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Methods for treating allergic asthma using descarboethoxyloratadine

a technology of descarboethoxyloratadine and asthma, which is applied in the direction of biocide, drug composition, immunological disorders, etc., can solve the problems of other severe adverse electrophysiologic side effects, similar incidence of fatigue, headache, nausea, etc., and avoid the concomitant liability of adverse side effects

Inactive Publication Date: 2002-04-04
HANDLEY DEAN A +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

DCL is at least 20 times more potent at histamine receptors than loratadine, offering a lower dosage range with reduced side-effects, improved therapeutic efficacy, and a clearer therapeutic index, effectively managing allergic disorders with minimized cardiac arrhythmias and tumor promotion risks.

Problems solved by technology

Many antihistamines cause adverse side-effects.
Moreover, the incidence of fatigue, headache, and nausea was similar to those observed for terfenadine.
Furthermore, compounds within the class of non-sedating antihistamines, including loratadine, astemizole, and terfenadine, have been known to cause other severe adverse electrophysiologic side-effects.
Additionally, it is also known that ketoconazole and / or erythromycin interfere with cytochrome P450, and thereby inhibit the metabolism of non-sedative antihistamines such as terfenadine and astemizole.
Because of the interference with the metabolism of loratadine, there exists a greater potential for adverse interaction between loratadine or other non-sedating antihistamines and drugs known to inhibit cytochrome P450, such as but not limited to ketoconazole, itraconazole, and erythromycin.

Method used

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  • Methods for treating allergic asthma using descarboethoxyloratadine

Examples

Experimental program
Comparison scheme
Effect test

example 1

5.1 Example 1

Preparation of Loratadine and its Metabolites

[0053] Loratadine can be synthesized by methods disclosed in U.S. Pat. No. 4,282,233. The metabolites are prepared similarly, by reaction steps conventional in the art, as described in U.S. Pat. No. 4,659,716 which is incorporated here by reference in its entirety. One common method of preparing DCL is to reflux loratadine in the presence of sodium hydroxide and ethanol as depicted below. 1

[0054] Extraction of Commercially Available Claritin Tablets (600.times.10 mg):

[0055] Tablets of loratadine, were diluted with water and chloroform. The mixture was stirred, then filtered through celite, rinsed with chloroform until the filtrate contained no 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.

[0056] Saponification of Loratadine:

[0057] Loratadine (...

example 2

5.2 Example 2

[0058] Antihistaminic Activity

[0059] 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 predicative of its efficacy as a peripheral histamine H-1 receptor.

[0060] Methods:

[0061] Experiments were performed on pieces of ileum taken from male guinea pigs (Hartley strain, 419-560 grams; Elm Hill Breeding Laboratories, Chelmsford, Mass.). The tissues were suspended in tissue chambers containing 40 ml of Tyrode's solution aerated with 95% oxygen and 5% carbon dioxide at 35.degree. C. The Tyrode's solution contained (in mM) 137 NaCl, 2.7 KCl, 2.2 CaCl.sub.2, 0.025 MgCl.sub.2, 0.4 NaHPO.sub.4, 11.9 NaHCO.sub.3 and 5.5 glucose. Contractions in response to histamine were recorded with isotonic transducers (Model 357, Harvard Apparatus Company, South Natick, Mass.) using an ink-writing polygraph (Model 7, Grass Instrument Company, Quin...

example 3

5.3 Example 3

[0069] Receptor Binding Studies

[0070] Receptor binding studies on the binding affinities of loratadine and DCL at histamine H-1 receptors were performed.

[0071] The methods described by Dini et al., which is hereby incorporated by reference herein (Agents and Actions, 33: 181-184, 1991), were used for these binding studies. Guinea pig cerebella membranes were incubated with 0.5 nM 3H-pyrilamine for 10 min at 25.degree. C. Following incubation, the assays were rapidly filtered under vacuum through GF / B glass fiber filters (Whatman) and washed several times with ice-cold buffer using a Brandel Cell Harvester. Bound radioactivity was determined with a liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation cocktail (Formula 989, DuPont NEN).

[0072] IC.sub.50 values were determined for compounds tested and pyrilamine at the H-1 histamine receptor:

3TABLE 3 Inhibition of Pyrilamine Binding at H-1 Receptor H-1 receptor Compound IC.sub.50 (nM) (nH) Loratadine...

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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

1. FIELD OF THE INVENTION[0001] The present invention relates to methods of treatment involving the administration of a therapeutically effective amount of a metabolic derivative of loratadine known as descarboethoxyloratadine.2. DESCRIPTION OF THE RELATED ART[0002] Loratadine is an antagonist of the H-1 histamine receptor protein. The histamine receptors H-1 and H-2 are two well-identified forms. The H-1 receptors are those that mediate the response antagonized by conventional antihistamines. H-1 receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of man and other mammals.[0003] Loratadine binds preferentially to peripheral rather than to central H-1 receptors. Quercia et al., Hosp. Formul. 28: 137-53 (1993). Loratadine has been shown to be a more potent inhibitor of serotonin-induced bronchospasm 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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/445A61K31/4545A61K45/06A61P11/06A61P37/08A61P43/00
CPCA61K31/445A61K31/4545A61K45/06Y10S514/826Y10S514/864A61P11/06A61P37/08A61P43/00A61K31/44
Inventor HANDLEY, DEAN A.RUBIN, PAUL D.
Owner HANDLEY DEAN A
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