MXPA99007405A - Methods and compositions for treating allergic asthma and other disorders using descarboethoxyloratadine - Google Patents

Abstract

Methods utilizing descarboethoxyloratadine ("DCL"), for the treatment of allergic disorders, while avoiding the concomitant liability of adverse side-effects associated with other non-sedating antihistamines. Also included are methods for the treatment of allergic asthma using DCL and either a decongestant or a leukotriene inhibitor, while avoiding the concomitant liability of adverse side-effects associated with other non-sedating antihistamines. The invention also encompasses the administration of DCL in a nasal or oral spray.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF ALLERGIC ASTHMA AND OTHER DISORDERS USING DESCARBOETOXYLORATADINE 1- FIELD OF THE INVENTION The present invention relates to methods of treatment that includes the administration of a therapeutically effective amount of a metabolic derivative of loratadine known as descarboethoxyloratadine.

DESCRIPTION OF THE RELATED ART Loratadine is an antagonist of the histamine H-1 receptor protein. The histamine H-1 and H-2 receptors are two well-identified forms. The H-l receptors are those that mediate the response antagonized by conventional antihistamines. The H-1 receptors are present, for example, in the ileum, skin and bronchial smooth muscle of men and other mammals. Loratadine binds preferentially to peripheral receptors rather than to central receptors. Quercia et al., Hosp. Formu1. 28: 137-53 (1993). Loratadine has been shown to be a more potent inhibitor of bronchospasm induced by serotonin guinea pigs rather than terfenadine. Id. At 137-38. Its antialergenic activity in animal models showed to be comparable to that of terfenadine and astemizole. Id. At 138. However, using normal tests on animal models, milligram to milligram, loratadine was shown to be four times more potent than terfenadine in the inhibition of allergic bronchospasm. Id. In addition, the antihistamine activity of loratadine was demonstrated in humans by evaluating the drug's ability to suppress the formation of hives. Id. Clinical evidence of efficacy indicates that loratadine is an effective H-l antagonist. See Clissold et al., Drugs 37: 42-57 (1989). Through the responses mediated by the H-2 receptor, histamine stimulates the secretion of gastric acid in mammals and the chronotropic effect in the isolated mammalian atrium. Loratadine has no effect on the secretion of gastric acid induced by histamine or modify the chronotropic effect of histamine in the atrium. Thus, loratadine has no apparent effect on the histamine H-2 receptor. Loratadine is well absorbed but considerably 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 reported to have antihistaminic activity in U.S. Patent No. 4,659,716. This patent recommends an oral dose range of 5 to 100 mg / day and preferably 10 to 20 mg / day.

