MXPA00001803A - Treatment of cell-mediated immune diseases - Google Patents
Treatment of cell-mediated immune diseasesInfo
- Publication number
- MXPA00001803A MXPA00001803A MXPA/A/2000/001803A MXPA00001803A MXPA00001803A MX PA00001803 A MXPA00001803 A MX PA00001803A MX PA00001803 A MXPA00001803 A MX PA00001803A MX PA00001803 A MXPA00001803 A MX PA00001803A
- Authority
- MX
- Mexico
- Prior art keywords
- eczema
- cis
- retinoic acid
- pharmaceutically acceptable
- composition
- Prior art date
Links
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Abstract
9-cis retinoic acid and pharmaceutically acceptable salts and pharmaceutically acceptable hydrolyzable esters thereof, 9-cis retinal and pharmaceutically acceptable acetals thereof, and 9-cis retinol and pharmaceutically acceptable hydrolyzable esters thereof as well as metabolites of 9-cis retinoic acid have been found to be efficacious in treating T-helper cell type 1 mediated immune diseases in well tolerated doses. Preferably, the active ingredient is formulated as a medicament for oral or topical administration.
Description
TREATMENT OF IMMUNE DISEASES MEDIATED BY CELLS
FIELD OF THE INVENTION
The present invention relates to the use of 9-cis retinoic acid and its derivatives or precursors for the manufacture of a medicament for the treatment of immune diseases mediated by T-helper cells type 1 as well as to the use of active substances for the treatment of such diseases.
BACKGROUND OF THE INVENTION
Despite intensive clinical research with retinoids in the last 27 years, these have not been reported for their clinical use in the therapy of immunologically mediated diseases. None of the diseases caused by cellular immunity that depend on T-helper type-1 (Thl) cells, or diseases caused by humoral immunity of T-helper type-2 (Th2) cells, have been reported to respond to retinoids. About the classification in which Thl diseases are dependent - such as immune diseases and other immune diseases mediated by cells, for example.
REF. : 32798 rheumatoid arthritis, multiple sclerosis, uveoretinitis, tíroiditis, Crohn's disease, diabetes ellitus that depend on insulin, eczema and systemic lupus erythematosus, as well as rejection of allogeneic organ transplants - and diseases that depend on Th2 - that is, diseases with dominant humoral immunity or diseases mediated by antibodies such as allergic disorders, for example, atopic dermatitis, allergic rhinitis, hay fever and allergic bronchial asthma - the reference is made to Romagnani, ed, Th 1 and Th 2 Cells in Health and Disease. Chem. Immunol. , Karger, Basel, 63, pp. 158-170 and .187-203 (1996).
For the first time, completely unexpectedly, it has now been found that a retinoid - such as 9-cis retinoic acid as well as its salts, its esters and its metabolic precursors or prodrugs as well as the metabolites of 9-cis retinoic acid, such as 4-oxo-9-cis retinoic acid - is clinically effective in the therapy of diseases that depend on Thl.
Within the scope of the present invention the term "metabolic precursors and prodrugs as well as the metabolites of 9-cis retinoic acid" encompassing compounds that are metabolically converted to 9-cis retinoic acid, and includes, in particular, 9-cis retinal and 9-cis rβtinol as well as pharmaceutically acceptable 9-cis retinal acetates and pharmaceutically acceptable hydrolysable esters of 9-cis retinol as well as the metabolites of 9-cis retinoic acid such as 4-oxo-9-cis retinoic acid or its glocuronides.
In accordance with this invention, it was found that the administration of 9-cis retinoic acid, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, 9-cis retinal, its pharmaceutically acceptable acetals, 9-cis retinol and its pharmaceutically acceptable hydrolysable esters , as well as the metabolites of 9-cis retinoic acid, are effective in the treatment of patients with immune diseases mediated by T-helper cells type 1 (Th 1).
The invention relates to the use of 9-cis retinoic acid, a pharmaceutically acceptable salt or its pharmaceutically acceptable hydrolysable ester, the 9-cis retinal or its pharmaceutically acceptable acetal or the 9-cis retinol or its pharmaceutically acceptable hydrolysable ester as well as the metabolites of the 9-cis retinoic acid for the manufacture of a medicament for the treatment of immune diseases mediated by T-helper cells type 1 (Th 1).
The invention also relates to a method for treating patients having immune diseases mediated by T-helper cells type 1 (Th 1) comprising what is administered to said patient by giving a compound selected from the group belonging to 9-cis retinoic acid, its pharmaceutically acceptable salts and their pharmaceutically acceptable hydrolysable esters, the 9-cis retinal and its pharmaceutically acceptable acetals as well as the 9-cis retinol and its pharmaceutically acceptable hydrolysable esters, as well as the metabolites of 9-cis retinoic acid ie compounds that are administered in an effective amount to treat the disease.
