MXPA00004525A - Treatment of t-helper cell type 2 mediated immune diseases - Google Patents

Abstract

Retinoids with retinoid receptor antagonistic activity, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, have been found efficacious in treating T-helper cell type 2 (Th2)-mediated immune diseases, such as immunoglobulin E (IgE)-mediated allergic diseases.

Description

THE USE OF RETINOID ANTAGONISTS FOR THE TREATMENT OF IMMUNE DISEASES MEASURED BY THE T-2 STIMULATING CELLS FIELD OF THE INVENTION The present invention relates to the use of retinoid antagonists comprising retinoids with selective antagonistic activity to the Retinoic Acid Receptor (RAR), Retinoid Receptor X (RXR) antagonist activity or mixed RAR-RAR antagonist activity, for the preparation of a medicament for the treatment of immune diseases mediated by T-helper Type 2 (Th2) cells such as mediated allergic diseases or allergic diseases mediated by immunoglobulin E (IgE), as well as the use of said active substances for the treatment of such diseases.

BACKGROUND OF THE INVENTION Retinoids are a class of compounds structurally related to vitamin A, which comprise natural and synthetic compounds. It has been REF .: 119719 found that retinoids are clinically useful in the treatment of dermatological and oncological diseases. It is believed that the activity of retinoids is mediated by the nuclear retinoid receptors RARa, ß,? and RXRa, ß,?, which belong to the superfamily of steroids, thyroid hormone, vitamin D, peroxisome proliferator-activated receptors [Pfahl et al., Vitamins and Hormones 49, 327-382 (1994)]. Retinoids with receptor agonist activity bind and activate receptors, whereas retinoids with receptor antagonistic activity bind to receptors but do not activate them. Experimentally, it has been demonstrated that retinoids with retinoid receptor agonist activity are active not only in model systems for the treatment of dermatological and oncological diseases but also in models for the treatment of immunological diseases. Retinoids with retinoid receptor agonist activity are active in the treatment of adjuvant arthritis [Brinckerhoff et al., Science 221, 756-758 (1983)] and experimental allergic encephalomyelitis [Massacesi et al., J. Clin. Invest. 88, 1331-1337 (1991); Racke et al., J. Immunol. 154, 450-458 (1995)], animal models for rheumatoid arthritis and multiple sclerosis, respectively. It is considered that both diseases belong to the immune diseases mediated by cells, mediated by Thl. Experimentally, retinoids with retinoid receptor antagonist activity (retinoid antagonists) are effective in counteracting, many properties of retinoids with retinoid receptor agonist activity (retinoid agonists) such as inhibition of cell proliferation, induction of cell differentiation, induction of apoptosis and inhibition of angiogenesis [Bollag et al., Int. J. Cancer 7_0, 470-472 (1997)]. Retinoid antagonists also suppress toxic side effects of retinoid agonists such as the signs and symptoms of hypervitaminosis A syndrome and teratogenesis [Standeven et al., Toxicol. Appl. Pharmacol. 138, 169-175 (1996); Eckhardt and Sch itt, Toxicol. Letters 70, 299-308 (1994)). Therefore, they can be clinically useful to prevent or treat adverse events caused by retinoid agonists. Retinoid antagonists have been proposed for clinical use in the prevention and therapy of toxicity and side effects induced by retinoids, particularly the so-called hypervitaminosis A syndrome. It has also been proposed to use retinoid antagonists in combination with receptor agonists. retinoid or other nuclear receptor agonists for the prevention and treatment of preneoplastic or neoplastic lesions, vitreous retinopathy and retinal detachment. In addition, retinoid antagonists could be used as simple agents, based on their antiproliferative effect, for the treatment of certain neoplasms insensitive to retinoid receptor agonists [WO 97/09297]. For the first time, almost unexpectedly, it has now been found that retinoid antagonists are effective in the treatment of immune diseases mediated by T-helper type 2 (Th2) cells, such as allergic diseases mediated by immunoglobulin E (IgE) or diseases mediated by the cytokines related to Th2.

