MXPA00009454A - Methods and compositions for treating allergic rhinitis and other disorders using descarboethoxyloratadine - Google Patents

Abstract

Methods are disclosed utilizing DCL, a metabolic derivative of loratadine, for the treatment of allergic rhinitis, and other disorders, while avoiding the concomitant liability of adverse side-effects associated with other non-sedating antihistamines.

Description

"METHODS AND COMPOSITIONS TO TREAT ALLERGIC RHINITIS AND OTHER DISORDERS USING DESCARBOETOXYLORATADINE" 1. BACKGROUND OF THE INVENTION The methods of the present invention comprise administering a therapeutically effective amount of a metabolic derivative of loratadine. Chemically, this derivative is 8-chloro-6,11-dihydro-11- (4-piperidylidene) -5H-bextzo [5, 6] cyclohepta [1,2-b] pyridine and is known as descarboethoxyloratadine (DCL). This compound is specifically described in the article by Quercia et al., Hosp. For ul. , 28: 137-53 (1993) and in the North American Patent Number 4,659,716. - ~~ Loratadine is an antagonist of the histamine H-1 receptor protein. The hüamine H-1 and H-2 receptors are two well-identified forms. The H-l receptors are those that intervene in the anthogonized response by conventional antihistamines. The H-1 receptors are present, for example, in the ilium, skin and bronchial smooth muscle of man and other mammals. Loratadine is preferably linked to peripheral H-1 receptors instead of central ones. Quercia and others, Hosp. Formul. 28: 137-53 (1993). Loratadine 'has been shown to be a more potent inhibitor of bronchispasm induced by serotonin in guinea pigs than terfenadine. Id. At 137-38. Its anti-allergenic activity in animal models was shown to be comparable to that of terfenadine and astemizole. Id. At 138. However, using standard animal model tests, on a milligram per milligram basis, loratadine was shown to be four times more potent than terfenadine in the inhibition of allergic bronchiospasm. Id. In addition, the antihistamine activity of loratadine was demonstrated in humans by evaluating the drug's ability to suppress pustule formation. Id. Clinical efficacy trials indicated that loratadine is an effective H-l antagonist. See Clissold et al., Drugs 37: 42-57 (1989). Through responses intervened by the H-2 receptor, histamine stimulates the secretion of gastric acid in mammals from the chronotropic effect in isolated mammalian atria. Loratadine has no effect on the secretion of gastric acid induced by histamine, nor does it alter the chronotropic effect of histamine in the atria. Therefore, loratadine has no apparent effect on the histamine H-2 receptor. Loratadine is well absorbed, but it is extensively metabolized. Hilbert et al., J. Clin. Pharmacol. 27: 694-98 (1987). The main metabolite, DCL, which has been identified, is reported to be pharmacologically active. Clissold, Drugs 37: 42-57 (1989). It is also disclosed as having antihistaminic activity in U.S. Patent No. 4,659,716. This patent recommends an oral dosage scale of 5 to 100 milligrams per day and preferably 10 to 20 milligrams per day. The efficacy "of loratadine for treating seasonal allergic rhinitis is comparable to that of terfenadine." Quercia et al., Hosp._ Formul. 28: _ 137, 141 (1993) Loratadine also has a faster onset of action than astemizole, Id. Clissold et al., Drugs 37: 42, 50-54 (1989) describes studies that loratadine was effective for use in seasonal and perennial rhinitis, colds (with pseudoephedrine), and chronic urticaria. loratadine would be useful for the treatment of allergic asthma Temple and others, Prostaglandins 35: 549-554 (1988). Loratadine may also be useful for the treatment of motion sickness and vertigo. Some antihistamines have been found to be effective for the prophylaxis and treatment of motion sickness. See from Wood, Drugs, 17: 471-79 (1979). Some antihistamines have been shown to be useful in treating vestibular disorders, such as Meniere's disease, and in other types of vertigo. See Cohen et al., Archives of Neurology, 27: 129-35 (1972). further, loratadine may be useful in the treatment of diabetic retinopathy and other disorders of the thin vessel associated with diabetes mellitus. In tests in rats with streptozocin-induced diabetes, treatment with antihistamines prevented the activation of retinal histamine receptors that had been implicated in the development of diabetic retinopathy. The use of antihistamines to treat retinopathy and disorders and the thin vessel associated with diabetes mellitus is disclosed in U.S. Patent No. 5,019,591. It has also been suggested that loratadine, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, would be useful for the treatment of symptoms of cough, cold, cold and / or flu-like and the discomfort, pain, pain of head, fever and malaise associated with them. These compositions used in the methods for treating the symptoms described above may optionally include one or more active components, including a decongestant agent (such as pseudoephedrine), a suppressant / cough suppressant (such as dextromethorphan) or an expectorant (such as guaifenesin). Many antihistamines cause side effects pe judicial. These harmful side effects include, but are not limited to, a sedative effect, gastrointestinal affliction, dry mouth, constipation or diarrhea. Loratadine has been found to cause a relatively minor sedative effect compared to other antihistamines. In addition, the incidence of fatigue, headache and nausea was similar to those observed for terfenadine. See de Quercia et al., Hosp. Formul. 28: 137-142 (1993). In addition, compounds within the class of non-sedating antihistamines, including loratadine, astemizole and terfenadine, are known to cause other serious deleterious electrophysiological side effects. These detrimental side effects are associated with a prolonged QT interval and include but are not limited to ventricular fibrillation and cardiac arrhythmias, such as ventricular tachyarrhythmias or torsades de pointes. Kno them, in Canadian Journal Hops. Pharm., 45: 33, 37 (1992); Craft, British Medical Journal, 292: .660 (1986); Simons et al., Lancet, 2: ^ 24. { 1988) and from an unknown, Side Effects of Drugs Annual, 12: _ 142 and 14: 135.

