COMPOSITION AND FORMULATIONS AND THEIR USE AS NOCICEPTIC, ANTI-ANXIOLYTIC AND ANABOLIC AGENTS

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: COMPOSITION AND FORMULATIONS AND THEIR USE AS NOCICEPTIC, ANTI-ANXIOLYTIC AND ANABOLIC AGENTS Technical Field This invention relates to a composition and formulations compπsmg folinic acid, pharmaceutically acceptable salts thereof or mixtures thereof, and other agents such as analgesics, anti-inflam atoπes, muscle relaxants, anti-migraine agents, anti-emetics, diuretics, and the like The products are suitable as nociceptics, for treatment of wastmg disorders, anxiety, irritability associated with Pre Menstrual Syndrome and for administration either m conjunction with steroids or to compensate adenosme depletion common m steroid users. Background Art Folinic acid is an intermediate product of the metabolism of fo c acid, and is believed to be the active form into which fohc acid is converted in the body It is also known that ascorbic acid or Vitamin C is required as a necessary factor m the conversion of fo c acid to folinic acid Folinic acid has been used therapeutically as an antidote to fohc acid antagonists such as methotrexate which block the conversion of fohc acid into folinic acid Additionally, folinic acid has been used as an anti-anemic, because of its ability to combat folate deficiency Folinic acid has heretofore never been used m patients afflicted with adenosine depletion nor m a method to therapeutically elevate adenosine levels in the brain or other organ Adenosme is a puπne involved in intermediary metabolism Adenosine also participates in the regulation of physiological activity in a variety of mammalian tissues as well as m many local regulatory mechanisms, such as those occurring in synapses in the central nervous system (CNS) and at neuroeffector junctions in the peripheral nervous system In the CNS, adenosine inhibits the release of a variety of neurotransmitters, such as acetylchohne, noradrenahne, dopamine, serotonin, glutamate and GABA, depresses neurotransmission, induces spmal analgesia possibly by reducing neuronal firing and possesses anxiolytic properties In the heart, adenosine suppresses pacemaker activity, slows AV conduction, possesses antiarrhythmic and arrhythmogenic effects, modulates autonomic control and triggers the synthesis and release of prostaglandms In addition, adenosine has potent vasodilatory effects and modulates vascular tone At present, adenosine is used clinically for the treatment of SupraVentricular Tachycardia (SVT) and other cardiac anomalies, as well as for testing cardiovascular function Adenosine analogues are also being investigated for use as anticonvulsant, anxiolytic and neuroprotective agents Adenosine is also protective of tissues subjected to ischemia (oxygen deprivation) and aids reperfusion of these tissues, e g brain following stroke or other acute or chronic brain ischemia-producing conditions and diseases, heart following heart attack or other acute or chronic heart ischemia-producing conditions or diseases, and other organs at πsk for ischemia associated with diseases and condition processes, acute and chronic physiological events and m transplantable organs during the harvest and transportation stages prior to tranplantation as well as in already transplanted organs, among others Adenosine analogues also are bemg investigated for use as anti-convulsant, anxiolytic and neuroprotective agents Adenosme, m addition, is a natural anti-inflammatory agent which, for example, is known to mediate the anti-inflammatory effect of methotrexate Adenosme also promotes and accelerates wound healmg and regulates neutrophil function via activation of a seπne/threonine phosphatase Although adenosme has vaπous therapeutic applications as descπbed above, it has an extremely short half life (about a second) Adenosme's short half life and its propensity to cause angina-like pain make it a poor choice for therapeutic applications. In view of the foregoing, it is readily apparent that a large reduction m adenosme levels or adenosme depletion may lead to a broad variety of deleteπous conditions, and that the ability to treat, reverse and prevent adenosine depletion is an extremely useful means of therapeutic intervention. An agent with a longer half life would provide a great advantage for use as a nociceptic and for the therapeutic and prophylactic treatment of a variety of diseases and conditions such as anxiety, irritability associated with Pre Menstrual Syndrome (PMS) and wastmg disorders, and to counter the effects of steroids, among others. Disclosure of Invention The present invention relates to a composition, formulations and a method of preventmg and treating anxiety, nausea, irritability associated with Pre Menstrual Syndrome, wastmg disorders, including bulimia and anorexia nervosa, as well as to increase muscle (protem) mass, which comprises administering to a sub j ect m need of such treatment a pharmaceutical composition comprising a first agent selected from the group consisting of folinic acid, pharmaceutically acceptable salts thereof and mixtures thereof and a second agent such as other anti- anxiolytic agents, nociceptis, anti-depressants, anti-inflammatory agents and analgesics, among others The composition may also compπse formulation ingredients and a physiologically acceptable earner. This method, thus, is applicable to the prophylactic and therapeutic treatment and reduction in severity of the diseases and conditions descπbed above, regardless of their origin, or whether they are accompanied by a decrease in adenosine levels or not (whether due to endogenous abnormalities or the result of exogenously administered substances) Of particular importance is the application of the composition and formulations of the invention to the treatment and prevention of some diseases and conditions affecting the central nervous system (CNS) such as nausea, anxiety, symptoms of Pre Menstrual Syndrome, to treat CNS problems associated with steroids, wasting disease, to induce weight gain m anorexia nervosa and bulimia and to increase body mass generally, particularly muscle mass The present agents may be provided as various pharmaceutical formulations in bulk or in unit form, as well as in the form of a foodstuff with other edible ingredients, e g energy bars, chewing gum, candy, drinks, cakes, salad dressings, pasta, etc Best Mode for Carrying Out the Invention The present invention arose from a desire by the inventor to improve on pπor technology for the prevention and treatment of wastmg disorders, anorexia nervosa or bulimia, anxiety, irritability associated with Pre Menstrual Syndrome, nausea, anxiety and other related pathologies which are often associated with adenosine depletion in the central nervous system (CNS) The present treatment is effective whether or not there is a marked adenosme reduction or depletion and whatever its cause, e g. due to use of steroids and other adenosine depletmg drugs, deficient adenosme synthesis, high adenosme metabolism or any other cause. Adenosine is known to be a natural agent provided with analgesic, anti-inflammatory, anti-ischemic, soporific and anti-anxiety properties The present inventor found, unexpectedly, that the first agent also exhibits sustamable activity as a nociceptic, anti-anxiety agent, to treat and prevent detrimental symptoms associated with the intake of steroids, such as bizarre behavior, crazmess and aggression He also found through his research that the first agent has substantial activity for treating and preventmg irritability and other abnormal mood behaviors associated with Pre Menstrual Syndrome, wasting syndrome (the first agent acts as an anabolic) and bulimia and anorexia nervosa, among others In the particular case of Pre Menstrual Syndrome, the inventor found that the symptoms are often associated with cyclic alterations m adenosme levels, perhaps due to fluctuations in levels of neuronal steroids. Because it has an extremely short half life (about a second), and because it exhibits a propensity to cause