DESCRIPTION OF THE INVENTION Within the scope of the present invention, the term "retinoid antagonists" is used for retinoids or compounds with RAR, RXR or mixed RAR-RXR antagonist activity. It includes compounds with neutral receptor antagonist activity (neutral antagonists), reverse receptor agonist activity (inverse agonists) and negative hormonal activity (negative hormones) [Klein et al., J. Biol. Chem. 271, 22692-22696 (1996) ] In the scope of the present invention the term "retinoid antagonists" comprises the compounds of formulas: a) RAR-a antagonists of formulas IH; wherein R is alkyl of 5 to 10 carbon atoms, and R 2 and R 3 independently of one another are hydrogen or fluorine; such compounds are described in U.S. Patent No. 5 391 766 and J Med. Chem. 1997, 40, 2445; _ b) RAR antagonists, ß of the formulas SAW; Y wherein R 4 is diamantyl, X is O or NH, R 5 is phenyl or benzyl, and wherein ring A or ring B is optionally present; such compounds are described in Med. Chem. Res. 1991, 1 ' 220; Biochem. Biophys. Res. Com. 1997, 231, 243; J. Med.

Chem. 1994, 37, 1508; c) RAR ß antagonists,? of formula wherein R6 and R7 independently of one another is hydroxy, alkoxy of 1 to 4 carbon atoms, optionally alkyl of 1 to 5 carbon atoms branched or adamantyl; such compounds are described in J. Med. Chem. 1995, 38, 4993; d) RAR antagonists? of formulas such compounds are described in Cancer Res 1995, 55, 4446; e) RAR antagonists a, β,? of formulas XI; wherein Y is -CH2- or sulfur and Z is -CH = or nitrogen, and R8 is hydrogen or alkyl of 1 to 4 carbon atoms; such compounds are described in J. Mcd. Chem. 1995, 38, 3163 and 4764; J. Biol. Chem. 1996, 271, 11897 and 22692; f) RXR antagonists of formulas where the point link is optional; and, when the dot bond is present, R is methyl and R10 is hydrogen; and, when the dot bond is absent, R 9 and R 10 taken together are methylene to form a cis-substituted cyclopropyl ring; R11 is alkoxy of 1 to 4 carbon atoms; such compounds are described in the patent application EP No. 97 107 843.1; J. Med. Chem. 1996, 39, 3229; and Nature 1996, 383, 450.