The efficacy of loratadine in the treatment of seasonal allergic rhinitis is comparable with 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 the studies that show loratadine as effective for use in seasonal or perennial rhinitis, colds (with pseudoephedrine) and chronic urticaria. It has also been suggested that loratadine would be useful for the treatment of allergic asthma. Temple et al., Prostaglandins 35: 549-554 (1988). Loratadine may also be useful for the treatment of disease 'of movement and vertigo. Some effective antihistamines have been found for the prophylaxis and treatment of motion sickness. See Wood, Drugs, 17: 471-79 (1979). Some antihistamines have also been shown to be useful for the treatment of vestibular disorders, such as Menier's disease, and in another type of vertigo. See Cohen et al., Archives of Neurology, 27: 129-35 (1972). In addition, loratadine may be useful in the treatment of diabetic retinopathy and other disorders of small spleens associated with diabetes mellitus. In tests in rats with streptozocin-induced diabetes, treatment with antihistamines prevented the activation of histamine retinal receptors, which have been involved in the development of diabetic retinopathy. The use of antihistamines to treat retinopathy and small spleen disorders associated with diabetes mellitus is described in U.S. Pat. No. 5, 019,591. It has also been suggested that loratadine, in combination with non-spheroidal anti-inflammatory agents or other non-narcotic analgesics would be useful for the treatment of cough, cold, cold and / or flu-like symptoms and discomfort, pain, headache, fever and general malaise associated with them. Large amount of antihistamines cause adverse effects. These side effects include, but are not limited to, sedation, gastrointestinal upset, dry mouth, constipation, or diarrhea. It has been found that loratadine causes relatively less sedation compared to other antihistamines. In addition, the incidence of fatigue, headache and nausea was similar to those observed for terfenadine. See Quercia et al., Hosp Formul. 28: 137, 142 (1993). In addition, it is known that compounds within the non-sedating antihistamine class, which includes loratadine, astemizole and terfenadine, cause other severe electrophysiological adverse effects. These adverse effects are associated with the prolonged QT interval and include, but are not limited to, ventricular fibrillation and cardiac arrhythmias, such as ventricular tachyarrhythmias or torsades de pointes. Knowles, Canadian Journal Hosp. Pharm. 45: 33, 37 (1992); Craft, British Medical Journal, 292: 660 (1986); Simons et al-, Lancet, 2: 264 (1988); and Unknown, Side Effects of Drugs Annual, 12: 142 and 14: 135. Quercia et al. Hosp. Formul. 28: 137, 142 (1993) observed that serious cardiovascular adverse effects, including torsades de pointes and other ventricular arrhythmias were reported in "healthy" patients who received terfenadine together with ketoconazole or erythromycin. Quercia et al. Also establish that arrhythmias have also been reported with concomitant administration of astemizole and erythromycin or erythromycin plus ketoconazole. In this way, it is warned against the use of loratadine concurrently with ketoconazole, itraconazole and macrolides such as erythromycin. In addition, it is also known that ketoconazole and / or erythromycin interfere with cytochrome P450, and therefore 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 adverse interaction between loratadine and other non-sedating antihistamines and drugs known to inhibit cytochrome P450, such as but not limited to ketoconazole, itraconazole and erythromycin. In Brandes et al., Cancer Res. (52) 3796-3800 (1992), Brandes showed that the propensity of drugs to promote tumor growth in vivo correlates with the potency to inhibit the stimulation of concanavalin A from mitogenesis of lymphocytes. In Brandes et al., J. Nat'l Cancer Inst, 86 (10): 771-775 (1994), Brandes evaluates loratadine in an in vitro assay to predict the improvement of tumor growth in vivo. It was found that loratadine and astemizole were associated with the growth of melanoma and fibrosarcoma tumors. The dose of loratadine in this study was 10 mg / day. Thus, it would be particularly desirable to find treatment methods with the advantages of the known non-sedating antihistamines which do not have the aforementioned disadvantages. 3. SUMMARY OF THE INVENTION The present invention provides methods and compositions that include descarboethoxyloratadine, ie, 8-chloro-6,11-dihydro-11- (4-piperilidene) -5H-benzo [5,6] cyclohepta [1,2 -b] pyridine ("DCL"). This compound is specifically described in Quercia et al. Hosp. Formul., 28: 137-53 (1993) and U.S. Patent No. 4,659,716.

In one aspect, this invention provides a method for the treatment of allergic asthma in a human while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines, consists in administering to a human a composition, containing the composition : (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, (ii) a therapeutically effective amount of a decongestant; and a pharmaceutically acceptable carrier. The invention also provides a method of treating allergic asthma in a human while avoiding the concomitant probability of adverse effects associated with the administration of non-sedating antihistamines, which consists of administering a composition to a human, containing the composition ( i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof; (ii) a leukotriene inhibitor selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, and leukotriene D antagonists; and a pharmaceutically acceptable carrier. This invention is also directed to a method of treating allergic asthma in a human, while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines, which consists in administering to a human a therapeutically effective amount of DCL. and a therapeutically effective amount of a decongestant. Furthermore, this invention provides a method of treating allergic asthma in a human while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines, which consists of administering to a human a therapeutically effective amount of DCL and a Therapeutically effective amount of a leukotriene inhibitor. This invention also provides a method- of treating dermatitis in a human, while avoiding the concomitant probability of adverse effects associated with the administration of non-sedating antihistamines, "which consists of administering to a human a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof. 4. DETAILED DESCRIPTION OF THE INVENTION The present invention comprises a method of treating allergic asthma in a human, while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines, which consists of administering a composition to a human, the composition (i) containing a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of a decongestant; and a pharmaceutically acceptable carrier. The DCL and a decongestant can also be administered separately in an allergic asthma treatment method. For example, DCL and a decongestant can be administered at the same time or in sequence, that is, DCL and a decongestant can be administered in combination either concurrently or by sequential administration of DCL and decongestant or administration in sequence of a decongestant and DCL.; Thus, the present invention also comprises a method of treating allergic asthma in a human, while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines., which consists of administering to a human a therapeutically effective amount of DCL and a therapeutically effective amount of a decongestant. The present invention also relates to a method of treating allergic asthma in a human, while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines, which consists of administering a composition to a human, containing the composition: (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of a leukotriene inhibitor selected from the group consisting of 5-lipoxygenase inhibitors ("5-LO"), 5-lipoxygenase activating protein ("FLAP) antagonists, and leukotriene O4 antagonists ( "LTD4") and a pharmaceutically acceptable carrier The administration of DCL and a leukotriene inhibitor in the methods of the present invention for the treatment of allergic asthma may be concurrently or sequentially, ie the DCL and an inhibitor of leukotriene can be administered as a combination, concurrently or separately or by sequential administration of DCL and the leukotriene inhibitor or sequential administration of a leukotriene and DCL inhibitor.Thus, the present invention comprises a method of treatment of allergic asthma in a human, while avoiding the concomitant likelihood of adverse effects associated with the administration of antihistamines sedatives, which comprises administering to a human a therapeutically effective amount of DCL and a therapeutically effective amount of a leukotriene inhibitor.

