitation. Suitable compositions that are used in a nebulizer consist of the active ingredient in a liquid carrier, the active ingredient comprises up to 40% by weight of the composition, but preferably less than 20% by weight of carrier, which is usually water or a dilute aqueous alcohol solution, preferably isotonic with body fluids by the addition, for example, of sodium chloride. Optional additives include preservatives if the The composition is not prepared in sterile form, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants. The aerosols of solid particles comprising the active compound can likewise be produced with any aerosol generator of particulate medicaments, which is commercially available. Aerosol generators for delivering solid particulate medicaments 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 rate suitable for administration in humans. Examples of these aerosol generators include inhalers and insufflators in measured doses. The second agent (s) can be administered simultaneously with the active compound, and can be an agent to prevent and treat absence of sleep, mood disorders, anxiety, irritability, debilitating disorders, bulimia, anorexia nervosa , cancer, viral and microbial infections, heart conditions, ischemia, menopause, pain, inflammation, wounds and burns, muscle tension, low bone calcification, inflammatory diseases such as diseases autoimmune diseases, COPD and inflammatory bowel disease and many more, inflammatory conditions, wound healing, ischemia and reperfusion injury, to treat and prevent side effects from steroid use and to improve body weight and increase muscle mass, preference in the same composition as mentioned above. The phrase "administered simultaneously" in the sense used herein means that the folinic acid or its salt and the second agent (s) are administered either: (a) simultaneously in time and preferably by formulating the two together in a common pharmaceutical vehicle; or (b) at different times during the course of a common treatment scheme. In the latter case, the two compounds are administered at effective time intervals to supplement their half-lives and thereby compensate for a reduction in the maximum level of one with an increasing level of the other and thereby counteract any decrease in the activity of one with a increase in the activity of the other, as a result of its alternative administration scheme. Thus, the active compound may or may not be administered for a sufficient time to return the endogenous adenosine levels to the previous levels in the subject. If the present formulations or composition are administered for a sufficient time to regenerate the endogenous adenosine levels (if they decreased with with respect to the previous levels in the same subject), then the folinic acid, its salts or its mixtures and the second agent are administered in effective amounts to increase the levels of adenosine to a desired level. Then, the doses of the two or more agents can be reduced to maintain adenosine levels, if the second agent has activity that overlaps with the active compound or if it has different activity, the dose of the second agent can be reduced along with that of the compound active in cases of reduced risk of relapse. If the active compound is administered for a sufficient time to regenerate the endogenous adenosine levels and this is achieved, the continuation of the treatment will depend on whether the adenosine levels are maintained or not in the absence of the treatment. Furthermore, if the dose of the second agent (s) is reduced or not, it will depend on whether or not it is necessary to continue its administration or that the subject remains stable. If the physician perceives the need to compensate for a future relapse, such as a decrease in adenosine levels or even its depletion and / or the need or benefit from a continuous administration of the second agent (s), treatment may be continued with meticulous monitoring. Additional agents, whose examples are listed above, can be administered as such or in a form of pharmaceutically acceptable salts. When used in medicine, the salts of these agents should be pharmacologically and pharmaceutically acceptable, but conveniently salts that are not pharmaceutically acceptable can be used to prepare the free active compound or pharmaceutically acceptable salts thereof and are not excluded from the scope of this invention. These pharmacologically and pharmaceutically acceptable salts include, in a non-exclusive form, those which are prepared from hydrochloric, hydrobromic, acid. sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic, malonic, succinic, naphthalene-2-sulfonic and benzenesulfonic acids, among others. The pharmaceutically acceptable salts can also be prepared as alkali metal or alkaline earth metal salts, such as sodium, potassium or calcium salts of the carboxylic acid group. The present