In accordance with this invention, it has been found that the administration of retinoid antagonists, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolysable esters thereof, are effective to treat patients with diseases mediated by T-helper type 2 (Th2) cells. It has also been found that the administration of retinoid antagonists is effective in treating patients with diseases mediated by Th2-related cytokines, such as interleukin-4 (IL-4) and IL-5. The invention, therefore, in one aspect, relates to the use of retinoid antagonists, their pharmaceutically acceptable salts and pharmaceutically acceptable hydrolysable esters thereof, for the preparation of a medicament for the treatment of immune diseases mediated by T-helper cells. type 2 (Th2). In another aspect the invention relates to the use of retinoid antagonists, their pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof for the preparation of a medicament for the treatment of diseases mediated by Th2-related cytokines, such as IL-4 and IL- 5. The invention also relates to a method for treating relatives having immune diseases mediated by T-helper type 2 (Th2) cells which comprises administering to said human patient a compound selected from the group of retinoid antagonists, pharmaceutically acceptable salts and hydrolysable esters pharmaceutically acceptable thereof, said compound being administered in an amount effective to treat said disease. The term "treatment" or "treating" includes preventive and / or therapeutic treatment. As used herein, the term "immune diseases mediated by T-helper type 2 cells" refers to diseases that involve immunoglobulin E (IgE) and to the priming cells due to the development and activation of allergen-specific Th2 cells and comprises allergic diseases, such as atopic dermatitis, other dermatological diseases associated with atopy; allergic rhinitis or hay fever, allergic bronchial asthma in its acute or chronic forms, mild or severe, with or without acute or chronic bronchitis. Elevated serum levels of immunoglobulin E (IgE) and hypereosinophilia may be associated with these diseases. Retinoid antagonists are effective in all those immune diseases that are linked with an increase in the activity of Th2 cells and an increased secretion of related cytokines, such as IL-4 and IL-5. The therapeutic effect of retinoid antagonists is due to a decrease in Th2 cell activity, a decreased secretion of related cytokines, such as IL-4 and IL-5, and / or an increase in the activity of Thl cells. due to the increased production of IL-12 by activated myelomonocytic cells [S. Romagnani, Ann. Rev. Immunol. 12, 227-257 (1994); Romagnani, ed., Thl and Th2 Cells in. Health and Disease. Chem. Im unol. , Karger, Basel, 63, p. 187-203 (199 * 6); Abbas et al., Nature 383, 787-793 (1996)]. The efficacy of the retinoid antagonists according to the present invention can be demonstrated by their ability to up-regulate the activity of Thl cells or to induce / stimulate the production of cytokines, such as IL-12, IFN ?, TNF; and / or down-regulating the activity of Th2 cells, or inhibiting the production of cytokines such as IL-4 and IL-5. Retinoid antagonists are active in the treatment of allergic bronchial asthma. The hallmarks of inflammation associated with asthmatic disease are the presence of activated eosinophils, an increased sensitivity of the airways (hypersensitivity), edema, mucosal hypersecretion and cough. This inflammatory process is mediated by the generation and activation of Th2-type cells. The ability of retinoid antagonists to promote a Thl-like response and therefore to suppress the Th2-type response is thought to be the mechanism underlying the efficacy of these compounds in allergic inflammation of the lungs / asthma. The retinoid antagonists act on Thl-like cells, inhibiting the signs and symptoms of allergic inflammation of the lungs / asthma [Gavett et al., J. Exp. Med. 182, 1527-1536 (1995); Kips et al., Am. J. Respir. Crit. Care Md. 153, 535-539 (1996)]. They are active in animals that were administered and sensitized with antigens / allergens (eg, ovalbumin). Retinoid antagonists, administered systemically or topically by aerosol, are effective in attenuating, inhibiting or reversing bronchoconstriction, airway edema and mucosal hypersecretion; inflammation of the respiratory tract, accumulation of eosinophils and neutrophils in bronchoalveolar tissue and bronchoalveolar lavage respectively, as well as hypersensitivity of the respiratory tract to nonspecific stimuli. For treatment, the active compound, i.e., a retinoid antagonist, a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrolyzable ester thereof, is administered systemically or topically. Preferably, said compound is administered as a composition containing said active compound and a pharmaceutically acceptable carrier or diluent compatible with said active compound. To prepare such a composition, any conventional pharmaceutically acceptable carrier can be used. When the drug is administered orally, it is usually administered at regular intervals, conveniently with meals or. once a day. It has been established that this compound is effective in doses that do not cause side effects or only very mild when administered orally or topically. Therefore, oral or topical administration of the active compound is generally preferred. To treat diseases of the skin, mouth, nose, pharynx, larynx, bronchi, etc., oral administration combined with topical can also be advantageously used. In the treatment of immune diseases mediated by T-helper type 2 cells, retinoid antagonists, when administered orally, do not induce the adverse events of the toxic syndrome of hypervitaminosis A, such as mucocutaneous, musculoskeletal, neurological manifestations and the elevation of transaminases, triglycerides and cholesterol. Furthermore, they are not, or are less, teratogenic in comparison to the retinoid agonists of the receptor that is used clinically in the treatment of dermatological and oncological diseases, such as all-trans retinoic acid (tretinoin), 13-cis retinoic acid ( isotretinoin), etretinate and acitretin. In the treatment of immune diseases mediated by T-helper type 2 cells, the retinoid antagonists, the pharmaceutically acceptable salts or pharmaceutically acceptable hydrolysable esters thereof, may be used alone or in combination with other measures, e.g. , in combination with other pharmaceutically active substances such as topical or systemic corticosteroids, antihistamines and bronchodilator agents. If used in combination with other substances, the retinoid antagonists and the other substances may be administered separately or incorporated in effective amounts in a pharmaceutical composition. Within the scope of the present invention, "pharmaceutically acceptable salts" include any salt chemically acceptable in the art for retinoid antagonists and applicable to human patients in a pharmaceutically acceptable preparation. Any conventional pharmaceutically acceptable salt of this type of retinoid antagonists can be used. Among the conventional salts that may be used are the basic salts included, for example, the alkali metal salts, such as the sodium or potassium salts, the alkaline earth metal salts, such as the calcium or magnesium salts, and the salts thereof. Ammonium or alkyl-ammonium salts. In accordance with this invention the retinoid antagonists can also be administered in the form of their pharmaceutically acceptable hydrolysable esters. Any pharmaceutically acceptable hydrolysable ester can be used in the compositions and methods of this invention. Among the preferred esters are: aromatic esters such as benzylic esters in which the benzyl moiety is unsubstituted or substituted with lower alkyl, halo, nitro, thio, or substituted thio; or lower alkyl esters, e.g. , ethyl, t-butyl, cyclopentyl, cyclohexyl or cycloheptyl, or 9-fluorenylmethyl esters. Within the scope of the present invention the term "alkyl" means branched or cyclic straight-chain alkyl residues, in particular those containing from 1 to 12 carbon atoms, such as methyl, ethyl, propyl, isopropyl, t-butyl, decyl , dodecyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "lower alkyl" means alkyl groups containing from 1 to 7 carbon atoms. The aforementioned retinoid antagonists, salts and esters thereof are useful especially in oral or topical pharmaceutically acceptable forms. These pharmaceutical compositions contain said active compound in association with a compatible pharmaceutically acceptable carrier material. Any conventional carrier material can be used. The carrier material may be an inert organic or inorganic carrier material suitable for oral administration. Suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, and the like. In addition, the pharmaceutically active preparations may contain other pharmaceutically active agents. Additionally, additives such as flavoring agents, preservatives, stabilizers, emulsifying agents, buffers and the like can be added, in accordance with accepted practices for the formulation of pharmaceutical compounds. The pharmaceutical preparations can be made in any conventional manner including, among others: (a) a solid form for oral administration such as tablets, capsules (e.g., soft or hard gelatin capsules), pills, sachets, powders, granules and the like; (b) preparations for topical administrations such as solutions, suspensions, ointments, creams, gels, micronized powders, sprays, aerosols and the like. The pharmaceutical preparations can be sterilized and / or can contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure and / or buffers.