Quercia and others., Hosp. Formul. 28: 137, 142 (1993) observed that they were given. to know serious cardiovascular adverse effects, including torsades de pointes and other ventricular arrhythmias, and "healthy" patients who received terfenadine simultaneously with either ketoconazole or erythromycin. Quercia and others also state that arrhythmias have become known with La. concomitant administration of astemizole and erythromycin or erythromycin plus ketoconazole. Therefore, it recommends against the use of loratadine simultaneously with ketoconazole, itraconazole and macrolides, such as erithromycin. In addition, it is known that ketoconazole and / or erythromycin interfere with cytochrome P450 and thus inhibit the metabolism of non-sedating antihistamines, such as terfenadine and astemizole. Due to interference with the metabolism of loratadine, there is a greater potential for harmful interaction between loratadine and other non-sedating antihiscamines and drugs known to inhibit cytachrome P450, such as but not limited to ketoconazole, inraconazole and erythromycin. In the article Brandes et al., Cancer Res. (52) 3796-3800 (1992), Brandes showed that the propensity of drugs to stimulate tumor growth in vivo correlated with the potency to inhibit the stimulation of concanavalin A of lymphocyte mitogenesis. In the article by Brandes et al., J. Nat '1 Cancer Inst., 86: (10) 771-775 (1994), Brandes evaluated loratadine in an in vitro assay to predict improvement of tumor growth in vivo. He found that loratadine and astemizole were associated with the growth of both melanoma tumors and fibrosarcoma. The dose for loratadine in this study was 10 milligrams per day. None of the aforementioned references disclose or allow methods of the invention comprising administering DCL to a human being, while avoiding the deleterious side effects associated with the administration of other non-sedating antihistamines; and other references alone or in combination, suggest these methods. Therefore, it would be particularly desirable to find treatment methods with the advantages of the known non-sedating antihistamines which did not have the aforementioned disadvantages. 2. SUMMARY OF THE INVENTION It has now been discovered that DCL_ is an effective non-sedating antihistamine that is useful for treating allergic rhinitis in a human being, while avoiding the deleterious side effects normally associated with the administration of other compounds within the class of non-sedating antihistamines, such as loratadine, astemizole or terfenadine. These detrimental side effects include but are not limited to cardiac arrhythmias, cardiac conduction disturbances, fatigue, headache, gastrointestinal distress, appetite stimulation, weight gain, dry mouth and constipation or diarrhea. In addition, DCL is useful for treating allergic rhinitis while preventing tumor promotion associated with loratadine and other non-sedating antihistamines. Therefore, this invention also relates to novel methods for treating allergic rhinitis in a human being that has a higher than normal propensity for, or incidence of, cancer. Likewise, it has also been discovered that DCL is useful for treating allergic asthma in a human being, while avoiding the deleterious side effects associated with the administration of other non-sedating antihistamines. As stated above, examples of these side effects are appetite stimulation, weight gain, tumor promotion, cardiac arrhythmias, and cardiac conduction abnormalities. For the time being, this invention also relates to novel methods for treating allergic asthma in a human being who has a propensity greater than normal for, or incidence of cancer. In addition, DCL is useful in treating such disorders in a human being as retinopathy and thin vessel disorders associated with diabetes mellitus, while avoiding the deleterious side effects associated with the administration of other non-sedating antihistamines and while preventing the promotion of associated tumors, with the administration of loratadine and other non-sedating antihistamines. Therefore, this invention also relates to novel methods for treating retinopathy and thin vessel disorders associated with diabetes mellitus in a human being that has a higher than normal propensity for, or incidence of, cancer. It has also been discovered that DCL, in combination with non-steroidal anti-inflammatory agents or other non-narcotic analgesics, is useful for the treatment of symptoms of cough, cold, cold and / or flu-like and discomfort, pain, headache, fever and malaise associated with TLos themselves in a human being, while avoiding the deleterious side effects associated with the administration of other non-sedating anihistamines .. The use of these pharmaceutical compositions, containing DCL, and non-narcotic analgesics or anti-inflammatory agents do not steroidal drugs, such as aspirin, acetaminophen or ibuprofen, may optionally include one or more other active components including a decongestant agent (such as pseudoephedrine), a cough suppressant / antitussive (such as dextromethorphan) or an expectorant. { such as guaifenesin). The present invention also involves the use of the compositions described above to treat the conditions described above, while avoiding the tumor promotion associated with loratadine and other non-sedating antihistamines. Thus, the present invention also relates to the use of these compositions to treat these conditions in a human being that has a higher than normal propensity, for, or incidence of cancer. The present invention also relates to a method for preventing the interaction between DCL and a drug that inhibits cytochrome P450, including, but not being limited to, ketoconazole, itraconazole, erythromycin and others known to those skilled in the art, while treating the allergic rhinitis, allergic asthma, diabetic retinopathy and other disorders of the thin vessel due to diabetes. This invention is also directed to a method to prevent the interaction between DCL and a drug that inhibits cytochrome P450 including, but not being limited to, ketoconazole, itraconozole, erythromycin and other drugs known to those skilled in the art, while treating the symptoms of cough, cold, cold and / or flu-like and discomfort, pain head, pain, fever and malaise associated therewith, in a human being who understands to administer a composition to a human being, this composition comprising DCL and a non-steroidal anti-inflammatory agent or a non-narcotic analgesic. The aforementioned compositions may optionally contain one or more other active components, including a decongestant, cough suppressant / cough suppressant or expectorant. It has also been discovered that DCL is useful to treat other allergic disorders related to its activity as an antihistamine, including but not limited to urticaria and symptomatic dermographism, in a human being, while avoiding the effects. adverse effects associated with the administration of other non-sedating antihistamines and / or while preventing the promotion of tumors associated with the administration of loratadine and other non-sedating antihistamines. In this way, this invention also relates to novel methods for treating allergic disorders, including but not being limited to urticaria and symptomatic dermatography in a human being that has a greater than normal propensity to, or incidence of cancer. The present invention also relates to methods for preventing interaction between loratadine or other non-sedating antihistamines and a drug that inhibits cytochrome P450, including but not limited to ketoconazole, itraconazole and erythromycin, and others known to those skilled in the art, while treating allergic disorders, including but not limited to urticaria and symptomatic dermographism where it is administered to human DCL. 3. DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses a method for treating allergic rhinitis in a human being, while avoiding the concomitant possibility of deleterious side effects associated with the administration of non-sedating antihistamines, which comprises administering to man a therapeutically effective amount of DCL or a salt pharmaceutically acceptable thereof. The present invention also encompasses a method for treating allergic asthma in a human being, while avoiding the concomitant possibility of side effects. detrimental associated with the administration of non-sedating antihistamines, which comprises administering to the human being a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof. Also included in the present invention is a method for treating retinopathy or other thin vessel diseases associated with diabetes mellitus, in a human being, while avoiding the concomitant possibility of deleterious side effects associated with the administration of non-sedating antihistamines