Within the scope of the present invention, the term "immune diseases mediated by T-helper cells type 1" relates to diseases with dominant cellular immune response, and encompasses, in particular, autoimmune diseases and other immune diseases mediated by cells, such such as rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyroiditis, Crohn's disease, diabetes mellitus that depends on insulin, eczema, systemic lupus erythematosus and rejections of allogenic grafts (for example rejection of allogenic skin, kidney, heart, liver or lung transplants) ). The term "eczema" relates, in particular, to eczema due to the hypersensitivity of the delayed type. The term "treatment" or "treating" includes preventive and / or therapeutic treatments.
The 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs, as well as the metabolites of 9-cis retinoic acid when administered to patients is effective, particularly in the therapy of the following diseases mediated by T-helper cells type 1 (Thl): rheumatoid arthritis, multiple sclerosis, uveoretinitis, thyroiditis, Crohn's disease, diabetes mellitus that depends on insulin, systemic lupus erythematosus as well as eczema with its various kinds of exogenous eczema, such as irritant dermatitis, dermatitis allergic contact, tick-like or ponophilic eczema, endogenous eczema, such as seborrheic eczema (also called seborrheic dermatitis or seborrheic dermatitis), asteatotic eczema and discoid eczema, and eczema located at various sites in the body. 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs are effective in all these immune diseases that could in some way be linked with an inse in Thl cell activity and an inse in seion of related cytokines, interleukin- 12, interleukin-2, interferon? and the necrosis factor
tumor a, ß.
For the treatment of Thl mediated diseases such as eczema, the active compound, i.e. 9-cis retinoic acid, a pharmaceutically acceptable salt or its pharmaceutically acceptable hydrolysable ester, the 9-cis retinal or its pharmaceutically acceptable acetal or the -cis retinol or its pharmaceutically acceptable hydrolyzable ester or the metabolites of 9-cis retinoic acid, are administered orally. For the treatment of eczema, the active compound is administered orally or topically. Preferably, said compound is administered with a composition containing said active compound and a pharmaceutically acceptable carrier or diluent compatible with said active compound. In the preparation of 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 at mealtime or once daily. It has been established that this compound is effective in doses that show no or only mild side effects when given orally or when given topically. Accordingly, oral administration of the active compound is generally preferred. For treatment of eczema, however topical administration can also be used salefully.
In the treatment of immune diseases mediated by T-helper cells type 1, 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs and their metabolites, when administered orally, are therapeutically effective in doses that do not induce adverse or only mild side effects such as dry lips and transient headache. Currently, all retinoids exert the therapeutic effect in dermatological and oncological indications, they have been administered orally in doses that induce more or less noticeable side effects, which belong to the toxic syndrome of hypervitaminosis A, such as mucocutaneous manifestations, musculoskeletal and neurological, particularly headache. In addition, they produce laboratory abnormalities such as elevated transaminase (ALAT, ASAT), elevated alkaline phosphatase, as well as elevated triglycerides and cholesterol. In contrast, daily doses of 9-cis retinoic acid and its derivatives and metabolic precursors and prodrugs and metabolites of 9-cis retinoic acid (typically 20 to 60 mg) therapeutically effective in immune diseases mediated by T-helper cells type 1 produce only very slight side effects, such as dry lips and transient headache, considering all other toxic signs and symptoms of hypervitaminosis A syndrome, including laboratory abnormalities, are not induced.These same low daily doses of 9-cis retinoic acid, however, do not have the therapeutic effect in non-malignant skin disorders, such as acne, psoriasis, lamellar ichthyosis, Darier's disease and lichen planus. In summary, it was found that low daily doses of 20 to 60 mg of 9-cis retinoic acid (and its derivatives and metabolic precursors and prodrugs) are well tolerated and are effective in the treatment of immune diseases mediated by T-helper cells type 1, therefore such doses are not effective in the treatment of non-malignant skin disorders, such as acne, psoriasis and other keratinizing dermatoses. In malignant diseases of the skin and solid tumors of other organs, when given daily high doses of 9-cis retinoic acid greater than 300 mg, they induce notable severe side effects, which do not lead to greater objectives of tumor regressions.
In the treatment of immune diseases mediated by T-helper cells type 1, 9-cis retinoic acid, a pharmaceutically acceptable salt or its pharmaceutically acceptable hydrolysable ester, the 9-cis retinal or its pharmaceutically acceptable acetal or the 9-cis retinol or its pharmaceutically acceptable hydrolysable ester or the metabolites of 9-cis retinoic acid can be used alone or in combination with other measures, for example, in combination with other pharmaceutically active substances such as topical or systemic corticosteroids and other immunosuppressive agents (cytostatic, antimetabolite, biological response modifiers, for example, interferons, interleukins and other cytokines). If used in combination with other substances, 9-cis retinoic acid or its derivatives or metabolic precursors or prodrugs or its metabolites and other substances can be administered separately or, preferably, incorporated in effective amounts in a pharmaceutical composition.