angina-like pain, adenosine itself is a poor choice for the treatment of anxiety, Pre Menstrual Syndrome (PMS) symptoms, wasting disorders, anorexia nervosa and bulimia, and to counter the detrimental side effects of steroidal intake. The inventor posited that an agent such as folinic acid, which is capable of causing the synthesis of adenosine, has a significantly longer half life than adenosine and which does not produce angina-like pain, is better suited for administration to subjects afflicted with these conditions. Adenosine cannot be reasonably administered as a therapeutic, however, because it has an extremely short half life (about a second). This fact, and its propensity to cause angina-like pain make adenosine itself a poor choice for the treatment of pain and inflammation. An agent such as folinic acid, which is capable of causing the synthesis of adenosine, is better suited for administration to subjects afflicted with these conditions. The inventor has shown that the administration of folinic acid induces the de novo synthesis of adenosine. He showed that the oral administration of folinic acid causes a dramatic increase in adenosine levels in the brain 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 for increasing brain adenosine levels and is thereby suitable as a nociceptic, anti-anxiolytic and anti-bulimic agent, as well as for the treatment of anorexia nervosa, wasting diseases, to increase body mass and to counter steroidal CNS side effects. Folinic acid, its salts and their mixtures are efficacious in the prevention and treatment of these and other syndromes and conditions, where an increase in the level of adenosine is of therapeutic value. The agent of the invention is provided as a pharmaceutical composition in combination with agents currently used to treat the diseases, conditions, symptoms and syndromes described above, and to address other co- symptoms encountered in these patients. The present technology is of extreme utility in subjects where existing treatments are partially effective at best or where, although the treatment may have been effective initially, its efficacy has eroded with time. The present method is effective in stimulating adenosine synthesis and, thereby, treat subjects who, for example, have used or been administered steroids therapeutically, for treating or controlling anxiety, nausea and irritability (such as is the case in Pre Menstrual Syndrome), to increase weight gain and treat wasting 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 adenosine levels which are significantly reduced or depleted in one or more tissues, as compared to previous adenosine levels in the same subject or to a standard average level for the species (cut-off point), and conditions where adenosine levels are essentially the same as previous adenosine levels in that subject but, because of some other condition or alteration in that patient, a therapeutic benefit is achieved in the patient by increasing the adenosine levels as compared to previous levels. The present method is carried out, preferably, on patients where adenosine levels are reduced, e.g., by more than about 5%, about 10%, about 15%, about 20%, about 30% and more, to fully depleted as compared to previous adenosine levels in the subject. Although the present invention is primarily concerned with the treatment of human subjects, it also is employed for the treatment of vertebrates in general, particularly mammals. Among the animals treated may be domesticated and wild animals, large and small, for veterinarian purposes, and including house pets (cats, dogs and the like), zoo animals, race horses, farm animals (cows, sheep and the like) and many others. Folmic acid and its pharmaceutically acceptable salts, hereafter sometimes referred to as "active compounds/' are known and may be made in accordance with known procedures See generally, The Merck Index, Monograph No 4141 (11th Ed 1989), US Patent No 2,741,608 The second agent of the present composition may be one or more of a variety of therapeutic and diagnostic agents which are suitable for administration to humans and/or animals Some of the categories of agents suitable for incorporation into the present composition and formulations are analgesics, pre-menstrual medications, anti- menopausal agents such as hormones and the like, anti-agmg agents, anti-anxiolytic agents, nociceptic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, other agents suitable for the treatment and prophylaxis of diseases and conditions associated or accompanied with pa and inflammation, such as arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease such as Chron's disease and ulcerative colitis, autoimmune disease, muscle relaxants, steroids, soporific agents, antt-ischemic agents, anti-arrhythmic agents, contraceptives, vitamms, minerals, tranquilizers, neurotransmitter regulating agents, wound and burn healmg agents, anti-angiogenic agents, cytokmes, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacteπal agents, anti-viral agents, anti-gas agents, agents for reperfusion injury, counteractmg appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent and fluorescent contrast diagnostic and imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents, hair growth agents, etc Among the hormones are female and male sex hormones such as premaπn, progesterone, androsterones and their analogues, thyroxine and glucocorticoids, among the libido altermg agents are Viagra and other NO-level modulatmg agents, among the analgesics are over-the-counter medications such as lbuprofen, oruda, aleve and acetaminofen and controlled substances such as morphine and codeme, among the anti-depressants are tπcychcs, MAO inhibitors and epinephπne, γ-anuno butyric acid (GABA), dopamme and serotonin level elevating agents, e g Prozac, Amytryphlin, Wellbutπn and Zoloft, among the skin renewal agents are Retin-A, hair growth agents such as Rogame, among the anti-inflammatory agents are non-steroidal anti- inflammatory drugs (NSAIDs) and steroids, among the soporifics are melatonin and sleep inducing agents such as diazepam, cytoprotective, anti- lschemic and head injury agents such as enadohne, and many others Examples of agents in the different groups are provided in the following list Examples of analgesics are Acetominophen, Anilerdme, Aspirin, Buprenorphme, Butabital, Butorpphanol, Cholme Sahcylate, Codeine, Dezocme, Diclofenac, Diflunisal, Dihydrocodeine, Elcatoninin, Etodolac, Fenoprofen, Hydrocodone, Hydromorphone, lbuprofen, Ketoprofen, Ketorolac, Levorphanol, Magnesium Sahcylate, Meclofenamate, Mefenamic Acid, Mependine, Methadone, Methotπmeprazme, Morphine, Nalbuphine, Naproxen, Opium, Oxycodone, Oxymorphone, Pentazocine, Phenobarbital, Propoxyphene, Salsalate, Sodium Sahcylate, 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, Ketaszolam, Lorazepam, Meprobamate, Oxazepam and Prazepam, among others Examples of anti-anxiety agents associated with mental depression are Chlordiazepoxide, Amitnptyhne, Loxapine Maprotiline and Perphenazine, among others Examples of anti-inflammatory agents are non-rheumatic Aspirin, Cholme Sahcylate, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Floctafemne, Flurbiprofen, lbuprofen, Indomethacin, Ketoprofen, Magnesium Sahcylate, Meclofenamate, Mefenamic Acid, Nabumetone, Naproxen, Oxaprozm, Phenylbutazone, Piroxicam, Salsalate, Sodium Sahcylate, Sulindac, Tenoxicam, Tiaprofenic Acid, Tolmetin. Examples of anti-inflammatories for ocular treatment are Diclofenac, Flurbiprofen, Indomethacin, Ketorolac, Rimexolone (generally for postoperative treatment). Examples of anti-inflammatories for non-infectious nasal applications are Beclomethaxone, Budesonide, Dexamefhasone, Flunisolide, Triamcinolone, and the like. Examples of soporifics (anti-insomnia/sleep inducing agents) such as those utilized for treatment of insomnia, are Alprazolam, Bromazepam, Diazepam, Diphenhydramine, Doxylamine, Estazolam, Flurazepam, Halazepam, Ketazolam, Lorazepam, Nitrazepam, Prazepam Quazepam, Temazepam, Triazolam, Zolpidem and Sopiclone, among others. Examples of sedatives are Diphenhydramine, Hydroxyzine, Mefhotrimeprazine, Promethazine, Propofol, Melatonin, Trimeprazine, and the like. Examples of sedatives and agents used for treatment of petit mal and tremors, among other conditions, are Amitriptyline HC1, Chlordiazepoxide, Amobarbital, Secobarbital, Aprobarbital, Butabarbital, Ethchiorvynol, Glutethimide, L-Tryptophan, Mephobarbital, MethoHexital Na, Midazolam HC1, Oxazepam, Pentobarbital Na, Phenobarbital, Secobarbital Na, Thiamylal Na, and many others. Agents used in the treatment of head trauma (Brain Injury/Ischemia) include Enadoline HC1 (e.g. for treatment of severe head injury, orphan status, Warner Lambert). Examples of cytoprotective agents and agents for the treatment of menopause and menopausal symptoms are Ergotamine, Belladonna Alkaloids and Phenobarbitals. 