pharmaceutical formulations, whether for veterinary or human use, may further comprise the active compound and one or more additional agents, one or more pharmaceutically acceptable carriers and, optionally, any other therapeutic ingredient that is suitable for specific types of diseases and conditions. . The vehicles must be pharmaceutically acceptable in the sense that they are compatible with the other ingredients of the formulation and not excessively harmful to the receiver thereof. Formulations of the present invention suitable for oral administration may be presented as discrete units, for example, capsules, pills, tablets or troches, each with a predetermined amount of the enhancing agent, such as powder or granules or a suspension in an aqueous liquid or non-aqueous, for example, a syrup, an elixir, an emulsion or a dry form. A tablet can be made by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing in an appropriate equipment, the active compound which is in a fluid form, for example, powder or granules and which is optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or an agent dispersant. The molded tablets constituted by a mixture of the active compound sprayed with a suitable vehicle can be made by molding in a suitable equipment. A syrup can be made by adding the active compound to a concentrated aqueous solution of a sugar, for example, sucrose to which an additional agent can also be added. This additional ingredient it may include flavors, suitable preservatives, an agent for delaying the crystallization of sugar and an agent for increasing the solubility of any other ingredient, such as a polyhydric alcohol, for example, glycerol or sorbitol. Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound, which is preferably isotonic with the blood of the recipient. Nasal spray formulations comprise purified aqueous solutions of the active compound with preservatives and isotonic agents. Said formulations are preferably adjusted to a pH and an isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vaginal administration may be presented as a suppository with a suitable vehicle, for example, cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a method similar to nasal spray, with the exception that the pH and isotonic factors are preferably adjusted to match those of the eye. Otic formulations are generally prepared in viscous vehicles, for example, oils and the like, as is known in the art. technique, so that they can easily be administered in the ear without spilling. Topical formulations comprise the active compound dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydric alcohols or other bases used for topical pharmaceutical formulations. It may be convenient to add other auxiliary ingredients, as mentioned above. In addition to the aforementioned ingredients, the formulations of this invention may further include one or more additional ingredients selected from diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. As is known in the art, other ingredients can also be used. Since this invention has been generally described, it can be better understood by referring to certain specific examples, which are included herein for purposes of illustration only and are not intended to limit the invention or any modality thereof, unless so is specified.

EXAMPLES In the following examples and in all this patent, "DHEA" means dehydroepiandrosterone, "F.A." means folinic acid, "M" means methyltestosterone, "s" means seconds, "mg" means milligrams, "kg" means kilograms, "kw" means kilowatts, "Mhz" means megahertz and "nmol" means nanomoles.

Examples 1 and 2; In vivo effects of folinic acid and DHEA on adenosine levels Young adult male Fisher 344 rats were administered dehydroepiandrosterone (DHEA) (300 mg / kg) or methyltestosterone (40 mg / kg) in carboxymethylcellulose by gavage, once a day for fourteen days. Folinic acid (50 mg / kg) was administered intraperitoneally, once a day for fourteen days. On the fifteenth day, the animals were sacrificed by microwave pulses (1.33 kw, 2450 Mhz, 6.5 s) in the skull, which immediately denatures the entire brain protein and prevents the metabolism of adenosine. The hearts of the animals were removed and immediately frozen in nitrogen at 10 seconds after death. The liver and lungs were removed en bloc and were instantly frozen under nitrogen 30 seconds after death. The brain tissue was then excised. Tissue adenosine was extracted, it was derived to 1, N6-ethenoadenosine and analyzed by high performance liquid chromatography (HPLC) by spectrofluorometric detection according to the method of Clark and Dar (J. of Neuroscience Methods 25: 243 (1988)). The results of these experiments are summarized below in table 2. The results are expressed as the mean + SEM, with X p < 0.05 compared to a control group and 0 p < 0.05 was compared with groups treated with DHEA or methyltestosterone.