Within the scope of the present invention, pharmaceutically acceptable salts include any salt chemically permissible in the art for 9-cis retinoic acid and applicable to patients in a pharmaceutically acceptable preparation. Any conventional pharmaceutically acceptable salt of 9-cis retinoic acid can be used. Among the conventional salts that may be used are the basic salts included, for example, alkali metal salts such as the sodium or potassium salt, rare alkali metal salts such as the calcium or magnesium salt, and ammonium salts or salts thereof. ammonium rented.
In accordance with this invention 9-cis retinoic acid can also be administered in the form of its pharmaceutically acceptable hydrolyzable ester. 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 portion is unsubstituted or is substituted with short chain alkyls, halo, nitro, uncle, or uncle substituents; short chain alkyl esters, for example ethyl, tertiary butyl, cyclopentyl, cyclohexyl esters or cycloheptyl esters; or the 9-fluorenylmethyl ester.
Within the scope of the present invention the term "alkyls" means straight chain, branched or cyclic alkyl residues, in particular these contain from 1 to 12 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, tert-butyl group, decyl, dodecyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "short chain alkyls" means alkyl groups containing from 1 to 7 carbon atoms.
In accordance with this invention a metabolic precursor or prodrug of 9-cis retinoic acid or its metabolites of 9-cis retinoic acid, in particular, 9-cis retinal, 9-cis retinol, a pharmaceutically acceptable 9-cis retinal acetal or a pharmaceutically acceptable hydrolysable ester can be used in alternative form instead of 9-cis retinoic acid, and any pharmaceutically acceptable acetal of the 9-cis retinal and any pharmaceutically acceptable hydrolyzable ester of the 9-cis retinol or the 4-oxo-9-cis retinoic acid may be used in compositions and methods of this invention. Among the preferred acetals of the retinal are the dialkyl acetals, especially the di (short-chain alkyls) acetals such as di-ethyl acetal, and dibenzyl acetals, where the portions of the benzyl are not substituted or substituted with short-chain alkyls , halo, nitro, uncle or uncle substituents. Among the preferred hydrolysable esters of 9-cis retinol are esters formed with carboxylic acids from Ct-C20 such as the alkanoic acids from C2 and alkenoic acids from C, -C20.; particularly preferred are these carboxylic acid esters containing the same number of carbon atoms in the carboxylic acid moiety such as an acetate, stearate or palmitate.
The aforementioned 9-cis retinoic acid and its salts, its esters and its metabolic precursors or prodrugs, as well as its metabolites are used especially in oral or topical modes: pharmaceutically acceptable. 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 organic material or an inorganic 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, pharmaceutically active preparations may contain other pharmaceutically active agents. Additionally, additives such as seasoning agents, preservatives, stabilizers, emulsifying agents, buffers and the like can be added in accordance with accepted practices of the pharmaceutical component.
The pharmaceutical preparations can be made in any conventional form including inter alia: (a) a solid form for oral administration such as tablets, capsules (e.g., hard or soft gelatin), pills, pads, powders, granules, and the like; and (b) preparations for topical administrations such as solutions, suspensions, ointments, creams, gels, micronized powders, aerosols and the like. The pharmaceutical preparations may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, soaking agents, emulsifiers, salts for varying the osmotic pressure and / or buffers.
For topical administration to the skin or mucous membrane the aforementioned derivatives are preferably prepared as ointments, dyes, creams, gels, solutions, lotions, sprays, suspensions, shampoos, hair soaps, perfumes and the like. In fact, any conventional composition can be used in this invention. Among the preferred methods of application the composition containing the agents of this invention is in the form of an ointment, cream or lotion. The pharmaceutical preparation for topical administration to the skin can be prepared by mixing the aforementioned active ingredient with the non-toxic, therapeutically inert, solid or liquid carriers commonly used in such preparation. These preparations generally contain at least about 0.0005 weight percent, preferably from 0.0005 to about 0.05, and more preferably from about 0.001 to about 0.01 weight percent, of the active ingredient (this is 9-cis retinoic acid). derivatives or their metabolic precursors, prodrugs or metabolites) on the basis of the total weight of the composition. As the toxicity and irritability of the active ingredient varies, depending on the type of tissue - normal or pathologically altered - on which it is applied, it can often be used in topical compositions in amounts up to 0.15 per cent by weight and even higher amounts. It is also preferable to apply these preparations once or twice daily on the skin. These preparations can be applied according to the needs of the patient. In the preparation of this invention, the active ingredient can be applied in an aqueous solution or in an alcohol solution such as ethanol.