which comprises administering to the human being a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof. The present invention further encompasses a method for treating the symptoms of coughs, colds, cold and / or flu-like and the discomfort, headache, pain, fever and malaise associated with them in a human being, while avoiding concomitant possibility of harmful side effects associated with the administration of non-sedating antihistamines, comprises administering to a human being a composition, the composition comprising (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of at least one non-steroidal anti-inflammatory agent or a non-narcotic analgesic, such as acetylsalicylic acid, acenophene acetaminophen, ibuprofen, ketoprofen and naproxen or a pharmaceutically acceptable salt thereof. In addition, the present invention encompasses a method of treating symptoms of cough, cold, cold and / or flu-like and the discomfort, headache, pain, fever and malaise associated therewith in a human being, while avoiding concomitant possibility of the deleterious side effects associated with the administration of non-sedating antihistamines, which comprises administering to the human being a composition, the composition (i) comprising a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and (ii) a Therapeutically effective amount of a decongestant, such as pseudoephedrine or a pharmaceutically acceptable salt thereof. It has been found that MCI is five to seven times less active for tumor promotion than loxatadine. Therefore, the present invention further encompasses a method for treating allergic rhinitis in a human being while avoiding the concomitant possibility of tumor promotion associated with the administration of loratadine and other non-sedating antihistamines, which comprises administering to a human being an amount Therapeutically effective of DCL or a pharmaceutically acceptable salt thereof. A further aspect of the present invention includes a method for treating allergic asthma in a human being while avoiding the concomitant possibility of tumor promotion associated with the administration of loratadine and other non-sedating antihistamines, which comprises administering to the human being a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof. The present invention further encompasses a method for treating retinopathy or other diseases of the thin vessel associated with diabetes mellitus in a human being while avoiding the concomitant possibility of. tumor promotion associated with the administration of loratadine and other non-sedating antihistamines, which comprises administering to the human being a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof. Because DCL is much less active than loratadine in promoting tumors, a further aspect of this invention is a method of treating allergic rhinitis in a human being wherein the human has a higher than normal propensity for, or incidence of, cancer, which comprises administering to the human being an amount Therapeutically effective of DCL or a pharmaceutically acceptable salt of the is'ma. The present invention further encompasses a method for treating allergic asthma in a human being, wherein the human being has a higher than normal propensity for, or cancer incidence comprising, administering to man a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt thereof. Also included in the present invention is a method for treating retinopathy or other diseases of the thin vessel associated with diabetes mellitus in a human being wherein the human being has a higher than normal propensity for, or incidence of cancer, which comprises administering to the human being a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt thereof. In addition, the present invention also includes a method for treating symptoms of cough, cold, cold and / or flu-like and the discomfort, headache, pain, fever and malaise associated therewith in a human being, wherein the human being has a higher than normal propensity for, or incidence of cancer, which comprises administering to the human being a composition, the composition comprising (i) a therapeutically effective amount of DCL or a salt pharmaceutically acceptable thereof and (ii) a therapeutically effective amount of a non-steroidal anti-inflammatory agent or a non-narcotic analgesic, such as acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen and naproxen, or a pharmaceutically acceptable salt thereof. In addition, the present invention further encompasses a method for treating symptoms of cough, cold, cold-like, and / or influenza-like, and the discomfort, headache, pain, fever, and general malaise associated therewith in a human being, in wherein the human being has a greater than normal propensity for, or incidence of cancer, which comprises administering to the human being a composition, the composition comprising (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and ( ii) a therapeutically effective amount of a decongestant, such as pseudoephedrine or a pharmaceutically acceptable salt thereof. It has also been found that when DCL is administered simultaneously with a drug that inhibits cytochrome P450, including but not limited to ketoconazole, itraconazole, erythromycin and others known to those skilled in the art, the interaction between DCL and the drug decreases , in comparison with the simultaneous administration of loratadine or other non-sedating antihistamines with the drug. Therefore, this invention also encompasses a method to prevent the interaction between DCL and a drug that inhibits cytochrome P450 including, but not being limited to ketoconazole, itraconazole, erythromycin and others known to those skilled in the art, while treats allergic rhinitis in a human being, wherein human DCL or a pharmaceutically acceptable salt thereof is administered to the human. Also, this invention also encompasses a method for preventing interaction between loratadine or other non-sedating antihistamines and a drug that inhibits citrochrome P450, including but not limited to ketoconazole, itraconazole, erythromycin and others known to those persons skilled in the art. the technique, while allergic asthma is treated in a human being where human DCL or a pharmaceutically acceptable salt thereof is administered. This invention also encompasses the method for preventing the interaction between DCL and a drug that inhibits cytochrome P450, including but not limited to ketoconazole, itraconazole, erythromycin and others known to those skilled in the art, while treating retinopathy or other vessel diseases thin associated with diabetes mellitus wherein human DCL or a pharmaceutically acceptable salt thereof is administered to the human. Also encompassed by the present invention is a method to prevent the interaction between DCL and a drug that inhibits cytochrome P450 including but not limited to ketoconazole, itraconazole, erythromycin and others known to those skilled in the art, while treating the symptoms of cough, cold, cold and / or flu-like and the discomfort, headache, pain, fever and malaise associated with the same, in a human being, which comprises administering to the human being a composition, the composition comprising (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of an anti-inflammatory agent not steroidal or a non-narcotic analgesic, such as acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen and naproxen, or a pharmaceutically acceptable salt thereof. A further aspect of the invention is a method to prevent the interaction between DCL and a drug that inhibits cytochrome P450, including but not limited to ketoconzole, itraconzole, erythromycin and others that are known. 2nd by those skilled in the art while treating cough, cold, cold and / or flu-like symptoms and the incompetence, headache, pain, fever and malaise associated with them in a human being, which comprises administering to the human being a composition, the composition comprising (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a decongestant, such as pseudoephedrine or a pharmaceutically acceptable salt thereof. . A further aspect of this invention includes a method for treating urticaria in a human being while avoiding the concomitant possibility of harmful side effects associated with the administration of the non-sedating antihistamines, which comprises administering to the human being a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof. In addition, the present invention includes a method for treating symptomatic dermographism in a human being, while avoiding the concomitant possibility of deleterious side effects associated with the administration of non-sedating antihistamines, which comprises administering to man a therapeutically effective amount of DCL, or a pharmaceutically acceptable salt of laccase a.