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 treatment of symptoms of Pre Menstrual Syndrome (PMS) are Progesterone, Progestin, Gonadotrophic Releasing Hormone, oral contraceptives, Danazol, Luprolide Acetate and Vitamin B6. Examples of agents for the treatment of emotional/psychiatric treatments are Tricyclic Antidepressants including Amitriptyline HC1 (Elavil), Amitriptyline HC1, Perphenazine (Triavil) and Doxepin HC1 (Sinequan). Examples of tranquilizers, anti-depressants and anti-anxiety agents are Diazepam (Valium), Lorazepam (Ativan), Alprazolam (Xanax), SSRI's (selective Serotonin reuptake inhibitors), Fluoxetine HC1 (Prozac), Sertaline HC1 (Zoloft), Paroxetine HC1 (Paxil), Fluvoxamine Maleate (Luvox), Venlafaxine HC1 (Effexor), Serotonin, Serotonin Agonists (Fenfluramine), and other over the counter (OTC) medications. Examples of anti-migraine agents are Imitrex and the like. Pharmaceutically acceptable salts should be both pharmacologically and pharmaceutically acceptable. Such pharmacologically and pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as 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. Pharmaceutical compositions for use in the present invention include systemic and topical formulations and, among these, preferred are formulations suitable for inhalation, oral, rectal, vaginal, nasal, ophthalmic, otical, intracavitary, intraorgan, topical (including buccal, sublingual, dermal and intraocular), parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and transdermal administration, 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 which are well known in the art of pharmacy. The composition of the invention may also be provided in the form of a kit, whether already formulated or with instructions for its formulation and administration regime. The kit may also contain other agents, such as those described above and, for example, when for parenteral administration, they may be provided with a carrier in a separate container, where the carrier may be steπle. The present composition may also be provided in a separate contamer which may be steπle for addition of a liquid earner pπor to admmistration. See, e.g. US Patent No 4,956,355, UK Patent No. 2,240,472; EPO Patent Application Serial No. 429,187, PCT Patent Application Senal No 91/04030, the relevant preparatory and compound portions of which are incorporated by reference above See, also Mortensen, S. A., et al , Int. J. Tiss. Reac. XII(3). 155-162 (1990); Greenberg, S., et al., J. Chn. Pharm. 30 596-608 (1990); Folkers, K., et al., Proc. Nat'l. Acad. Sci. 87: 8931-8934 (1990), the relevant preparatory and compounding portions of which are also incorporated herein by reference. Formulations suitable for oral and parenteral admmistration are preferred, and inhalable preparations are also preferred. All methods include the step of bringing the active compound into association with a earner which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into desired formulations. Compositions suitable for oral admmistration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound, as a powder or granules, as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-m-water or water-m-oil emulsion Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable earner In general, the compositions of the mvention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid earner, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or mold g a power or granules containmg 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 a binder, lubricant, inert diluent, and/or surface active/dispensing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder. Compositions for oral admmistration may optionally include entenc coatings known m 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 lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth and pastilles compnsmg the compound m an inert base such as gelation and glycenn or sucrose and acacia Compositions suitable for parenteral administration compnse 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 contam antioxidants, buffers, bactenostats and solutes which render the compositions isotonic with the blood of the mtended recipient. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored m a freeze-dried (lyophilized) condition requiring only the addition of the stenle liquid earner, for example, salme or water-for-mjection immediately pnor to use. Extemporaneous injection solutions and suspensions may be prepared from stenle powders, granules and tablets of the kmd previously descnbed. Compositions suitable for topical application to the skm preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carners which may be used include vaseline, lanohne, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Compositions suitable for transdermal admmistration may be presented as discrete patches adapted to remam m mtimate contact with the epidermis of the recipient for a prolonged penod of tune. Compositions suitable for transdermal admmistration may also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3, 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. The active compound of this mvention (first agent) is provided within broad amounts of the composition. For example, folinic acid, its salts and their mixtures may be contamed 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 about 99%, more preferably about 2% to 40%, and still more preferably about 2% to about 10% of the composition. These amounts may be adjusted when and if additional agents with overlappmg activities are included as discussed above. The dosage of the active compound may vary depending on age, weight, and condition of the subject. Treatment may be initiated with a small dosage which is less than the optimal dose of the first agent of the invention, be it folinic acid or one of its salts. The dose may be increased until a desired and/or optimal effect under the circumstances is reached. In general, the dosage is about 1, about 5, about 10, about 20, about 50 mg/kg body weight and up to about 100, about 200, about 500 or about 1000 mg/kg body weight Currently, prefened are dosages of about 5 to about 500 mg/kg body weight of the subject, more prefened are dosages of about 10 to about 200 mg/kg, and still more prefened are dosages of about 50 to about 100 mg/kg body weight of the subject Higher or lower doses, however, are also contemplated and are, therefore, within the confines of this patent In general, the active agent is preferably admmistered at a concentration that will afford effective results without causing any unduly harmful or deletenous side effects, and may be admmistered either as a single unit dose, or if desired m convenient subunits administered at suitable times throughout the day The second therapeutic or diagnostic agent(s) is (are) admmistered m amounts which are known in the art to be effective for the intended application. In cases where the second agent has an overlapping activity with the principal agent, l e folmic acid and its salts, the dose of one of the other or of both agents may be adjusted to attain a desirable effect without exceeding a dose range which avoids untoward side effects Thus, for example, when other analgesic and anti-inflammatory agents