Table 1: In vivo effect of DHEA, d-1-methyltestosterone and folinic acid on adenosine levels in various tissues of rats Intracellular adenosine (nmol / mg protein) Heart Lung Brain Control 10.6 ± 0.6 3.1 ± 0 0.5 ± 0.04 (n = 12) (n = 6) (n = 12) DHEA 6.7 ± 0.5 2.3 ± 0.3 0.19 ± 0.01 (300 mg / kg) (n = 12) (n = 6) (n = 12) Methyltestosterone 8.3 ± 1.0 N.D. 0.42 ± 0.06 (40 mg / kg) (n = 6) (n = 6) Methyltestosterone (M) 6.0 ± 0.4 N.D. 0.32 ± 0.03 (120 mg / kg) (n = 6) (n = 6) Folinic acid (F.A.) 2 ^ + 2 ± N.D. Q? 2 + Q Q9 (5 ° "S / ^ (n = 5) (n = 5) DHEA + F.A. l l m l ± 0 6 N.D. Q 55 ± Q _ Q9 (300 mg / kg, 50 mg / kg) (r? _t- { N ~; D> (n = 5) M + F, A '9.1 ± 0.4 N-D- 0.60 ± 0.06 (120 mg / kg, 50 mg / kg) (n = 6) (n = 6) N.D. = Not determined The results of these experiments indicate that rats given DHEA or methyltestosterone daily for two weeks showed exhaustion of multi-organ adenosine. The exhaustion 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. The folinic acid administered alone induces an increase in adenosine levels for all the organs studied. Now that the invention has been fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications may be made thereto without departing from the spirit or scope of the invention, as set forth herein. The aforementioned examples are illustrative of the present invention and are not considered to be limiting thereof. The invention is defined by the following claims, with equivalents thereof included.

Claims (13)

1. CLAIMS; A pharmaceutical composition comprising a solid or liquid pharmaceutical or veterinarily acceptable carrier; a first agent comprising folinic acid, physiologically acceptable salts thereof or mixtures thereof in an effective amount against the foreign behavior or aggression associated with the use of steroid products, weakening, bulimia, anorexia nervosa, anxiety or irritability and a second agent comprising analgesics, anti-menstrual syndrome agents, anti-menopausal agents, anti-aging agents, anti-anxiety agents other than the first agent, agents for mood disorders, antidepressants, agents for bipolar mood disorders, antischizophrenic agents, antimigraine agents, alkaloids, agents for controlling blood pressure, hormones, anti-inflammatory agents, muscle relaxants, anticancer agents, nociceptics agents other than the first agent, steroids, soporific agents, anti-ischemic agents, antiarrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, antiangiogenic agents, cytokines, factors of growth, antimetastatic agents, antacids, antihistaminic agents, antibacterial agents, antiviral agents, antiflatulent agents, appetite suppressants, agents against debilitating disorders, antibulimic agents, antianrexia nervosa agents, agents against brain lesions, agents against cardiac infarction, adenosine, releasing agents of adenosine or adenosine receptor stimulating agents, sunscreens, emollients, products to lower the temperature of the skin, agents for the study of fluorescent and phosphorescent radioactive contrast and fluorescent contrast agents, libido modifying agents, bile acids, laxatives, antidiarrheal agents, skin regenerating agents, hair growth agents and optionally an agent comprising antioxidants, flavoring agents, coloring agents, aromatic agents, volatile oils, buffers, dispersants, surfactants, propellants or preservatives.
2. Adores The composition according to claim 1, in the form of a systemic or topical formulation comprising an oral, intrabuccal, intrapulmonary, rectal, intrauterine, intradermal, topical, dermal, parenteral, intratumoral, intracranial, buccal, sublingual, nasal, intramuscular formulation , subcutaneous, intravascular, intrathecal, Inhalable, transdermal, intraarticular, intracavitary, implantable, transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otic, intravenous, intramuscular, intraglandular, intraorganic, intralymphatic, implantable, slow release and enteric layer.
3. 3. The composition according to claim 1, in the form of a food product further comprising other edible ingredients.
4. The composition according to claim 3, wherein the food product is selected from the group consisting of energy bars, chewing gum, candies, beverages, cakes, pasta and salad dressings.
5. The composition according to claim 1, wherein the vehicle comprises a hydrophobic vehicle which may contain lipid vesicles or particles in the form of liposomes or microcrystals.
6. 6. A kit comprising, in separate containers, the composition according to claim 2, a delivery device and instructions for use; wherein the delivery device may comprise an inhaler dispensing predetermined individual doses of the formulation, optionally in the form of a nebulizer or insufflator and wherein the device may further comprise a capsule or cartridge pierceable or open, with solid particles of the composition.