It has also been found that DCL is at least about 20 times more potent for the histamine receptor when compared to loratidine. Therefore, the dosing scale by the modes of administration described herein and for use in the methods of the present invention are from about 0.1 milligram to less than about 10 milligrams per day. This is significantly lower than what has been recommended for other non-sedating antihistamines, including loratadine which has a recommended oral dose of 5 milligrams to 100 milligrams per day. However, due to the significantly lower side effects, DCL can be provided in higher doses than those suggested for loratadine, thus offering an improved therapeutic scale than loratadine. Loratadine and the other non-sedating antihistamines have an antihistaminic activity and provide therapy and a reduction of symptoms for a variety of conditions and disorders related to allergic rhinitis and other allergic disorders ^ diabetes mellitus and other conditions; However, these drugs, even when they offer efficacy, cause harmful side effects. The use of MCI results in clearer definitions of efficacy related to the dose, detrimental side effects decreased and therefore, an improved therapeutic index. Therefore, it is more desirable to use DCL than to use loratadine itself or other non-sedating antihistamines. The term "detrimental effects" includes, but is not limited to cardiac arrhythmias, cardiac conduction disturbances, appetite stimulation, weight gain, sedative effects, gastrointestinal distress, headache, dry mouth, constipation and diarrhea. The term "cardiac arrhythmias" includes, but is not limited to, ventricular tachyarrhythmias, torsades de pointes, and ventricular fibrillation. The phrase "therapeutically effective amount" means the amount of DCL that provides a therapeutic benefit in the treatment or administration of allergic rhinitis and other allergic disorders, such as urticaria, symptomatic dermographism, allergic asthma, retinopathy and other associated thin vessel disorders. with diabetes mellitus and the symptoms associated with allergic rhinitis, such as cough, cold, cold and / or flu-like symptoms, including, but not limited to, sneezing, runny nose, lagri ation, and skin irritation. The term "allergic asthma" is defined as a disorder characterized by increased responses of the trachea and bronchi to the different stimuli that it gives for result in symptoms that include whistling, coughing and dyspnea. The term "diabetic retinopathy" or "retinopathy associated with diabetes mellitus" is that disorder caused by the increased permeability of capillaries in the eye that leads to hemorrhaging and edema in the eye and can lead to blindness. The term "thin vessel disorders associated with diabetes mellitus" includes, but is not limited to, diabetic retinopathy and peripheral vascular disease. The magnitude of a prophylactic or therapeutic dose of MCI in the acute or chronic administration of the disease will vary with the seriousness of the condition to be treated and the route of administration. The dose, and possibly the frequency of the dose, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dosage scale for the conditions described herein is from about 0.1 milligram to less than about 10 milligrams which is administered in individual or diluted doses orally, topically, transdermally or locally, by inhalation. For example, a "preferred oral daily dose" scale should be from about 0.2 milligram to about 5 milligrams. especially preferred is from about 0.2 milligram to about 1 milligram. It is further recommended that children, patients older than 65 years and those with impaired renal or hepatic function initially receive low doses, so that they can be assessed based on the individual response (s) or level (s) of blood. It may be necessary to use dosages outside these scales in some cases as will be apparent to those skilled in the art. In addition, it will be noted that the physician, clinician or treatment will know how and when they should interrupt, adjust or terminate the therapy along with the patient's individual response. The term "therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof" is encompassed by the dosage amounts described above. In addition the terms "the composition comprising (1) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof and (li) a therapeutically effective amount of at least one non-steroidal anti-inflammatory agent or a non-narcotic drug or a pharmaceutically acceptable salt thereof "; and "the composition comprises (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and (ii) a Therapeutically effective amount of a decongestant agent, such as pseudoephedrine or a pharmaceutically acceptable salt thereof, are also encompassed by the dosage amounts described above, and the dose frequency schedule.Any appropriate administration route can be employed to provide the patient an effective dosage of MCI in accordance with the methods of the present invention For example, forms of oral, parenteral, transdermal, subcutaneous, intramuscular rectal, and the like can be employed Dosage forms include pellets, troches, dispersions, suspensions, solutions , capsules, patches and the like The pharmaceutical compositions used in the methods of the present invention comprise DCL, the metabolic derivative of loratadine, as an active ingredient or a pharmaceutically acceptable salt thereof and may also contain a pharmaceutically acceptable carrier. ceptable and optionally other therapeutic ingredients. The term "therapeutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including the inorganic acids or bases or organic acids or bases. The examples of these inorganic acids are hydrochloric, 16 -. 16 - Bromhydric, iodide, sulfuric and phosphoric. Suitable organic acids can be selected, for example, from classes of organic aliphatic acids, aromatic, carboxylic and sulphonic, examples of which are formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furobic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pam.), methanesulfonic , etapsulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic and galacturonic. Examples of these inorganic bases include metal salts, which are made of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Suitable organic bases may be selected, for example, from N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, eglumaine (N-methylglucamine), usin, and procaine. Compositions for use in the methods of the present invention include compositions such as suspensions, solutions and elixirs; aerosol sprays; carriers, such as starches, sugars, microcrystalline cellulose, diluents, granulating agent, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as powders, capsules and tablets), with the solid oral preparations, Preferred in relation to preparations oral liquids. Especially preferred oral solid preparations are the pills. Due to their ease of administration, the tablets and capsules represent the most venting oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, the tablets can be coated by normal aqueous or non-aqueous techniques. In addition to the common dosage forms noted above, the compound for use in the methods of the present invention is also administered by controlling the delivery medium and / or delivery devices, such as those described in US Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3, 598,123; and 4,008,719; the exhibits of which are incorporated herein by reference. Pharmaceutical compositions for use in the methods of the present invention suitable for oral administration may be presented as dicrate units, such as capsules, wafers or lozenges or aerosol sprays, each containing a predetermined amount of the active ingredient, such as a powder or granules or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. These Compositions can be prepared by any of the pharmacy methods, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more of the necessary ingredients. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more of the necessary ingredients. The tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent in a suitable machine. The molded tablets can be manufactured by molding in a suitable machine, a mixture of the pulverized compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 0.1 milligram to less than about 10 milligrams of the active ingredient, and each wafer or capsule contains from about 0.1 milligram to about less than 10 milligrams of the active ingredient, ie, DCL.