are added to the composition, they may be added in amounts known in the art for their intended application or in doses somewhat lower that when admmistered by themselves In general, the present composition is provided in a vanety of systemic and topical formulations The systemic or topical formulations of the invention are selected from the group consisting of oral, intrabuccal, intrapulmonary, rectal, mtrautenne, intradermal, topical, dermal, parenteral, mtratumor, intracranial, buccal, sublingual, nasal, intramuscular, subcutaneous, mtravascular, mtrathecal, inhalable, transdermal, intraarticular, intracavitary, implantable, transdermal, lontophoretic, intraocular, ophthalmic, vagmal, otical, intravenous, intramuscular, mtraglandular, intraorgan, mtralymphatic, implantable, slow release and enteric coating formulations The actual preparation and compounding of these different formulations is known m the art and need not be detailed here. The active compounds may be admmistered once or several tunes a day. The active compounds disclosed herem may be admmistered to the lungs of a subject by any suitable means, but are preferably admmistered by generatmg an aerosol compπsed of respirable particles, the respirable particles comprised of the active compound, which particles the subject inhales, i.e., by inhalation admmistration. The respirable particles may be liquid or solid. Particles compnsed of active compound for practicing the present mvention should include particles of respirable size, that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. In general, particles rangmg from about 0 5 to about 10 microns m size, more particularly, less than about 5 microns m size, are respirable Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is preferably minimized For nasal administration, a particle size in the range of 10-500 m is preferred to ensure retention m the nasal cavity Liquid pharmaceutical compositions of active compound for producmg an aerosol may be prepared by combmmg the active compound with a stable vehicle, such as stenle pyrogen free water Solid particulate compositions containing respirable dry particles of rmcronized active compound may be prepared by grinding dry active compound with a mortar and pestle, and then passing the micronized composition through a 400 mesh screen to break up or separate out large agglomerates A solid particulate composition compnsed of the active compound may optionally contam a dispersant which serves to facilitate the formation of an aerosol A suitable dispersant is lactose, which may be blended with the active compound m any suitable ratio, e g , a 1 to 1 ratio by weight Aerosols of liquid particles compnsmg the active compound may be produced by any suitable means, such as with a nebulizer See, e g US Patent No 4,501,729 Nebulizers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a nanow ventun orifice or by mens of ultrasonic agitation Suitable compositions for use m nebulizer consist of the active ingredient in liquid earner, the active ingredient compnsmg up to 40% w/w composition, but preferably less than 20% w/w earner being typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example sodium chlonde Optional additives mclude preservatives if the composition is not prepared steπle, for example, methyl hydroxybenzoate, antioxidants, flavonng agents, volatile oils, buffering agents and surfactants Aerosols of solid particles compnsmg the active compound may likewise be produced with any sold particulate medicament aerosol generator Aerosol generators for admimstenng solid particulate medicaments to a subject product particles which are respirable, as explamed above, and generate a volume of aerosol contammg a predetermined metered dose of a medicament at a rate suitable for human admmistration Examples of such aerosol generators mclude metered dose inhalers and insufflators The second agent(s) may be admmistered concunently with the active compound, and may be an agent for preventmg and treating sleeplessness, mood disorders, anxiety, irritability, wasting disorders, bulimia, anorexia nervosa, cancer, viral and microbial mfections, heart conditions, ischemia, menopause, pain, inflammation, wounds and burns, muscle tension, low bone calcification, mflammatory diseases such as autoimmune diseases, COPD, and inflammatory bowel disease, and many more, mflammatory conditions, wound healmg, ischemia and reperfusion injury, to treat and prevent steroid mtake secondary effects and to improve body weight and mcrease muscle mass, preferably m the same composition as descnbed above The phrase "concunently administering," as used herem, means that the folmic acid or its salt and the second agent(s) are admmistered either (a) simultaneously m tune, and preferably by formulating the two together m a common pharmaceutical earner, or (b) at different times duπng the course of a common treatment schedule In the latter case, the two compounds are admmistered at times effective to complement then- half lives and, thereby offset a reduction m peak level of one with an increasing level of the other and, thereby, counter balance any decrease in activity of one with an mcrease m activity of the other as a result of their alternate admmistration schedule Thus the active compound may or may not be admmistered for a time sufficient to bring endogenous adenosme levels back to prior levels m the subject If the present composition or formulations are administered for a time sufficient to replenish endogenous adenosine levels (if lowered with respect to prior levels in the same subject), then the folinic acid, its salts or their mixtures and the second agent are administered in amounts effective to increase adenosine levels to a desired level. Thereafter, the doses of the two or more agents may be reduced so as to maintain adenosine levels, whether the second agent has overlapping activity with the active compound or, if of different activity, the dose of the second agent may be reduced along with that of the active compound in cases of reduced risk of relapse. If the active compound is administered for a time sufficient to replenish endogenous adenosine levels, and this is attained, the continuation of treatment will depend on whether the adenosine levels are maintain in the absence of treatment or not. Moreover, whether the dose of the second agent(s) is reduced or not will depend on whether or not it is necessary to continue its administration or the subject remains stable. If the practitioner perceives a need to offset a future relapse, be it as a decrease in adenosine levels or even its depletion and/or a need or benefit from a continued administration of the second agent (s), the treatment may be continued with close monitoring. The additional agents, examples of which are listed above, may be administered per se or in the form of pharmaceutically acceptable salts. When used in medicine, the salts of these agents should be pharmacologically and pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare the free active compound or pharmaceutically acceptable salts thereof and are not excluded from the scope of this invention. Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p- toluenesulfonic, tartaric, citric, methanesulphonic, formic, malonic, succinic, naphthalene-2-sulphonic and benzenesulphonic acids, among others. Pharmaceutically acceptable salts also may be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. The present pharmaceutical formulations, whether veterinary or human use, may comprise, in addition to the active compound and one or more additional agents, one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients suitable for specific types of diseases and conditions. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the potentiating agent as a powder or granules or a suspension in an aqueous liquor or nonaqueous liquid such as a syrup, an elixir, an emulsion or a drought. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which is optionally mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine. A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservatives, an agent to retard crystallization of the sugar, and an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol. Formulations suitable for parenteral admmistration conveniently compnse a steπle aqueous preparation of the active compound, which is preferably isotonic with the blood of the recipient. Nasal spray formulations compnse puπfied aqueous solutions of the active compound with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vagmal admmistration may be presented as a suppository with a suitable earner such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye Otical formulations are generally prepared m viscous earners, such as oils and the like, as is known in the art, so that they may be easily administered into the ear without spilling Topical formulations compnse the active compound dissolved or suspended m one or more media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical formulations The addition of other accessory ingredients, vide infra, may be desirable In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ιngredιent(s) selected from diluents, buffers, flavonng agents, binders, disintegrants, surface active agents, thickeners, lubncants, preservatives (including antioxidants) and the like Other ingredients may also be utilized as is known m the art Having now generally descnbed this invention, the same will be better understood by reference to certain specific examples, which are mcluded herem for purposes of illustration only and are not intended to be limiting of the invention or any embodiment thereof, unless so specified EXAMPLES In the following examples, and throughout this patent, "DHEA" means dehydroepiandrosterone, "F A " means folmic 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 & DHEA on Adenosine Levels Young adult male Fischer 344 rats (120 grams) were admmistered dehydroepiandrosterone (DHEA) (300 mg/kg) or methyltestosterone (40 mg/kg) in carboxymethyl cellulose by gavage once daily for fourteen days Folmic acid (50 mg/kg) was admmistered intrapeπtoneally once daily for fourteen days On the fifteenth day, the animals were sacnficed by microwave pulse (1.33 kw, 2450 MHZ, 6 5 s) to the cranium, which mstantly denatures all bram protem and prevents further metabolism of adenosme. Hearts were removed from animals and flash frozen m liquid nitrogen withm 10 seconds of death Liver and lungs were removed en bloc and flash frozen within 30 seconds of death. Bram tissue was subsequently dissected. Tissue adenosme was extracted, deπvatized to 1, N6-ethenoadenosme and analyzed by high performance liquid chromatography (HPLC) usmg spectrofluorometnc detection according to the method of Clark and Dar (J of Neuroscience Methods 25 243 (1988)) Results of these expenments are summarized in Table 2 below Results are expressed as the mean ± SEM, with X p<0 05 compared to control group and 0 p<0 05 compared to DHEA or methyltestosterone-treated groups. Table 1: In vivo Effect of DHEA, δ-1 -methyltestosterone & Folinic Acid on Adenosine Levels in various Rat Tissues Intracellular Adenosine (nmol/mg protein; 1 Heart une Brain Control 10 6+06 3 1+0 0 5+004 (n=12) (n=6) (n=12) DHEA 6 7+0 5 2 3+03 0 19+001 (300 mg kg) (n=12) (n=6) (n=12) Methyltestosterone 8 3+1 0 N D 042+006 (40 mg kg) (n=6) (n=6) Methyltestost. (M) 6 0+04 N D 0 32+0 03 (120mg/kg) (n=6) (n=6) DHEA+ F.A. 1 1 1+0 6 N D 0.55+0.09 (300mg kg, 5 0mg kg) (n=5) (n=5) M + F.A. 9 1+04 N D 0 60+0 06 (120mg kg,50mg kg) (n=6) (n=6 " ) N D = Not Determined The results of these expenments indicate that rats administered DHEA or methyltestosterone daily for two weeks showed multi-organ depletion of adenosme. Depletion was dramatic in bram (60% depletion for DHEA, 34% for high dose methyltestosterone) and heart (37% depletion for DHEA, 22% depletion for high dose methyltestosterone). Co-administration of folinic acid completely abrogated adenosine depletion Folinic acid admmistered alone induces increases m adenosme levels for all organs studied The mvention now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth therem. The foregoing examples are illustrative of the present invention, and are not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein

Claims: CLAIMS 1. A pharmaceutical composition, compnsmg a first agent selected from the group consisting of folmic acid, physiologically acceptable salts thereof and mixtures thereof in an anh-wastmg, anti-bulimic, anti-anorexia nervosa, anti-anxiolytic, anti-irntabihty or anti- steroid associated bizane behavior or agression effective amount; and a second agent selected from the group consisting of analgesics, anti-Pre Menstrual Syndrome agents, anti- menopausal agents, anti-agmg agents, other anti-anxiolytic agents, mood disorder agents, anti-depressants, anti- bipolar mood disorder agents, anti-schizophrenic agents, anti-migraine agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, muscle relaxants, other nociceptic agents, steroids, soporific agents, anti-ischemic agents, anti-anhythmic agents, contraceptives, vitamms, minerals, tranquihzers, neurotransmitter regulatmg agents, wound healing agents, anti-angiogemc agents, cytokmes, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, anti-wasting disorder agents, anti-bulimic agents, anti-anorexia nervosa agents, bram injury agents, heart attack agents, adenosine, adenosine releasing agents and adenosine receptor stimulating agents, sun screens, emollients, skin temperature loweπng agents, radioactive phosphorescent and fluorescent contrast diagnostic and imaging agents, libido altermg agents, bile acids, laxatives, anti-dianheic agents, skm renewal agents and hair growth agents. 2. The composition of claim 1, further comprising a earner. 3. The composition of claim 2, wherein the earner comprises a physiologically acceptable earner. 4. The composition of claim 3, wherein the physiologically acceptable earner compnses a pharmaceutically acceptable earner. 5. The composition of claim 2, wherein the earner is selected from the group consisting of solid and liquid earners. 6 The composition of claim 1, further compnsmg an agent selected from the group consisting of anti-oxidants, flavonng agents, colonng agents, aromatic agents, volatile oils, buffering agents, dispersants, surfactants, propellants and preservatives. 7. The composition of claim 4, m the form of a systemic or topical formulation. 8. The composition of claim 7, which is selected from the group consisting of oral, intrabuccal, intrapulmonary, rectal, mtrautenne, intradermal, topical, dermal, parenteral, intratumor, mtracranial, buccal, sublmgual, nasal, intramuscular, subcutaneous, mtravascular, mtrathecal, inhalable, transdermal, intraarticular, intracavitary, implantable, transdermal, lontophoretic, intraocular, ophthalmic, vagmal, otical, intravenous, intramuscular, mtraglandular, intraorgan, lntralymphatic, implantable, slow release and entenc coating formulations. 9. The formulation of claim 8, which is an oral formulation selected from the group consistmg of capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions and emulsions. 10. The formulation of claim 9, wherem the solutions and suspensions are selected from the group consistmg of aqueous and non-aqueous liquid solutions and suspensions, and the emulsions are selected from the group consisting of oil-m-water and water-in-oil emulsions. 11. The formulation of claim 9, which is a buccal or sub-lmgual formulation selected from the group consistmg of lozenges further comprising a flavoring agent selected from the group consisting of sucrose, acacia and tragacanth; and pastilles further comprising an inert base selected from the group consisting of gelatin, glycerin, sucrose and acacia. 12. The oral formulation of claim 9, further comprising an enteric coating. 13. The formulation of claim 8, which is a parenteral formulation selected from the group consisting of injectable solutions or suspensions, which may further comprise anti-oxidants, buffers, bacteriostatic agents and solutes which render the solution or suspension isotonic with the blood of any intended recipient. 