For topical administration to the skin or mucous membrane the aforementioned derivative is preferably prepared as ointments, tinctures, creams, gels, solutions, lotions, sprays; aerosols and dry powder for inhalation, suspensions, shampoos, hair soaps, perfumes and the like. In fact, any conventional composition can be used in this invention. Among the preferred methods for applying the composition containing the agents of this invention are the forms of ointment, gel, cream, lotion, spray; spray or dry powder for inhalation. The pharmaceutical preparation for topical administration to the skin can be prepared by mixing the aforementioned active ingredient with non-toxic, therapeutically inert, solid or liquid carriers, which can be commonly used in such preparation. These preparations generally contain 0.01 to 5.0% by weight, preferably 0.1 to 1.0% by weight, of the active ingredient, based on the total weight of the composition. In the preparation of the topical preparations described above, such conventional preservatives, thickeners, perfumes and the like can be used in the art of formulating topical pharmaceutical compositions. In addition, conventional antioxidants or mixtures of conventional antioxidants can be incorporated into topical preparations containing the aforementioned active agent. Conventional antioxidants that can be used in these preparations include N-methyl-α-tocopherol amine, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, ethoxyquin and the like. The cream-based pharmaceutical formulations containing the active agent used in accordance with this invention are composed of aqueous emulsions containing a fatty acid alcohol, semi-solid petroleum hydrocarbons, ethylene glycol and an emulsifying agent. Ointment formulations containing the active agent according to this invention comprise mixtures of a semi-solid petroleum hydrocarbon with a solvent dispersion of the active material. Cream compositions containing the active ingredient for use in this invention preferably comprise emulsions formed from an aqueous phase of a humectant, a viscosity stabilizer and water, an oil phase of a fatty acid alcohol, a petroleum hydrocarbon. semi-solid and an emulsifying agent and a phase containing the active agent dispersed in an aqueous buffer-stabilizer solution. Stabilizers can be added to the topical preparation. Any conventional stabilizer according to this invention can be used. In the oil phase, the fatty acid alcohol components function as a stabilizer. These fatty acid alcohol components are derived from the reduction of a long chain saturated fatty acid containing at least 14 carbon atoms. In addition, conventional perfumes and lotions generally used in the topical hair preparation may be used in accordance with this invention. In addition, if desired, conventional emulsifying agents can be used in the topical preparations of this invention. For the topical treatment of allergic rhinitis and allergic bronchial asthma inhalation and nasal aerosols are used. Formulations for such aerosols are described in Drugs and Pharmaceutical Sciences, Marcel Dekker, New York, 1996, vol. 72, pgs. 547-574. In addition, the active compound can be released by inhalation of dry powder. Such formulations and devices are described in Pharmaceutical Technology, June 1997, p. 117-125. A preferred oral dosage form comprises tablets, pills, sachets or hard or soft gelatin capsules, methylcellulose or other suitable material that can be easily dissolved in the digestive tract. Each tablet, pill, pouch or capsule may preferably contain from about 5 to about 200 mg, more preferably from about 20 to about 100 mg, of active ingredient. The oral doses contemplated in accordance with the present invention will vary according to the need of the individual patient as determined by the attending physician. Generally, however, a daily dose from 0.05 to 20 mg per kg of body weight, preferably 0.1 to 7 mg, and more preferably from about 0.3 mg to about 1.5 mg per kg of the patient's body weight is used. This dose can be administered according to any dosage scheme determined by the doctor according to the patient's requirements. The dose for the treatment typically depends on the route of administration, the age, the weight and the condition of the individual's disease. Suitable dosage forms are known in the art or can be easily obtained in a manner known per se. The formulations of lotions, gels, creams, sprays; aerosols and dry powders for inhalation, soft or hard gelatine capsules, tablets and sachets that are particularly suitable within the scope of the present invention or that can be easily adjusted in accordance with the teachings set forth above are found in the art.