The invention is further defined by reference to the following examples which describe in detail the preparation of the compound and the compositions used in the methods of the present invention, as well as their utility. It will be apparent to those skilled in the art that many modifications to both materials and methods can be implemented, which are within the scope of this invention. 4. EXAMPLES 4. 1 Example 1: Preparation of loratadine and its metabolites Loratadine can be synthesized by methods disclosed in U.S. Patent Number 4,282,233. The metabolites are prepared in a similar manner by conventional reaction steps in the art, such as is described in U.S. Patent No. 4,659,716 which is incorporated herein by reference in its entirety. A common method for preparing DCL is to reflux loratadine in the presence of sodium hydroxide and ethanol as will be illustrated below Claritin or DCL Loratadine Extraction of Commercially Obtainable Claritin Tablets (600x10 milligrams): The loratadine tablets were diluted with water and chloroform. The mixture was stirred and then filtered through celite, rinsed with chloroform until the filtrate did not contain loratadine. The separated aqueous layer was extracted with chloroform twice. The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated to give pure loratadine as a white solid.

Saponification of loratadine: Loratadine (4.0 grams) was added to a solution of sodium hydroxide (5.9 grams) in 280 milliliters of absolute ethanol and the mixture was stirred at room temperature. reflux for four days. The mixture was cooled and concentrated to remove the ethanol. The residue was diluted with water and the aqueous layer was extracted with methylene chloride five times. The combined organic layer was washed with brine water and dried through sodium sulfate. The solvent was evaporated to provide 2.82 grams (87 percent) of the pure loratadine derivative (or metabolite) as a pale tan solid. 4. 2 Example 2 ' Antihistamine activity The antihistamine activity of loratadine and DCL were compared in isolated strips of guinea pig ileus contracted with histamine. This preparation is generally accepted by those skilled in the art as predictive of its efficacy - as a peripheral Histamine H-1 receptor.