Another aspect of the present invention includes a method of treating dermatitis in a human, while avoiding the concomitant probability of the adverse effects associated with the administration of non-sedating antihistamines, which consists in administering to a human a therapeutically effective amount of DCL. or a pharmaceutically acceptable salt thereof. Adverse effects that can be avoided by the methods of the present invention include, but are not limited to, cardiac arrhythmia and tumor growth. It has been found that when DCL is administered concurrently with a drug that inhibits cytochrome P450 including, but not limited to ketoconazole, itraconazole, erythromycin, and others known to those skilled in the art, drug-drug interactions decrease compared to the concurrent administration of loratadine or other non-sedating antihistamines with this drug. In this manner, the methods of the present invention, as described above, are particularly useful in the treatment of allergic disorders such as dermatitis and asthma in a human having a higher than normal propensity for or incidence of cancer and / or avoiding at the same time the interaction with a drug that inhibits cytochrome P450. The present invention also includes novel compositions for use in the methods described above.

It has been found that DCL is at least about 20 times more potent at the histamine receptor when compared to loratadine. Thus, the dose range by the modes of administration described herein and for use in the methods of the present invention, is from about 0.1 to less than about 10 mg per day. This dose range is significantly less than what has been recommended for other non-sedating antihistamines, including loratadine which has a recommended oral dose of 5 to 100 mg per day. However, due to the significantly lower adverse effects, MCI can be administered in higher doses than those suggested for loratadine, thereby offering an improved therapeutic range compared to loratadine. Loratadine and other non-sedating antihistamines have antihistaminic activity and provide therapy and a reduction in symptoms for a variety of conditions and disorders related to allergic rhinitis and other allergic disorders, diabetes mellitus and other conditions; However, these drugs, although they offer the expectation of efficacy, cause adverse effects. The use of MCI results in greater clarity in the definitions related to the dose of efficacy, diminished adverse effects and, consequently, an improved therapeutic index. Therefore, the use of DCL is more desirable than the use of loratadine or other non-sedating antihistamines. The term "adverse effects" includes, but is not limited to, tumor growth, cardiac arrhythmias, disturbances in cardiac conduction, appetite stimulation, weight gain, sedation, gastrointestinal upset, 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 that the amount of DCL that provides a therapeutic benefit in the treatment or management of allergic disorders such as urticaria, allergic rhinitis, symptomatic dermographism, dermatitis, allergic asthma, retinopathy and other disorders of small spleen associated with diabetes mellitus, and symptoms associated with allergic rhinitis such as cough, cold, cold-like symptoms and / or flu, including but not limited to, sneezing, runny nose, tearing, and skin irritation. The term "allergic asthma" is defined as a disorder characterized by the increased response of the trachea and bronchi to the different stimuli that give rise to symptoms including wheezing, cough and dyspnea. The term "dermatitis" is the disorder caused by inflammation of the skin that includes endogenous and contact dermatitis such as, but not limited to: actinic dermatitis (or photodermatitis), atopic dermatitis, chemical dermatitis, cosmetic dermatitis, dermatitis aestivalis and seborrheic dermatitis. The term "leukotriene inhibitor" includes any agent or compound that inhibits, limits, retards or otherwise interacts with the action or activity of the leukotrienes, such as, but not limited to, the 5-lipoxygenase inhibitors (" 5-LO "), antagonists of the 5-lipoxygenase activating protein (" FLAP ") and leukotriene D4 antagonists (" LTD-; ") The term" 5-lipoxygenase inhibitor "or" 5-LO inhibitor "includes any agent or compound that inhibits, limits, retards or otherwise interacts with the enzymatic action of 5-lipoxygenase, such as, but is not limited to zileuton, docebenone, piripost and ICI-D2318.The term "antagonist of the 5-lipoxygenase activating protein" or "FLAP antagonist" includes any agent or compound that inhibits, limits, retards or otherwise interacts. with the activity or action of the 5-lipoxygenase activating protein, such as, but not limited to MK-591 and MK-886. The term "leukotriene antagonist D -_" or "LTD antagonist" includes any agent or compound that inhibits, limits, retards or otherwise interacts with the action or activity of leukotriene D, such as, but not limited to zarfirlukast (ICI-204219) The magnitude of a prophylactic or therapeutic dose of DCL in the acute or chronic management of a disorder or condition or allergic will vary with the severity of the condition being treated and the route of administration. The dose, and perhaps the frequency of the