14. The parenteral formulation of claim 13, wherein the solutions and suspensions are selected from the group consisting of sterile aqueous and non-aqueous injection solutions and suspensions, which may further comprise suspending agents and thickening agents. 15. The parenteral formulation of claim 13, which is in a single or multi-unit dose provided in a container selected from the group consisting of sealed ampules and vials. 16. The composition of claim 7, in single or multi-unit dose form. 17. The composition of claim 7, in bulk. 18. The composition of claim 7, which is freeze-dried or lyophilized. 19. The formulation of claim 8, which is a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. 20. The topical formulation of claim 19, further comprising a carrier selected from the group consisting of vaseline, lanoline, polyethylene glycols, alcohols and trans-dermal enhancers. 21. The formulation of claim 8, which is a transdermal formulation. 22. The transdermal formulation of claim 21, which is in the form of a solution or suspension of the first agent, which may further comprise a buffer and one or more second agent (s). 23. The formulation of claim 21 , provided along with a transdermal delivery device. 24. The formulation of claim 23, wherein the device is a patch. 25. The formulation of claim 8, which is an inhalable formulation. 26. The inhalable formulation of claim 25, which is an aerosol comprising liquid or solid particles of the agent, and which may further comprise an agent selected from the group consisting of preservatives, antioxidants, flavoring agents, coloring agents, aromatic agents, volatile oils, buffering agents, dispersants and surfactants. 27. The composition of claim 7, wherein the carrier comprises a hydrophobic carrier. 28. The formulation of claim 27, provided in a capsule. 29. The formulation of claim 8, which is a suppository. 30. The formulation of claim 8, which is an implant. 31. The formulation of claim 8, which is an slow release formulation. 32. The formulation of claim 8, which is an ophthalmic formulation. 33. The formulation of claim 8, which is an otical formulation. 34. The formulation of claim 8, which is a vaginal formulation selected from the group consisting of creams, gels, and vaginal suppositories and implants. 35. The composition of claim 2, comprising the first agent, a second agent selected from the group consisting of other analgesic agents, anti-inflammatory agents, muscle relaxant agents, anti-migraine agents, anti- depressants and other mood altering agents, vitamins, minerals, proteins and physiologically acceptable carriers. 36. The composition of claim 35, wherein the second agent comprises an analgesic. 37. The composition of claim 36, wherein the analgesic is selected from the group consisting of acetaminophen, salicylic acid, salts or esters thereof, naproxin, ibuprofen and narcotic analgesics. 38. The composition of claim 35, wherein the second agent comprises an anti-depressant and/or an anti-migraine agent. 39. The composition of claim 35, wherein the second agent comprises a barbiturate and or an anti- migraine agent. 40. The composition of claim 35, wherein the second agent comprises a muscle relaxant. 41. The composition of claim 35, wherein the second agent comprises an anti-Pre Menstrual Syndrome agent. 42. The composition of claim 4, in the form of a foodstuff further comprising other edible ingredients. 43. The composition of claim 42, wherein the foodstuff is selected from the group consisting of energy bars, chewing gum, candy, drinks, cakes, pasta and salad dressings. 44. The composition of claim 7, which is an iontophoretic transdermal formulation, wherein the carrier is selected from the group consisting of aqueous and alcoholic solutions, oily solutions and suspensions and oil-in-water and water-in-oil emulsions, and wherein the formulation further comprises a transdermal transport promoting agent. 45. The formulation of claim 44, in the form of an implantable capsule or cartridge. 46. The composition of claim 4, wherein the carrier comprises a hydrophobic carrier. 47. The composition of claim 46, wherein the carrier comprises lipid vesicles or particles. 48. The composition of claim 47, wherein the vesicles comprise liposomes, and the particles comprise microcrystals. 49. The composition of claim 48, wherein the vesicles comprise liposomes which comprise the first agent, and further comprising optionally a second agent. 50. The composition of claim 49, wherein the vesicles comprise N-(l-[ 2, 3-dioleoxyloxi] propyl) - N,N,N- trimethyl- ammonium methylsulfate. 51. The composition of claim 8, comprising a respirable or inhalable formulation. 52. The formulation of claim 51 , comprising an intrapulmonary formulation. 53. The formulation of claim 51 , in the form of an aerosol. 54. The composition of claim 7, in the form of a kit, further comprising in a separate container, a delivery device; and instructions for addition of a carrier and administration. 55. The composition of claim 54, wherein the delivery device comprises an inhalator which delivers individual pre-metered doses of the formulation. 56. The composition of claim 54, wherein the inhalator comprises a nebulizer or insufflator, and further comprising a piercable or openable capsule or cartridge with solid particles of the composition. 57. The composition of claim 54, 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. 58. A method of preventing or countering anxiety and/or irritability, comprising administering to a subject prone to or afflicted with anxiety and/or irritability, the pharmaceutical composition of claim 1, and optionally a carrier, the composition comprising an anti-anxiety and/or anti-irritability effective amount of the first agent. 59. The method of claim 58, wherein the first agent is administered in an amount of about 1 to about 1,000 mg/kg body weight. 60. The method of claim 59, wherein the agent is administered in an amount of about 5 to about 500 mg/kg body weight. 61. The method of claim 58, wherein the second agent selected from the group consisting of analgesics, anti-Pre Menstrual Syndrome agents, anti-menopausal agents, anti-aging agents, anti-anxiolytic agents, mood disorder agents, anti-depressants, anti-bipolar mood disorder agents, anti-schizophrenic agents, anti-migraine agents, other nociceptic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti- inflammatory agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-anhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti- angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, anti-wasting disorder agents, anti-bulimic agents, anti-anorexia nervosa agents, brain injury agents, heart attack agents, adenosine, adenosine releasing agents and adenosine receptor stimulating agents, sun screens, emollients, skin temperature lowering agents, radioactive phosphorescent and fluorescent contrast diagnostic and imaging agents, libido altering agents, bile acids, laxatives, anti-dianheic agents, skin renewal agents and hair growth agents. 62. The method of claim 61, wherein the second agent comprises a mood disorder agent. 63. The method of claim 61, wherein the second agent comprises a muscle relaxant. 64. The method of claim 58, wherein the composition is administered by a systemic or topical route. 65. The method of claim 58, wherein the systemic or topical route is selected from the group consisting of oral, inhalable, topical, parenteral, and transdermal. 66. The method of claim 65, wherein the route of administration is selected from the group consisting of buccal, sublingual, dermal, intraocular, subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intrapulmonary, rectal, intrauterine, intradermal, topical, dermal, parenteral, intratumor, intracranial, buccal, nasal, intravascular, mtrathecal, inhalable, transdermal, intracavitary, implantable, transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otical, intraglandular, intraorgan, intralymphatic and implantable. 