Methods: Experiments were carried out on pieces of ileum taken from male guinea pigs (Hartley strain, 419 to 560 grams, HilL Breeding Laboratories, Chelmsford, MA). The tissues were suspended in tissue chambers containing 40 milliliters of Tyrode solution aerated with 95 percent oxygen and 5 percent carbon dioxide at 35 ° C. The Tyrode solution contained (in mM) 137 of NaCl, 2.7 of KC1, 2.2 of CaCl2, 0.025 of MgCl2, 0.4 of NaHP0, 11.9 of NaHC03 and 5.5 of glucose. Contractions in response to histamine were recorded in isotonic transducers (Model 357, Harvard Apparatus Company, South Natick, MA) using a polygraph for ink writing (Model 7, Grass Instrument Company, Quincy, MA). A one gram tension was maintained in all tissues at all times. In each experiment, three or four pieces of ileus were removed from a single animal, suspended in individual tissue chambers and allowed to equilibrate in the bath solution for one hour before the administration of any of the drugs. In four initial experiments in which the tissues were exposed to histamine at concentrations of lxlO- ^, lxlO-6 and lxlO- ^ moles per liter, histamine at lxlO- ^ moles per liter produced strong contractions in the linear portion of the curve of the Concentration effect of the graph and this concentration of histamine was selected for use in all additional experiments. To determine the antihistamine effects of loratadine and DCL, the tissues were briefly exposed (approximately 15 seconds) to lxlO- ^ moles per liter of 13 -. 13 - histamine at 15 minute intervals. After the two successive exposures to histamine produced contractions of approximately the same magnitude, loratadine or DCL at final concentrations that varied by three or ten times, was added to all but one of the tissue chambers, the untreated tissue serving. as a control for the treated tissues. After each exposure of drug-treated tissues to histamine, the fluid in the tissue chamber was replaced by a fluid free of histamine but containing the same drug at the same concentration. Challenges were made with histamnia at 5, 20, 35, 50, 65, 80, 95, 110 and 125 minutes of exposure to the drug, or for comparable periods of time in the control tissues. Subsequent analyzes of the results of each experiment involved (i) normalization of the data of each tissue for differences in inherent contractibility expressing all contractions as a percentage of the last pre-drug contraction (ii) normalization of the data for changes related to possible time in the contractibility expressing the contractions registered during the exposure to the drug as a percentage of the corresponding value for the untreated tissue and finally (iii) calculation of the reduction in percentage related to the drug of each contraction.

The resulting data sets for concentration and corresponding percent reduction of the drug in the histamine response were then used to calculate for each experiment the concentration of the drug that would have produced a 50 percent reduction in the histamine response, IC50- This was done by fitting straight lines to the data using the minimum-quadratic method and calculating the IC50 of the line equation. The mean error +/- of the values for the experiments in each drug were calculated, and the differences between the drugs were examined using the Kruskal Wallis unidirectional analysis of ranged variation ~ A summary of the results is shown in the. next two pictures. The percentages of reduction of contractions induced by histamine of the ileus of the isolated guinea pig produced for exposure for 125 minutes at different concentrations of each drug are indicated below: TABLE 1 - Reduction of Contractions of Guinea Pig Induced Induced Histamine (Percentage) Exp. Drog; Number Concentration of the drug 3xl0-10 lxlO-9 3xlCT9 lxicr8 3xl0-8 lxlCT7 Loratadine 1 19.05 - 13.33 - 88.57 2 - 28.32 54.42 98.66 3 - - 39.64 44.68 93.38 4 - - 55.86 45.83 86.46 DCL 1 11.93 73, .12 2 38.91 38. .81 56.71 3 40.00 62. .69 76.21 4 35.43 44., 13 76.43 TABLE 2 - Reduction of Icum Contractions of the Guinea Pig Induced by Histamine (IC50) Drug Expt IC50 (M) Loratadine 1 1.90x10"2 2.21x10" 3 2.10xl0_ 4 1.22x10- Medium 1.86x10"-tí S.E. 0.22 DCL 1 6.36x10"-10 2 19.2x10" -10 3 5.26x10"-10 4 8.66x10" -10 Medium 9.75x10"-10 S.E. 3.20 Note: There is a statistically significant drug-related difference in IC50 values (P = 0.0209).

These results indicate that DCL is approximately 20 times more potent in histamine results than loratadine. 4. 3 Example 3 Receptor Ligand Studies The receptor binding * studies and the binding affinities of loratadine and DCL in histamine H-1 receptors were carried out. The methods described by Dini et al., Which are incorporated herein by reference (Agents and Actions, 33: 181-184, 1991), were used for these binding studies. The guinea pig caravel membranes were incubated with 0.5 nM of 3H-pyrilamine for 10 minutes at 25 ° C. After incubation, the assays were rapidly filtered under vacuum through GF / B glass fiber filters (Whatman) and washed several times with an ice-cold stabilizer using a "Brandel Cell Harvester". The binding radioactivity was determined with a liquid scintillation counter (LS 6000, Backman) using a liquid scintillation cocktail (Formula 989, DuPont NEN).