Experimental Methods I. In vitro assay for the induction of IL-12 by retinoid antagonists THP-1 cells were obtained from the American Tissue Culture Collection and cultured in complete medium. For the assay of IL-12 production, THP-1 cells, 1.25 x 10 6 cells / ml, were stimulated with the Cowan strain of S. aureus (SAC) (1/1000) and interferon-? recombinant human (huIFN-?) (1000 U / ml) [Ma et al., J. Exp. Med. 183, 147-157 (1996)]. Alternatively, 0.5 x 106 human peripheral blood mononuclear cells (PBMC) (1 ml of 48-well plate culture) were primed with huIPN-? (1000 U / ml) for 16 hours at 37 ° C and then stimulated with SAC (1/1000). Supernatants were collected after 48 hours, and frozen at -20 ° C until tested [Panina-Bordignon et al., J. Clin. Invest. 100, 1513-1519 (1997)]. The production of IL-12 was measured by the enzyme-linked immunosorbent assay (ELISA), using 20C2 antibody (rat anti-human IL-12 p40-p35 heterodimer), at 2.5 μg / ml in coating buffer, and conjugated 4D6 antibody with peroxidase (rat anti-human IL-12) at 250 ng / ml in assay buffer as described [Zhang et al., J. Clin. Invest. 93, 1733-1739 (1994)]. Standard (recombinant human IL-12, 800 pg / ml to 6 pg / ml) and samples (100 μl) diluted in assay buffer in duplicate cavities were added. The absorbance was read at 450-650 nm. The unknown IL-12 concentrations of the samples were read from the corresponding standard curve and multiplied by the corresponding dilution factor. The production of maximal IL-12 varied between 200 and 400 pg / ml. The lyophilized retinoid antagonists were diluted in DMSO under yellow light, on ice at a concentration of 2 mM. Serial dilutions (1 μM-1 pM) were prepared in complete RPMI medium. 10 μl of each dilution was added to 1 ml of culture. The results of the experiments indicate that the tested retinoid antagonists influence the production of IL-12. In particular, the tested retinoid antagonists stimulate the production of IL-12 by activated human monocytes, see Table I and II.

Table I Retinoid antagonists specifically increase the production of IL-12 by activated monocytes NM IL-12 IL-10 TNF-α (pg / ml) (pg / ml) (pg / ml) medium 0 <10 < 10 SAC + IFN-? 120 1040 1840 RAR antagonist at 1000 251 1343 1912 Compound A 100 102 1050 1600 10 n.d. 1060 1392 Medium 0 < 10 < 10 SAC + I N-? 126 1040 2000 RAR antagonist aβ? 1000 321 1116 2884 Compound B 100 205 983 2752 10 173 971 2592 Medium 0 < 10 < 10 SAC + IFN-? 120 1040 1840 Antagonist RXR 1000 298 1700 1560 Compound C 100 161 1521 1812 10 106 1020 1484 Table II The retinoid antagonists increase the production of IL-12 by PBMC and THP-1 cells that have been primed with IFNα. and stimulated with SAC * Retinoid antagonists (1 μg) were added at time 0 together with IFN? or after 16 hours together with SAC.

Compound A 1 ', 1' - p- [(E) -2- [3 ', 4'-dihydro-4', 4'-dimethyl-7 '- (heptyloxy) -2'Hl-benzothiopyran- 6 '-yl] propenyl] benzoic Compound B acid 4- (7, 7, 10, 10-tetramethyl-l-pyridin-3-ylmethyl-4, 5, 7, 8, 9, 10-hexahydro-lH-naphtho [ 2, 3-g] indol-3-yl) -benzoic acid Compound C (2E, 4E, 6Z) -7- [2-butoxy-3,5-bis (1, 1-dimethylethyl) phenyl] -3-methyl -2, 4, 6- octatrienoic II In vitro assay for the inhibition of the differentiation of human native T cells in helper 2 (Th2) T cells by retinoid antagonists.