dose, will also vary according to the age, body weight and response of the individual patient. The appropriate total daily dose ranges can be easily determined by those skilled in the art. In general, the total daily dose range for MCI, for the conditions described herein, is from about 0.1 mg to less than about 10 mg administered in single or divided doses orally, topically, transdermally or locally by inhalation. For example, a preferred oral daily dose range should be from about 0.1 mg to about 5 mg. A more preferred oral dose is about 0.2 mg to about 1 mg. A preferred oral, daily, dose range of the decongestant such as pseudoephedrine should be from about 50 mg to about 300 mg, preferably about 150 mg to about 250 mg. In addition, suitable oral, daily, dose ranges of the leukotriene inhibitor can be readily determined by those skilled in the art.

It is also recommended that children, patients around the age of 65 and those with impaired renal or hepatic function receive low doses initially, and that these can then be titrated based on the individual response (s) or level (s). is) blood (s). It may be necessary to use doses outside these ranges in some cases as will be apparent to those skilled in the art. In addition, it will be noted that the treating physician or clinician will know how and when to adjust, interrupt or terminate therapy according to the response of an individual patient. The term "therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof" is comprised by the dose amounts described above. In addition, the terms "this composition contains: (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a decongestant"; and "the composition contains (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof, and (ii) a therapeutically effective amount of a leukotriene inhibitor" is also comprised of the above-described dosage amounts and schedule. of the frequency of the dose. It is possible to employ any suitable route of administration to provide the patient with an effective dosage of MCI according to the methods of the present invention. For example, it is possible to employ the oral, intraoral, rectal, parenteral, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, intradural, intraocular, intra-respiratory, intra-respiratory, oral or nasal inhalation form and similar administration forms. Topical administration is preferred for methods of treating dermatitis. Pharmaceutical compositions which are 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 and, as an option other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to the salt prepared from the non-toxic, pharmaceutically acceptable acids or bases which include the inorganic acids or bases or organic acids or bases. Examples of these inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acids. Suitable organic acids can be selected from, for example, the classes of organic acids aliphatic, aromatic, carboxylic and sulphonic, examples of which are formic acid, acetic acid, propionic acid, succinic, glycolic, glucuronic, maleic, furoric, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamico), methanesulphonic, ethanesulphonic, pantothenic, benzenesulfonic, stearic, sulphanilic, allenic and galacturonic. Examples of the inorganic bases include metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Suitable organic bases can be selected, for example, from N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglu aine (N-methylglucamine), lysine and procaine. The compositions for use in the methods of the present invention may include suitable excipients or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Dosage forms include tablets, pills, dispersions, suspensions, solutions, capsules, patches, syrups, elixirs, gels, powders, magmas, wafers, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal or oral sprays, aerosols and the like. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, the tablets can be covered by normal aqueous or non-aqueous techniques. In addition to the common dosage forms specified above, the compound for use in the methods of the present invention may also be administered by means of controlled release and / or delivery devices such as those described in US Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the description of which is incorporated herein by reference. The pharmaceutical compositions for use in the methods of the present invention can be prepared by any of the methods of the pharmacy, but all methods include the step of associating the active ingredient with the carrier constituting one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with the 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 accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine 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 dispersant. The molded tablets can be prepared by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. It is desirable that each tablet contain from about 0.1 mg to less than about 10 mg of the active ingredient and each capsule contains from about 0.1 mg to about less than 10 mg of the 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 multiple modifications of both materials and methods can be practiced within the scope of this invention.