7. 7. The kit according to claim 6, wherein the delivery device comprises a pressurized inhaler and the formulation comprises a suspension or solution in an aqueous or non-aqueous liquid or an oil-in-water or water-in-oil emulsion.
8. 8. A method to prevent or counteract nausea, weight loss, anxiety, premenstrual syndrome and / or irritability, which comprises administering to a subject prone or suffering from nausea, weight loss, anxiety, premenstrual syndrome and / or irritability, the pharmaceutical composition ading to claim 1 and optionally a vehicle , the composition ading to claim 1 comprises a nocypeptide, an amount effective to increase body mass, against premenstrual syndrome, anxiety and / or irritability of the first agent that may be present in an amount of about 1 to • about 1,000 mg / kg of body weight and wherein the second agent may comprise analgesics, anti-menstrual syndrome agents, anti-menopausal agents, anti-aging agents, anti-anxiety agents, agents for mood disorders, antidepressants, agents for bipolar mood disorders, agents antischizophrenics, antimigraine agents, nociceptics distinct of the first agent, anticancer agents, alkaloids, agents to control the pressure blood, hormones, anti-inflammatory agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, antiarrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, antiangiogenic agents, cytokines, growth factors, agents anti-metastatic agents, antacids, antihistaminic agents, antibacterial agents, antiviral agents, antiflatulent agents, appetite suppressant agents, agents against debilitating disorders, antibulimic agents, antianrexia nervosa agents, agents against brain lesions, agents against cardiac infarction, adenosine, adenosine-releasing agents or adenosine receptor stimulating agents, sunscreens, emollients, products to lower the temperature of the skin, fluorescent and phosphorescent radioactive contrast and imaging agents, libido modifying agents, Bile acids, laxatives, antidiarrheal agents, regenerating agents or skin agents for hair growth.
9. The method according to claim 8, wherein the composition is administered by means of a systemic or topical route comprising an oral, inhalable, topical, parenteral, transdermal, buccal, sublingual, dermal, intraocular, subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intrapulmonary, rectal, intrauterine, intradermal, topical, dermal, parenteral, intratumoral, intracranial, buccal, nasal, intravascular, intrathecal, transdermal, intracavitary, implantable, transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otic, intraglandular, intraorgan, intralinfática or implantable.
10. The method according to claim 8, wherein the subject is prone or suffering from bulimia, anorexia nervosa and / or debilitating disorder or has consumed or needs to consume steroids.
11. 11. Use of the composition according to claim 1, in the preparation of a medicament suitable for preventing or counteracting nausea, weight loss, anxiety, premenstrual syndrome and / or irritability, which comprises administering to a subject prone or suffering from nausea, loss of weight, anxiety, premenstrual syndrome and / or irritability. The use according to claim 11, wherein the medicament is for systemic or topical administration and comprises an oral, inhalable, topical, parenteral, transdermal, buccal, sublingual, dermal, intraocular, subcutaneous, intradermal, intramuscular, intravenous, medicament. intra-articular, intrapulmonary, rectal, intrauterine, intradermal, topical, dermal, parenteral, intratumoral, intracranial, buccal, nasal, intravascular, intrathecal, transdermal, intracavitary, implantable, transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otic, intraglandular, intraorgan, intralinfático or implantable. The method according to claim 11, wherein the subject is prone or suffers from bulimia, anorexia nervosa and / or debilitating disorder or has consumed, consumed or needs to consume steroids. ek in o oo 44 SUMMARY OF THE INVENTION Composition and formulations comprising a first agent such as folinic acid, pharmaceutically acceptable salts thereof or their mixtures and a second agent (s), eg, analgesics, muscle relaxants, agents for mood disorders, anti-inflammatories, antimigraine agents, antiemetic agents, diuretics, compositions with high protein content and the like. The products are suitable as nociceptics and for the treatment of debilitating disorders, bulimia, anorexia nervosa, anxiety, irritability and other symptoms associated with premenstrual syndrome, as well as for its administration either in combination with steroids or to compensate for the depletion of adenosine and / or the unusual behavior or aggression common to steroid users.