T cells native to cord blood were isolated and treated as described [Panina-Bordignon et al., J. Clin. Invest. 100, 1513-1519 (1997)]. Briefly, mononuclear cells derived from cord blood were incubated with anti-CD45RA and anti-CD4 monoclonal antibodies. After an incubation of 20 minutes, the cells were washed and incubated with magnetic beads coated with goat anti-mouse Ig. The positive cells were separated and seeded at 1 x 106 cells / ml in a 24-well plate, together with autologous adherent cells, PHA and IL-4 in the presence or absence of 1 ', 1'-p- [(E) -2- [3', 4'-dihydro-4 ', 4' -diioxide -dimethyl-7 '- (heptyloxy) -2'Hl-benzothiopyran-6'-yl] propenyl] benzoic acid (Compound A) or (2E, 4E, 6Z) -7- [2-butoxy-3,5-bis] acid (1, 1-dimethylethyl) phenyl] -3-methyl-2,4,6-octatrienoic (Compound C) at lmM for 5 days. The cells were then washed and placed again in culture in the presence of IL-2 (100 U / ml). After 10 days, the cells were harvested and again stimulated with PMA (50 ng / ml) and ionomycin (1 μg / ml) for 4 hours. Brefeldin A (10 μg / ml) was added in the last 2 hours. The cells were then fixed with 4% paraformaldehyde and permeabilized with saponin. The fixed cells were stained with FITC-anti IFN? and PE-anti-IL4mAbs and subjected to cytofluorimetric analysis.

. The results of the experiment indicated that the tested retinoid antagonists reduce the differentiation of native T cells into Th2 secreting IL-4 cells. (Table III).

Table III Suppression of IL-4 expression in Th2 cells by retinoid antagonist III. Murina model of inflammation and hypersensitivity of airways induced by allergens.

C57BL / 6 mice (8-9 weeks) are actively sensitized to ovalbumin (OA) on day 0 and day 14 by an intraperitoneal injection of 10 μg of OA + 1 mg of Al (OH) 3 (gel suspension) in 0.2 ml of sterile saline. On day 21, mice were exposed with 5.0% aerosolized OA for 18 minutes. The aerosol is generated by a De Vilbiss Ultra-Neb 90 ultrasonic nebulizer, whose output is connected to a small Plexiglas chamber containing the animals. Mice are dosed with the RXR Compound C antagonist (10 and 30 mg / kg peritoneally) daily for three days, 48 hours, 24 hours, and immediately prior to administration with OA. The animals are used on day 21.

Accumulation of Inflammatory Cells of the Respiratory Tract On day 24, three days after the last administration of aerosolized OA, the animals are anesthetized with urethane (2.4 g / kg) and tracheotomized with a 23 gauge catheter. The lungs are washed with aliquots (2 x 1 ml) of solution balanced Hank saline sterile without Ca ++ and Mg ++. The washed fluid was recovered after 30 seconds by gentle aspiration and a well was made for each animal. The samples were then centrifuged at 2000 rpm for 15 minutes at 5 ° C. The red blood cells were used from the resulting pellet with 0.5 ml of distilled water and the remaining cells in the pellet were reconstituted with 5 ml of HBSS. The samples were centrifuged a second time at 2000 rpm for 15 minutes at 5 ° C. The resulting pellet was suspended in 1 ml of HBSS. The number of total cells is determined from an aliquot of the cell suspension using a hemocytometer. For cytological preparations, the cells were fixed on colored cytospinded slides with a modified Wright stain. Differential counts in at least 300 cells were made using standard morphological criteria to classify the cells. The results of . the experiments indicate that the tested retinoid antagonists inhibit the allergen-induced accumulation of inflammatory airway cells (Table IV).

Table IV _ _ Suppression of the accumulation of inflammatory airway cells by retinoid antagonists in a mouse model of airway inflammation induced by allergens 1 Hypersensitivity of the Respiratory Tract On day 24, three days after administration with aerosolized OA, the animals were anesthetized with sodium pentobarbital (100 mg / kg, i.p.) and tracheotomized (PE-190). A jugular vein is cannulated with a silastic tube for administration of the drug in i.v. form. The animals were placed in a full body plethysmograph with a built-in pneumotachometer and mechanical breathing was performed (Vf = 150 / min., Vt = 0.3 ml, Model 683, Harvard Apparatus, S. Natic, MA) immediately followed by treatment with pancuronium bromide (0.1 mg / kg, iv). The volume of pulmonary ventilation was obtained from an integration of the respiratory flow signal using a differential pressure transducer (Validyne DP 103-08, Northridge, CA). Transpulmonary pressure is measured with a differential pressure transducer (Validyne DP 45-30, Northridge, CA) as the difference between intratracheal pressure and intrapleural pressure (obtained by a cannula inserted in the intercostal space). Changes in lung resistance (cm H20 / ml / s) at increasing doses of methacholine (30, 100, 300, 1000 μg / kg, i.v.) are calculated from transpulmonary pressure, volume of pulmonary ventilation, and respiratory flow measurements using a Modular Instrument Signal Processing System (Malvern, PA). The results of the experiments indicate that the retinoid antagonists can prevent or reverse the allergic inflammation of the respiratory tract and inhibit the bronchoconstriction induced by antigens, typical of allergic respiratory diseases, such as allergic bronchial asthma. Examples of formulations: capsules, tablets, pouches, lotions, gels, creams, aerosols and dry powder for inhalation. The active compounds in the following examples are 1,1'-p- [(E) -2- [3 ', 4'-dihydro-4,4'-dimeti-7' - (heptyloxy) -2'Hl-benzothio-pyran-6 'acid dioxide -yl] propenyl] benzoic acid or (2E, 4E, 6Z) -7- [2-butoxy-3,5-bis (1,1-dimethylethyl) phenyl] -3-methyl-2,4,6,6-octatrienoic acid.