. EXAMPLES 5.1 Example 1: Preparation of loratadine and its metabolites Loratadine can be synthesized by the methods described in U.S. Patent No. 4,282,233. The metabolites are prepared in the same manner by the conventional reaction steps in the art, as described in U.S. Patent No. 4,659,716 which is incorporated herein by reference in its entirety. A common method for the preparation of DCL is to reflux loratadine in the presence of sodium hydroxide and ethanol as depicted below.

Ctaiit-n or DCL Loíata -nß Extraction of commercially available clarithin tablets (600? 10 mg): The loratadine tablets were diluted with water and chloroform. The mixture was stirred, 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 obtain pure loratadine as a white solid.

Saponification of loratadine: Loratadine (4.0 g) was added to a solution of sodium hydroxide (5.9 g) in 280 ml of absolute ethanol and the mixture was stirred at reflux for 4 days. The mixture was cooled and concentrated to remove the ethanol. The residue was diluted with water and the aqueous layer extracted with methylene chloride, 5 times. The combined organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated to obtain 2.82 g (87%) of the pure loratadine derivative (or metabolite) as a pale brown solid. . 2 Example 2 Antihistaminic activity The antihistaminic activity of loratadine and DCL were compared in isolated strips of guinea pig ileum contracted with histamine. This preparation is generally accepted by those skilled in the art as predictive of its efficacy as a peripheral H-l histamine receptor.

Methods: The experiments were performed on ileus pieces taken from male guinea pigs (Hartley breed, 419-560 grams, Hill Breeding Laboratories, Chelmsford, MA). The tissues were suspended in tissue chambers containing 40 ml of Tyrode's solution aerated with 95% oxygen and 5% carbon dioxide at 35 ° C. The Tyrode solution contained (in mM) 137 NaCl, 2.7 KCl, 2.2 CaCl;, 0.025 MgCl :, 0.4 NaHP0, 11.9 NaHC03 and 5.5 glucose. Concentrations in response to histamine were recorded with isotonic transducers (model 357, Harvard Apparatus Company, South Natick, MA) using an ink-type pen (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 ileum were removed from a single animal, suspended in individual tissue chambers and left until equilibrium with the bath solution for one hour before the administration of any medication. In four initial experiments in which tissues were exposed to histamine at concentrations of 1x10", 1x10-" "and lxlO ~ E mol / 1, histamine at a concentration of 1x10" '"mol / 1 produced strong contractions in the linear portion of the concentration-effect curve log and this concentration of histamine was chosen for use in the other experiments.To determine the antihistamine effects of loratadine and DCL, the tissues were briefly exposed (approximately 15 seconds) to lxlO-6 mol / 1 of histamine at intervals of 15 minutes After two successive exposures to histamine produced contractions of approximately the same magnitude, loratadine or DCL, in final concentrations that varied three or ten times, was added in all but one of the tissue chambers, Untreated tissue served as control for the treated tissues After each exposure of the tissues treated with the drug to histamine, the fluid from the tissue chamber was replaced with fluid without histamine but with a content of the same drug at the same concentration. Histamine tests were performed at 5, 20, 35, 50, 65, 80, 95, 110 and 125 minutes of exposure to the drug or at comparable times in the control tissues. Subsequent analyzes of the results of each experiment included: (i) normalization of the data from each tissue for the differences in inherent contractility expressing all concentrations as percent of the last contraction before the drug, (ii) normalization of the data for possible changes related to time in contractility expressing the contractions registered during exposure to the drug as a percent of the corresponding value for the untreated tissue, finally (iii) the calculation of the percentage reduction, related to the drug, of each contraction. The resulting data series for each drug concentration and the corresponding percent reduction in the histamine response were then used to calculate in each experiment the drug concentration that had produced a 50% reduction in the histamine response, the IC5o - This was done by fitting the straight lines to the data using the least square method and calculating the IC50 of the line equation. The average +/- standard error of the values for the experiments in each drug were calculated, and the differences between the drugs were determined using the analysis of variance in a sense of Kruskal Wallis by ranges. A compendium of the results is shown in the following two tables. The percentages of the reduction of histamine-induced contractions of isolated guinea pig ileum produced by exposure for 125 minutes to the different concentrations of each drug are established in the following: TABLE 1 - REDUCTION OF ILEO CONTRACTIONS IN COBAYS, INDUCED BY HISTAMINE (per hundred to) Drug No. Exp. Drug concentration (mol / 1) 3x10"10 lxl O" 9 3x10"8 lxl O" 9 3x10"* 1x10" " 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 63.69 76.21 4 35.43 44.13 76.43 TABLE 2 - REDUCTION OF ICUM CONTRACTIONS IN COBAYS, INDUCED BY HISTAMINE (IC50) Medication Experiment ICsc (M) Loratadine 1 1.90x10"2 2.21xl0"? 3 2.10xl0"? 4 1.22xl0_i Average 1.86xl0"? E.e. 0.22 DCL 1 6.36x10"" 2 19.2xl0": i 3 5.26xl0" lc 4 8.66xl0": Average 9.75x10": e.e. 3.20 Note: There is a statistically significant difference related to the drug in the IC5- values (P = 0.0209). These results indicate that MCI is approximately 20 times more potent at the histamine receptor than loratadine.