The IC 50 values were determined for tested compounds and the pyrilamine in the histamine H-1 receptor: TABLE 3 - Inhibition of Pyrilamine Ligand in the Receptor H-1 - - Rec eptor H - -1 Compound IC50 (nM) (nH) Loratadine 721 (1.55) DCL 51.1 (1.12) Pyrilamine 1.4. (0.98) As shown above, the DCL was found to have an affinity 14 times greater than loratadine for histamine H-1 repellents. These results are compatible with the findings that demonstrate a greater power of DCL in relation to loratadine for inhibition of histamine-induced contractions of guinea pig ileus. These studies confirm that MCI has a greater potency for histamine receptors than loratadine. 4. 4 Example 4 Tumor Promotion Activity The inhibition of lymphocyte mitogenesis was used to select the potencies of loratadine and DCL as tumor promoting agents.

Myogenesis Studies: _ Fresh spleen cells (5x10 ^) obtained from BALB / c mice five weeks old (Charles River, ST, Constant, PQ) were suspended in RPMI 1640 medium containing 2 percent serum of fetal calf (Grand Island Biological Co., Grand Island, NY) seeded in duplicate microwell plates (Nunc) to which concanavalin (Con) A (2 micrograms per milliliter) was added; Sigma Chemical Co. , St. Louis, MO) and incubated (37 ° C, 95 percent air, 5 percent CO2) in the absence or presence of increased concentrations of test agents dissolved in saline or other vehicles. Forty-three hours after the addition of Con A, 0.25 nmol of ^ jj-tipiidiná (6.7 Ci / nmol, ICN Radiophar aceuticals, of Montreal, PQ) were added to each well. After an additional five hour incubation, the cells were washed from the wells in filter papers using an automatic cell sorter. The filters were placed in small bottles containing 5 milliliters of the scintillation fluid (Readysafe; Beckman) and the Radioactivity incorporated into DNA at 48 hours was determined (n = 3). The IC50 values for inhibition of mitogenesis were determined through a wide range of concentrations (from 0.1 to 10 micrometers).

TABLE 4 - Inhibition of Concavalin to Induced Stimulus of Lymphocysts (IC 0) Loratadine 1. OμM DCL 5.6μM These results indicate that DCL is five times less active than loratadine to promote tumor growth. __ 4. 5 Example 5 Cardiovascular Effects _ The effects of DCL on cardiac potassium currents were studied.

Methods: The ventricular-individual myocytes of the guinea pig and the rabbit were dissociated by enzymatic dispersion (see Cariet, J. Pharmacol, Exper. Ther., 1992, 262, 809-817, which were incorporated into the present by reference in its entirety). The individual suction patch electrode with a resistance of 2 to 5 MO was used for the voltage clamp (Axoclamp 200A). P-clamp software (Axon Instruments) was used to generate voltage-clamp protocols to record and analyze the data. The normal solution contained in mM: NaCl 137.6, KC1 5.4, CaCl 1.8, MgCl 2 0.5, HEPES 11.6 and glucose 5, and NaOH was added at a pH of 7.4. The intracellular solution contained KCl 120, MgCl 2, 6, CaCl 2 0.154, Na 2 ATP 5, EGTA 5, and HEPES 10, with KOH added to a pH of 7.2.

Effect on the Kl current of delayed rectification, (Ifrr) in rabbit ventricular myocytes: The voltage clamp protocol consisted of clamps with a retention potential of -5 'mV to +10 V over a duration of 4 seconds. The change in tail flow was measured as a function of the concentration of the drug. This concentration was changed between 10- ^ and 10 ~ 5 M in five steps. Exposure to each concentration lasted 15 minutes. In the end, the washing was treated for 30 minutes.

Effect in rectifying current in in guinea pig myocytes: The inward rectifier was measured by applying ramp voltage clamps starting from -120 mV and hyperpolarizing the membrane to -120 mV at a speed of 10 mV / second. The starting concentration was the 50 percent efficiency concentration that was determined in the previous experiments. Higher concentrations were applied if this initial concentration was without effect.

Effect of IKH on guinea pig ventricular myocytes: currents were measured in the tail after depolarization of the clamps from 2 seconds to potentials between -30 mV and +60 mV; retention potential of -50mV. The results of these studies indicate that MCI is less active than terfenadine in inhibiting the cardiac delayed rectifier and therefore does not have a potential for cardiac side effects. Therefore, the methods of the present invention are less toxic than methods using other non-sedating antihistamines. 4. 6 Example 6.

Inhibition of cytochrome P450 This study was carried out to determine the extent to which loratadine and DCL inhibit human cytochrome P4503A4 (CYP3A4). CYP3A4 is involved in many drug-drug interactions and quantification of CYP3A4 inhibition by loratadine or DCL indicates the potential of these drug-drug interactions. Inhibition is measured using substrate model testosterone CYP3A4 derived from cDNA in microsomes that were prepared from a human lymphoblastoid cell line designated h3A4v3.