Example 1 Lotion (solution) preferred Active compound 0.1-2.0 g Propylene glycol 5.00-20.00 g 10.00.g PEG-glyceryl cocoate * 0.00-20.00 g 10.00 g dl-a-Tocopherol 0.001-0.50 g 0.02 g Ascorbyl palmitate 0.01-0.20 g 0.10 g Propyl gallate 0.001 -0.02 g 0.002 g Citric acid, anhydr. ** 0.00-0.20 g 0.01 g Isopropanol *** 40.00-90.00 g 50.00 g Water, you want, up to 100.00 g 100.00 g resp. my * or other surfactants ** or other complexing agents, eg. , EDTA *** or other alcohols, eg. , Ethanol.

Example 2 Preferred gel Active compound 0.1-2.0 g Propylene glycol 5.00-20.00 g 10.00 g PEG-glyceryl cocoate * 0.00-20.00 g 10.00 g dl-a-Tocopherol 0.001-0.50 g 0.02 g Ascorbyl palmitate 0.01-0.20 g 0.10 g Propyl gallate 0.001- 0.02 g 0.002 g Citric acid, anhydr. ** 0.00-0.20 g 0.01 g Isopropanol *** 40.00-90.00 g 50.00 g HPMC **** 0.50-5.00 g 3.00 g Conservative ***** es. c. s Water, you want, up to 100.00 q 100.00 g resp. my or other surfactants or other complexing agents, e.g. , EDTA or other alcohols, eg. , Ethanol. Hydroxypropyl Methylcellulose or other polymers, eg. , Neutralized Carbomer, Methylcellulose, Sodium carboxymethyl cellulose. ***** Conservatives, eg. , paraben esters (methyl, ethyl, propyl, butyl). Sorbic acid, benzoic acid.

Example 3 Preferred cream Active compound 0.1-2.0 g Glycerol 0.00-10.00 g 5.00 g Na2EDTA 0.001-0.50 g 0.03 g Glycerides * 5.00-20.00 g 10.00 g Cetyl alcohol 0.50-5.00 g 1.00 g Stearyl alcohol 0.50-5.00 g 1.00 g Monoglycerol esterarate 1.00 -8.00 g 4.00 g Ceteareth ** 0.50-5.00 g 2.00 g dl-a-Tocopherol 0.001-0.50 g 0.02 g Preserver *** cs c.s. Water, you want, up to 100.00 g 100.00 g for ex. , Caprilic / Capric / triglyceride, triglycerides Caprilic / Capric / Linoleic, natural glycerides, as well as eg. , Propylene Glycol, Dicaprylate / Dicaprate and waxes, such as Stearyl, Stearate, Oleic Oleate, Isopropyl Myristate Ceteareth 5-30, or other emulsifiers such as Polysorbase 20-80, Sorbitan esters of fatty acids, fatty acid esters of PEG . Preservers, eg. , paraben esters (methyl, ethyl, propyl, butyl). Sorbic acid, benzoic acid.

Example 4 Fill mass for soft gelatine capsules Active compound 5.0-200.0 mg Oil * 1-3 parts Wax mixture ** 1-5 parts Fill volume 1-6 minimum natural vegetable oils, eg. , soybean oil, peanut oil and artificial glycerides composition of natural and artificial waxes or partially hydrated fats.