. EXAMPLE 3 Receptor binding studies Receptor binding studies were performed on the binding affinities of loratadine and DCL at histamine H-1 receptors. 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. Guinea pig cerebellum membranes were incubated with 0.5 nM 3 H-pyrilamine for 10 minutes at 25 ° C. After incubation, the assays were rapidly vacuum filtered through GF / B glass fiber filters (Whatman) and washed several times with ice-cooled buffer using a Brandel Cell Harvester. The bound radioactivity was determined with a liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation cocktail (Formula 989, DuPont NEN). The IC5o values for the tested compounds and pyrilamine in the histamine H-1 receptor were determined: TABLE 3 - INHIBITION OF THE PIRILAMINE UNION TO THE RECEIVER H-l Receptor H-l Compound IC50 (nM) (nH) Loratadine 721 (1.55) DCL 51.1 (1.12) Pyrilamine 1.4 (0.98) As already shown, it was found that MCI has an affinity 14 times greater than loratadine for histamine H-1 receptors. These results are consistent with the findings that demonstrate a higher potency of MCI over loratadine for the inhibition of histamine-induced contractions of guinea pig ileus. These studies confirm that DCL has a potency for histamine receptors greater than loratadine. . 4 Example 4 Activity in tumor growth Inhibition of lymphocyte mitogenesis was used to explore the potencies of loratadine and DCL as tumor-promoting agents.

Myogenesis studies: Fresh splenic cells (5x10) obtained from BALB / c mice 5 weeks old (Charles River, ST Constant, PQ) were suspended in RPMI 1640 medium containing 2% fetal bovine serum (Grand Island Biological Co ., Grand Island, NY) seeded in plates with micro wells in duplicate (Nunc) to which was added concanavalin (With) A (2 μg / ml; Sigma Chemical Co., St. Louis, MO) and incubated (37 ° C, 95% air, 5% CO_) in the absence or presence of increasing concentrations of the test dissolved in saline or other vehicles. 43 hours after the addition of. With A, 0.25 nmol of "H-thymidine (6.7 Ci / nmol, ICN Radiopharmaceuticals, Montreal, PQ) was added to each well, After incubation for an additional 5 hours, the cells were washed from the wells on filter papers using a automated cell sorter The filters were placed in small flasks containing 5 ml of scintillation fluid (Readysafe, Beckman), and the radioactivity incorporated in the DNA was determined at 48 hours (n = 3). Inhibition of mitogenesis were determined over a wide range of concentrations (0.1 to 10 μM).