Study Design: The inhibition study consists of the determination of the 50 percent inhibitory concentration (IC50) for the test substance. A single concentration of testosterone (120 micrometers, approximately twice the apparent Km) and ten concentrations of the test substance, separated for approximately 1/2 log, were tested in duplicate. The metabolism of testosterone was tested by the production of the metabolite 6 (beta) -hydroxytestosterone. This metabolite is easily quantified through HPLC separation with absorbance detection.

Storage / Preparation of test substances and addition to incubations: Test substances were stored at room temperature. The test substances will be dissolved in ethanol for addition to the incubations. The concentration of the solvent will be constant for all concentrations of the test substance.

Determination of CI 0 The final concentrations of the test substance will be 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0 micrometers. Each concentration of the test will be tested in duplicate incubations according to the method that will be presented below: Method: A 0.5 milliliter reaction mixture containing 0.7 milligram per milliliter of protein, 1.3 mM of NADP +, 3.3 mM of glucose-6-phosphate, 0.4 unit per milliliter of glucose-6-phosphate dehydrogenase, 3.3 mM Chloride magnesium and 120 microns of testosterone in 100 mM potassium phosphate (pH 7.4) will be incubated at 37 ° C for 30 minutes. A known amount of 11 (beta) -hydroxytestosterone will be added as an internal standard to correct for recovery during extraction. The The reaction mixture will be extracted with 1 milliliter of methylene chloride. The extract will be dried through anhydrous Mgnesium sulfate and evaporated in vacuo. The sample will be dissolved in methanol and injected onto a 4.6 x 250 millimeter HPLC column, 5u C18 and separated at 50 ° C with a methanol / water mobile phase at a flow rate of 1 milliliter per minute. Retention times are approximately 6 minutes for 6 (beta) -hydroxy, 8 minutes for 11 (-) -hydroxy and 12 minutes for testosterone. The product and the internal standard are detected by their absorbance at 254 nm and are quantified by correcting for the extraction efficiency using the absorbance of the peak of 11 (beta) -hydroxy, comparing to the absorbance of a normal curve for 6 (beta) - hydroxytestosterone.

Data Report: For each test substance, the concentration of the metabolite of 6 (beta) -hydroxytestosterone in each duplicate incubation was determined and the percentage of inhibition relative to the control of the solvent is calculated.

The IC50 is calculated by linear interpolation. Pharmaceutical dosage forms useful for the administration of the compounds used in the methods of the present invention, which can be illustrated as follows: 4. 7. Example 7 Capsules A large number of unit capsules were prepared by filling hard gelatin capsules of two standard pieces each with 0.1 to 10 milligrams of the powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate. 4. 8. Example 8 Soft Gelatin Capsules A mixture of the active ingredient is prepared in a digestible oil such as soybean oil, lecithin, cottonseed oil or olive oil and is injected by means of a positive displacement pump into the gelatin to form Soft gelatin capsules containing 0.1 to 10 milligrams of the active ingredient. The capsules are washed and dried. 4. 9 Example 9 Tablets A large number of tablets were prepared by conventional procedures so that the unit dosage was 0.1 to 10 milligrams of the active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase the good taste or to delay absorption. Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art of the foregoing description. These modifications are also intended to be within the scope of the appended claims. The foregoing discussion includes all the information deemed essential to enable those skilled in the art to carry out the claimed invention. Because the cited patents or publications may provide additional useful information, these cited materials are hereby incorporated by reference in their entirety.

Claims (14)

1. CLAIMS 1. The use of a therapeutically effective amount of descarboethoxyloratadine (DCL) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating allergic asthma in a human being, while avoiding the concomitant possibility of side effects per udiciales associated with the administration of non-sedating antihistamines.
2. 2. The use according to claim 1, wherein the harmful side effect is cardiac arrhythmia or the promotion of tumors.
3. 3. The use according to claim 1, wherein the human being has a higher propensity than normal for or the incidence of cancer.
4. 4. The use according to claim 1, wherein the interaction between DCL and a drug that inhibits cytochrome P450 is avoided.
5. 5. The use according to claim 1, wherein the amount of DCL administered is from about 0.1 milligrams to less than about 10 milligrams per day.
6. 6 - The use according to claim 5, wherein the amount of DCL administered is from about 0.1 milligrams to about 5 milligrams per day.
7. 7. - The use according to claim 1, in wherein the amount of the DCL or a pharmaceutically acceptable salt thereof is administered together with a pharmaceutically acceptable carrier.
8. 8. The use of a therapeutically effective amount of descarboethoxyloratadine (DCL) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating retinopathy or other diseases of the thin vessel associated with diabetes mellitus in a human being, while the concomitant possibility of harmful side effects associated with the administration of non-sedating antihistamines is avoided.
9. 9. The use according to claim 8, wherein the harmful side effect is cardiac arrhythmia or tumor promotion.
10. 10. The use according to claim 8, wherein the human being has a higher propensity than normal for or the incidence of cancer.
11. 11. The use according to claim 8, wherein the interaction between DCL and a drug that inhibits cytochrome P450 is avoided.
12. 12. The use according to claim 8, wherein the amount of DCL administered is from about 0.1 milligrams to less than about 10 milligrams per day.
13. 13. The use according to claim 12, - wherein the amount of DCL administered is from about 0.1 milligrams to about 5 milligrams per day.
14. 14. The use according to claim 8, wherein the amount of the DCL or a pharmaceutically acceptable salt thereof is administered together with a pharmaceutically acceptable carrier.