Soft gelatin capsules 20 mg Ingredients mg / capsule Active compound 20,000 dl-a-Tocopherol 0.028 Hydrogenated Beaver Oil 4,200 Caprilic / Capric / Stearic Triglyceride 56,000 (Synthetic Triglyceride) Triglyceride, Medium Chain 199,772 Total 280,000 mg Example 5 Hard gelatin capsules containing 20 mg of active substance: Composition: One capsule contains: Active compound 20.0 mg Gelatine Bloom 30 70.0 mg Maltodextrin MD 05 108.0 mg dl-a-Tocopherol 2.0 mg Sodium ascorbate 10.0 mg Microcrystalline cellulose 48.0 mg Magnesium stearate 2.0 mg (capsule content by weight) 260.0 mg Process : The active substance is crushed wet in a solution of gelatin, maltodextrin, dl-a-Tocopherol and sodium ascorbate. The wet crushed suspension is spray dried. The spray-dried powder is mixed with microcrystalline cellulose and magnesium stearate. 260 mg each of this mixture are filled into hard gelatin capsules of suitable size and color.

Example 6 The tablet contains 20 mg of active substance: Composition: Tablet Core: Active compound 20.0 mg Lactose anhydrous 130.5 mg Microcrystalline cellulose 80.0 mg dl-a-Tocopherol 2.0 mg Sodium ascorbate 10.0 mg Polyvinylpyrrolidone K30 5.0 mg Magnesium stearate 2.5 mg (core weight) 250.0 mg Film coating; Hydroxypropylmethylcellulose 3.5 mg Polyethylene glycol 6000 0.8 mg Talc 1.3 mg Iron oxide, yellow 0.8 mg Titanium dioxide 0.8 mg (film weight) 7.4 mg Process: The compound is mixed with anhydrous lactose and mictocrystalline cellulose. The mixture is granulated in water with a solution / dispersion of polyvinylpyrrolidone, dl-a-Tocopherol and sodium ascorbate. The granular material is mixed with magnesium stearate and then compressed as nuclei with 250 mg of weight. The cores are coated with a film with a solution / suspension of the aforementioned compositions.

Example 7 Sachet containing the active substance Composition: Active compound 200.0 mg Lactose, fine powder 990.0 mg Microcrystalline cellulose 1250.0 mg Sodium carboxymethylcellulose 14.0 mg dl-a-Tocopherol 5.0 mg Sodium ascorbate 20._0 mg Polyvinylpyrrolidone K30 10.0 mg Magnesium stearate 10.0 mg Example 8 Spray for inhalation, metered dose inhaler Active compound 0.5% (0.1-2.0%) Sorbitan trioleate 5% dl-a -Topoferol 0.4% Propellant (mixture of trichlorofluoromethane and dichlorodifluoromethane) 94.1% Example 9 Dry powder inhaler Active compound * 0.5 mg (0.1 mg 2.0 mg) Lactose monohydrate 25 mg * crushed by jet, spray drying It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which refers to the manufacture of the objects to the that it refers to Having described the invention as above it claims as property what is contained in the following

Claims (9)

1. The use of a compound selected from the group consisting of retinoid antagonists, pharmaceutically acceptable salts and pharmaceutically acceptable hydrolysable esters thereof, as an active ingredient for the preparation of a medicament for the treatment of immune diseases mediated by T-helper type 2 cells (Th2), such as allergic diseases mediated by immunoglobulin E (IgE) or for the treatment of diseases mediated by Th2-related cytokines, such as IL-4 and IL-5.

2. The use in accordance with the claim 1, wherein the active ingredient is used in combination with a pharmaceutically acceptable carrier.

3. The use in accordance with the claim 1 or 2, wherein the medicament is prepared for oral or topical administration.

4. The use according to claims 1 to 3, wherein the medicament is prepared as a tablet, capsule, pill, pouch, ointment, cream, lotion, sprayer; nasal spray and spray or dry powder for inhalation.

5. The use according to any one of claims 1 to 4, wherein the medicament is prepared as a tablet, capsule, pill or pouch containing 5 to 200 mg, preferably 20 to 100 mg, of active ingredient.

6. The use according to any one of claims 1 to 5, wherein the medicament is prepared for a daily oral dose of 0.05 mg to 20 mg, preferably 0.3 mg to 1.5 mg, per kg of body weight.

7. The use according to any one of claims 1 to 4, wherein the medicament is prepared as an ointment, cream, lotion, sprayer; nasal spray and aerosol or dry powder for inhalation containing 0.01 to 5% by weight, preferably 0.1 to 1.0% by weight, of the active ingredient.

8. The use according to any one of claims 1 to 7, wherein the active ingredient is selected from the group consisting of retinoid antagonists and alkali metal salts, alkaline earth metal salts, benzylic esters, lower alkyl esters and esters 9-fluorenylmethyl thereof.

9. The use according to any one of claims 1 to 8, wherein the medicament is prepared for the treatment of allergic diseases mediated by immunoglobulin E (IgE), such as atopic dermatitis, allergic rhinitis or allergic bronchial asthma.