TABLE 4 - Inhibition of lymphocyte stimulation induced by concanavalin A (IC50) Loratadine 1.0 uM DCL 5.6 μM These results indicate that MCI is 5 to 7 times less active than loratadine in the promotion of tumor growth.

. Example 5 Cardiovascular effects The effects of MCI on cardiac potassium currents were studied.

Medes: Individual ventricular myocytes of guinea pig and rabbit were dissociated by enzymatic dispersion (see Carmeliet, J. Pharmacol, Exper. Ther., 1992, 262, 809-817 which is incorporated herein by reference in its entirety. suction patch electrode, with a resistance of 2 to 5 MO was used for the tension clamp (7? xoclamp 200A) .P-clamp software (Axon Instruments) was used to generate the voltage clamp protocols and for record and analyze the data The standard solution contained, in mM: NaCl 137.6, KCl 5.4, CaCl-1.8, MgCl2 0.5, HEPES 11.6 and glucose 5, and NaOH was added until pH 7.4 The intracellular solution contained KCl 120, MgCl 2 , CaCl 0.154, Na, ATP 5, EGTA 5, and HEPES 10, with KOH added until pH 7.2.

Effect on the rectified K * rectification current (Ikr) in rabbit ventricular myocytes The tension clamp protocol consisted of clamps with a retention potential of -50 mV to +10 mV with a duration of 4 seconds. The change in tail flow was measured as a function of the concentration of the drug.

This concentration changed between 10"and 10 ~ 5 M in five steps.

The exposure to each concentration lasted 15 minutes. At the end a crawl wash was attempted for 30 minutes.

Effect on inward rectifying current in guinea pig myocytes: The inward rectifier was measured by applying ramp tension clamps starting from -50 mV and hyperpolarizing the membrane to -120 V at a speed of 10 mV / sec. The initial concentration was the concentration with 50% efficiency, determined in the previous experiments. Higher concentrations were applied if this initial concentration had no effect.

Effect on IKS in guinea pig ventricular myocytes: The tail currents were read after the depolarizing forceps of 2 seconds duration to potentials between -30 mV and +60 mV; Retention potential -50 mV. The results of these studies indicate that DCL is less active than terfenadine in inhibiting the delayed cardiac rectifier and thus has no potential for cardiac side effects. In this way, the methods of the present invention are less toxic than methods using other non-sedating antihistamines. , 5.6 Example 6 Inhibition of cytochrome P450 This study is performed to determine the extent to which loratadine and DCL inhibit human cytochrome P4503A4 (CYP3A4). CYP3A4 is involved in multiple drug-drug interactions and the quantification of CYP3A4 inhibition by loratadine or DCL indicates the potential of these drug-drug interactions. Inhibition is measured using the model of testosterone substrate and CYP3A4 derived from cDNA in microsomes prepared from a human lymphoblastoid cell line designated h3A4v3.

Study design: The inhibition study consists of the determination of 50% of the inhibitory concentration (IC5o) for the test substance. A single concentration of testosterone (120 μM, approximately twice the apparent Km) and 10 concentrations of the test substance, separated by approximately 1/2 log, are tested in duplicate. The metabolism of testosterone is tested by the production of the metabolite 6 (β) -hydroxytestosterone. This metabolite is easily quantified by HPLC separation with absorbance detection.

Storage / preparation of test substances and addition to incubations: Test substances will be 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 the IC50: 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 μM. Each test concentration will be tested in duplicate incubations according to the following method: Mede: 0.5 ml of the reaction mixture containing 0.7 mg / ml protein, 0.3 mM NADP +, 3.3 mM glucose-6-phosphate, 0.4 U / ml glucose-6-phosphate dehydrogenase, 3.3 M magnesium chloride and 120 μM testosterone in 100 mM potassium phosphate (pH 7.4) will be incubated at 37 ° C for 30 minutes. A known quantity of 11 (ß) -hydroxytestosterone will be added as an internal standard to correct recovery during extraction. The reaction mixture will be extracted with 1 ml of methylene chloride. The extract will be dried over anhydrous magnesium sulfate and evaporated in vacuo. The sample will be dissolved in methanol and injected to an HPLC column of 4.6 x 250 mm 5u C18 and separated at 50 ° C with a mobile phase methanol / water at a flow rate of 1 ml per minute. The retention times are approximately 6 minutes for 6- (ß) -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 quantified by correcting the extraction efficiency by using the absorbance of the peak 11 (ß) -hydroxy and comparing with the absorbance of a standard curve for 6- ( β) -hydroxytestosterone.