67. The method of claim 66, wherein the composition is administered as an oral formulation selected from the group consisting of capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions and emulsions. 68. The method of claim 67, wherein the oral formulation further comprises an enteric coating. 69. The method of claim 65, wherein the composition is administered as a buccal or sub-lingual formulation selected from the group consisting of lozenges further compnsmg a flavonng agent selected from the group consistmg of sucrose, acacia and tragacanth; and pastilles further compnsmg an inert base selected from the group consistmg of gelatin, glycerin, sucrose and acacia. 70. The method of claim 65, wherem the composition is admmistered as a parenteral formulation selected from the group consisting of injectable solutions or suspensions, which may further compnse antioxidants, buffers, bacteriostatic agents and solutes which render the solution or suspension isotonic with the blood of any intended recipient. 71 The method of claim 70, wherem the parenteral formulation is provided m bulk or multi-dose form selected from the group consisting of sealed ampules and vials 72. The method of claim 58, in unit-dose form. 73 The method of claim 58, wherem the formulation is m bulk or multi-dose form. 74 The method of claim 65, wherein the formulation is freeze-dπed or lyophilized, and the method further compnses adding a steπle liquid earner selected from the group consistmg of salme and water pnor to use 75 The method of claim 65, wherem the composition is admmistered as a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils, which may further compnse a earner selected from the group consistmg of vaseline, lanoline, polyethylene glycols, alcohols and trans-dermal enhancers. 76 The method of claim 65, wherem the composition is admmistered as a transdermal formulation m the form of a patch. 77 The method of claim 65, wherein the composition is administered as an lontophoretic formulation compnsmg a solution or suspension of the agent, and optionally a buffer and a second agent 78 The method of claim 65, wherem the composition is admmistered as an inhalable formulation. 79 The method of claim 78, wherem the inhalable formulation is an aerosol compnsmg liquid or solid particles of the agent, and which may further compnse an agent selected from the group consisting of preservatives, antioxidants, flavoring agents, volatile oils, buffenng agents, dispersants and surfactants 80 The method of claim 58, wherem the composition further compnses an agent selected from the group consistmg of physiologically acceptable earners, preservatives, anti-oxidants, flavonng agents, volatile oils, buffenng agents, dispersants and surfactants. 81 The method of claim 80, wherem the physiologically acceptable salt is selected from the group consisting of alkaline metal, alkaline earth salts and organic salts. 82. The method of claim 81, wherem the physiologically acceptable salts of the agents are selected from the group consisting of sodium, potassium, calcium and carboxylic acid salts. 83. The method of claim 58, wherem the subject is a human. 84 The method of claim 58, wherem the subject is an annual. 85. The method of claim 58, wherem , which is a prophylactic method 86 The method of claim 58, which is a therapeutic method. 87 The method of claim 58, wherem the anxiety and or lmtabihty is (are) associated with Pre Menstrual Syndrome. 88. A method of increasing body mass, comprising administering to a subject in need of the treatment a pharmaceutical composition comprising a first agent selected from the group consisting of folinic acid, salts thereof and mixtures thereof, and optionally a physiologically acceptable carrier, the composition comprising a body mass increasing effective amount of the first agent. 89. The method of claim 88, wherein the patient is prone to or is afflicted with bulimia, anorexia nervosa and/or a wasting disorder. 90. The method of claim 88, wherein the patient has taken or is in need of taking steroids. 91. The method of claim 88, wherein the first agent is administered in an amount of about 1 to about 1,000 mg/kg body weight. 92. The method of claim 91, wherein the agent is administered in an amount of about 5 to about 500 mg/kg body weight. 93. The method of claim 88, wherein the second agent selected from the group consisting of analgesics, anti-Pre Menstrual Syndrome agents, anti-menopausal agents, anti-aging agents, anti-anxiolytic agents, mood disorder agents, nociceptic agents, anti-migraine agents, anti-depressants, anti-bipolar mood disorder agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti- inflammatory agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-anhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti- angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, anti-wasting disorder agents, anti-bulimic agents, anti-anorexia nervosa agents, brain injury agents, heart attack agents, adenosine, adenosine releasing agents and adenosine receptor stimulating agents, sun screens, emollients, skin temperature lowering agents, radioactive phosphorescent and fluorescent contrast diagnostic and imaging agents, libido altering agents, bile acids, laxatives, anti-dianheic agents, skin renewal agents and hair growth agents. 94. The method of claim 93, wherein the second agent comprises a mood disorder agent. 95. The method of claim 93, wherein the second agent comprises a steroid. 96. The method of claim 88, wherein the composition is administered by a systemic or topical route. 97. The method of claim 88, wherein the systemic or topical route is selected from the group consisting of oral, inhalable, topical, parenteral, and transdermal. 98. The method of claim 97, wherein the route of administration is selected from the group consisting of buccal, sublingual, dermal, intraocular, subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intrapulmonary, rectal, intrauterine, intradermal, topical, dermal, parenteral, intratumor, intracranial, buccal, nasal, intravascular, intrathecal, inhalable, transdermal, intracavitary, implantable, transdermal, iontophoretic, intraocular, ophthalmic, vaginal, otical, intraglandular, intraorgan, intralymphatic and implantable. 99. The method of claim 98, wherein the composition is administered as an oral formulation selected from the group consisting of capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions and emulsions. 100. The method of claim 99, wherein the oral formulation further comprises an enteric coating. 101. The method of claim 97, wherein the composition is administered as a buccal or sub-lingual formulation selected from the group consisting of lozenges further compnsmg a flavonng agent selected from the group consistmg of sucrose, acacia and tragacanth; and pastilles further compnsmg an inert base selected from the group consisting of gelatin, glycenn, sucrose and acacia. 102. The method of claim 97, wherem the composition is admmistered as a parenteral formulation selected from the group consistmg of injectable solutions or suspensions, which may further compnse antioxidants, buffers, bactenostafac agents and solutes which render the solution or suspension isotonic with the blood of any intended recipient. 103. The method of claim 102, wherem the parenteral formulation is provided m bulk or multi-dose form selected from the group consistmg of sealed ampules and vials 104. The method of claim 88, in unit-dose form. 105 The method of claim 88, wherem the formulation is in bulk or multi-dose form. 106 The method of claim 97, wherem the formulation is freeze-dned or lyophilized and the method further comprises adding a steπle liquid earner selected from the group consistmg of salme and water prior to use. 107 The method of claim 97, wherem the composition is admmistered as a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils, which may further compnse a earner selected from the group consisting of vaseline, lanolme, polyethylene glycols, alcohols and trans-dermal enhancers. 108. The method of claim 97, wherein the composition is administered as a transdermal formulation in the form of a patch. 