Data reporting: For each test substance the concentration of the metabolite 6 (β) -hydroxytestosterone is determined in each incubation in duplicate and the percent inhibition relative to the solvent control is calculated. The IC¡ .: is calculated by linear interpolation. The pharmaceutical dosage forms useful for the administration of the compounds used in the methods of the present invention can be illustrated as follows: . 7 Example 7 Capsules A large number of unit capsules are prepared by filling hard gelatin capsules, two pieces, standard each with 0.1 to 10 milligrams of the active ingredient in powder, 150 milligrams of lactose, 50 milligrams of cellulose and 6 milligrams of stearate. of magnesium.

. Example 8 Soft gelatin capsules A mixture of active ingredient in an edible oil such as soybean oil, lecithin, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump in gelatin to form capsules of soft gelatin with a content of 0.1 to 10 milligrams of the active ingredient. The capsules are washed and dried.

. Example 9 Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit 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. To increase the acceptance or delayed absorption it is possible to apply suitable coatings. Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the aforementioned description. These modifications are also proposed to be within the scope of the appended claims. The aforementioned description includes all the information considered essential to enable those skilled in the art to practice the described invention. Because the aforementioned patents or publications can provide other useful information, these aforementioned materials are incorporated herein by reference in their entireties.

Claims (16)

1. A method of treating allergic asthma in a human while avoiding the concomitant possibility of adverse effects associated with the administration of non-sedating antihistamines, consists in administering to a human a composition, containing the composition: (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of a decongestant; and a pharmaceutically acceptable carrier.

2. A method of treating allergic asthma in a human, while avoiding the concomitant possibility of the adverse effects associated with the administration of non-sedating antihistamines, consists of administering to a human a composition, containing the composition: (i) a therapeutically effective amount of DCL or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of leukotriene inhibitor selected from the group consisting of the 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists and leukotriene D4 antagonists; and a pharmaceutically acceptable carrier.

3. A method of treating dermatitis in a human while avoiding the concomitant possibility of adverse effects associated with the administration of non-sedating antihistamines, consists in administering to a human a therapeutically effective amount of DCL or a pharmaceutically acceptable salt of the same.

4. The method of claims 1, 2 or 3, wherein the adverse effect is cardiac arrhythmia or tumor growth.

5. The method of claims 1, 2 or 3, wherein the human has a greater than normal propensity or incidence of cancer.

The method of claims 1, 2, 6, 3, wherein the interaction with a drug that inhibits cytochrome P450 is avoided.

The method of claims 1, 2 or 3, wherein the amount of DCL administered is from about 0.1 mg to less than about 10 mg per day.

The method of claim 7, wherein the administered amount of DCL is from about 0.1 mg to about 5 mg per day.

The method of claim 1, wherein the amount of DCL is from about 0.1 mg to about less than about [sic] 10 mg and the amount of the decongestant is from about 50 mg to about 300 mg per day.

10. One method of treating allergic asthma in a human, while avoiding the concomitant possibility of adverse effects associated with the administration of non-sedating antihistamines, consists of administering to a human a therapeutically effective amount of MCI and a therapeutically effective amount of a decongestant

11. A method of treating allergic asthma in a human, while avoiding the concomitant possibility of adverse effects associated with the administration of non-sedating antihistamines, consists in administering to a human a therapeutically effective amount of MCI and a therapeutically effective amount. of a leukotriene inhibitor.

12. A pharmaceutical composition consisting mainly of an amount of DCL from about

0. 1 to about less than 10 mg and about 50 mg to about 300 mg of decongestant.

13. A pharmaceutical composition consisting of a therapeutically effective amount of DCL and a therapeutically effective amount of a leukotriene inhibitor selected from the group consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating protein antagonists, and leukotriene D4 antagonists. .

The method of claims 1, 2 or 3, wherein the compositions are administered as a nasal or oral spray.

15. The method of claim 10, wherein the DCL is administered as a nasal or oral spray.

16. The method of claim 11, wherein the DCL is administered as a nasal or oral spray.