109 The method of claim 97, wherem the composition is admmistered as an lontophoretic formulation compnsmg a solution or suspension of the agent, and optionally a buffer and a second agent. 110 The method of claim 97, wherem the composition is admmistered as an inhalable formulation. 111. The method of claim 110, wherem the inhalable formulation is an aerosol compnsmg liquid or solid particles of the agent, and which may further compnse an agent selected from the group consisting of preservatives, antioxidants, flavoring agents, volatile oils, buffenng agents, dispersants and surfactants. 112. The method of claim 88, wherein the composition further compnses an agent selected from the group consistmg of physiologically acceptable earners, preservatives, anti-oxidants, flavoring agents, volatile oils, buffering agents, dispersants and surfactants. 113. The method of claim 112, wherem the physiologically acceptable salt is selected from the group consistmg of alkaline metal, alkaline earth salts and organic salts. 114. The method of claim 113, wherem the physiologically acceptable salts of the agents are selected from the group consisting of sodium, potassium, calcium and carboxylic acid salts. 115. The method of claim 88, wherem the subject is a human. 116 The method of claim 88, wherem the subject is an animal. 117. The method of claim 88, which is a prophylactic method. 118. The method of claim 88, which is a therapeutic method. 119 A method of countenng or preventmg nausea, compnsmg admmistenng to a subject in need of the treatment a pharmaceutical composition compnsmg a first agent selected from the group consisting of folmic acid, salts thereof and mixtures thereof, and optionally a physiologically acceptable earner, the composition compnsmg a nociceptic effective amount of the first agent. 120. The method of claim 119, wherem the first agent is admmistered in an amount of about 1 to about 1,000 mg/kg body weight. 121. The method of claim 120, wherem the agent is admmistered in an amount of about 5 to about 500 mg/kg body weight. 122. The method of claim 119, wherem the second agent selected from the group consisting of analgesics, anti-Pre Menstrual Syndrome agents, anfa-menopausal agents, anti-agmg agents, anti-anxiolyfac agents, mood disorder agents, nociceptic agents, anti-migraine agents, anti-depressants, anti-bipolar mood disorder agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controllmg agents, hormones, anti- lnflammatory agents, muscle relaxants, steroids, soponfic agents, anti-ischemic agents, anti-anhythmic agents, contraceptives, vitamms, minerals, tranquilizers, neurotransmitter regulating agents, wound healmg agents, anti- angiogemc agents, cytokmes, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bactenal agents, anti-viral agents, anti-gas agents, appetite suppressants, anti-wasting disorder agents, anti-bulimic agents, anti-anorexia nervosa agents, bram injury agents, heart attack agents, adenosine, adenosme releasing agents and adenosine receptor stimulating agents, sun screens, emollients, skm temperature lowering agents, radioactive phosphorescent and fluorescent contrast diagnostic and imaging agents, libido altenng agents, bile acids, laxatives, anti-dianheic agents, skm renewal agents and hair growth agents. 123. The method of claim 122, wherem the second agent compnses a mood disorder agent. 124. The method of claim 122, wherem the second agent compnses an anti-migrame agent, an anti- depressant, another nociceptic agent and/or a muscle relaxant. 125. The method of claim 119, wherem the composition is admmistered by a systemic or topical route. 126. The method of claim 119, wherem the systemic or topical route is selected from the group consisting of oral, inhalable, topical, parenteral, and transdermal. 127. The method of claim 126, wherein the route of administration is selected from the group consisting of buccal, sublmgual, dermal, intraocular, subcutaneous, intradermal, intramuscular, intravenous, intraarticular, mtrapulmonary, rectal, intrautenne, intradermal, topical, dermal, parenteral, intratumor, mtracranial, buccal, nasal, mtravascular, mtrathecal, inhalable, transdermal, intracavitary, implantable, transdermal, lontophoretic, intraocular, ophthalmic, vagmal, otical, intraglandular, intraorgan, lntralymphatic and implantable. 128. The method of claim 127, wherem the composition is admmistered as an oral formulation selected from the group consisting of capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions and emulsions. 129. The method of claim 128, wherem the oral formulation further compnses an enteric coating. 130. The method of claim 126, wherem the composition is admmistered as a buccal or sub-lingual formulation selected from the group consisting of lozenges further compnsing a flavonng agent selected from the group consisting of sucrose, acacia and tragacanth; and pastilles further compnsmg an inert base selected from the group consisting of gelatm, glycenn, sucrose and acacia. 131. The method of claim 126, wherein the composition is administered as a parenteral formulation selected from the group consisting of injectable solutions or suspensions, which may further comprise antioxidants, buffers, bacteriostatic agents and solutes which render the solution or suspension isotonic with the blood of any intended recipient. 132. The method of claim 131, wherein the parenteral formulation is provided in bulk or multi-dose form selected from the group consisting of sealed ampules and vials. 133. The method of claim 119, in unit-dose form. 134. The method of claim 119, wherein the formulation is in bulk or multi-dose form. 135. The method of claim 126, wherein the formulation is freeze-dried or lyophilized and the method further comprises adding a sterile liquid carrier selected from the group consisting of saline and water prior to use. 136. The method of claim 126, wherein the composition is administered as a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils; which may further comprise a carrier selected from the group consisting of vaseline, lanoline, polyethylene glycols, alcohols and trans-dermal enhancers. 137. The method of claim 126, wherein the composition is administered as a transdermal formulation in the form of a patch. 138. The method of claim 126, wherein the composition is administered as an iontophoretic formulation comprising a solution or suspension of the agent, and optionally a buffer and a second agent. 139. The method of claim 126, wherein the composition is administered as an inhalable formulation. 140. The method of claim 139, wherein the inhalable formulation is an aerosol comprising liquid or solid particles of the agent, and which may further comprise an agent selected from the group consisting of preservatives, antioxidants, flavoring agents, volatile oils, buffering agents, dispersants and surfactants. 141. The method of claim 119, wherein the composition further comprises an agent selected from the group consisting of physiologically acceptable carriers, preservatives, anti-oxidants, flavoring agents, volatile oils, buffering agents, dispersants and surfactants. 142. The method of claim 141, wherein the physiologically acceptable salt is selected from the group consisting of alkaline metal, alkaline earth salts and organic salts. 143. The method of claim 142, wherein the physiologically acceptable salts of the agents are selected from the group consisting of sodium, potassium, calcium and carboxylic acid salts. 144. The method of claim 119, wherein the subject is a human. 145. The method of claim 119, wherein the subject is an animal. 146. The method of claim 119, which is a prophylactic method. 147. The method of claim 119, which is a therapeutic method.

Inventors: NYCE JONATHAN W, NYCE, JONATHAN, W.
Applicants: NYCE JONATHAN W, NYCE, JONATHAN, W.
Application year: 2000
Main classification: A61F2
IPC codes: A23L1, A61K9, A61K31, A61K45, A61K47, A61P1, A61P3, A61P9, A61P11, A61P15, A61P17, A61P19, A61P21, A61P25, A61P29, A61P31, A61P35, A61P37, A61P43, C07D475