In the preparation of the topical preparations described above, additives such as preservatives, thickeners, perfumes and their like conventionally used in the pharmaceutical manufacturing technique of topical preparations can be used. In addition, conventional antioxidants or mixtures of conventional antioxidants can be incorporated into topical preparations containing the aforementioned active agent. Among the conventional antioxidants that can be used in these preparations are included N-methyl-α-trocopherol-amine, tocopherols, butylated hydroxyanisole, butylated hydroxytoluene, etoxikin and the like. The cream-based pharmaceutical formulations containing the active agent, used according to this invention, are composed of aqueous emulsions containing a fatty acid alcohol, semi-solid petroleum hydrocarbons, ethylene glycol and an emulsifying agent.
Ointment formulations that include the active agent according to this invention contain mixtures of a semi-solid petroleum hydrocarbon with a solvent dispersion of the active material. Cream compositions containing the active ingredient used in this invention preferably include emulsions formed from an aqueous phase of a humectant, a viscosity stabilizer and water, an oily phase of a fatty acid alcohol, a semi-solid petroleum hydrocarbon. and an emulsifying agent, and a phase containing the active agent dispersed in an aqueous buffer and stabilizer solution. The stabilizers can be added to the topical preparation. Any conventional stabilizer can be used in accordance with this invention. In the oily 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. Also, conventional perfumes and lotions generally used in topical hair preparations may be used in accordance with this invention. In addition to these, if desired, conventional emulsifying agents can be used in the topical preparations of this invention.
A preferred oral dosage form includes tablets, pills, sachets, or soft or hard gelatin capsules of methylcellulose or other suitable material easily dissolvable in the digestive tract. Each tablet, capsule pill or capsule may preferably contain about 5 to about 50 mg, and better preferably 10 to about 20 mg, of the active ingredient. The oral dosages contemplated according to the present invention will vary according to the needs of the individual patient as determined by the prescribing physician. Generally, however, a daily dose of about 0.05 mg to about 1.5 mg per kg of body weight and preferably about 0.3 mg to about 0.9 mg per kg of the patient's body weight is used. This dosage can be administered according to any dosage program determined by the physician according to the patient's requirements.
Daily oral doses of about 0.05 mg to about 1.5 g per kg of body weight and preferably of about 0.3 mg to about 0.9 mg per kg of body weight are administered in any dosing schedule continuously or intermittently for example in repetitive cycles of 3 continuous days weekly and four days without treatment, or in alternating cycles of 7 continuous days and 7 days without treatment. For the maintenance of a sufficiently high level of blood plasma or tissue, it may be necessary to avoid the simultaneous medication of P450 isoenzyme inducers and / or add inhibitors of P450 isoenzymes.
Dosage schedules depend on the type of Thl-mediated immune disease such as for example eczema, rheumatoid arthritis, multiple sclerosis or Crohn's disease, but also in the case of disease status, the level of 9-cis retinoic acid in plasma and tissue, simultaneous therapies with medications and patient conditions. Therapy with 9-cis retinoic acid may be given either as a continuous daily treatment or on an intermittent schedule as described above. The therapy with 9-cis retinoic acid may also consist of a continuous treatment, as well as an induction therapy, until an improvement is achieved, and subsequently followed by a treatment on an intermittent program, as maintenance therapy.
Treatment with 9-cis retinoic acid can be combined with other drugs used for the treatment of Thl-mediated diseases such as for example.
rheumatoid arthritis, multiple sclerosis or Crohn's disease, Such drugs are for example methotrexate, azathioprim, corticosteroids, cyclosporine, mycophenolic mofetil or interferons, for example interferon-ß.
The dose for treatment typically depends on the route of administration, the age, weight and conditions of the individual's disease. Suitable dosage forms are known in the art or can be easily obtained in a manner known per se. Formulations of lotions, gels, creams, hard or soft gelatin capsules, tablets and sachets that are particularly suitable in the field of the present invention or that can be easily adjusted according to the above teachings are disclosed for example in US-A- 5. 428, 071.
In a preferred embodiment, the treatment of eczematoid conditions is carried out orally or topically.
In one embodiment, this invention provides a method of treatment for the eczematoid condition in a human patient affected by such a condition, comprising oral administration or delivery to said patient of 9-cis retinoic acid in an amount effective to treat the condition in said patient. A patient who has lesions due to active eczema is treated to reduce the severity of eczema or other symptoms. In the case where a patient has previously had lesions due to active eczema, which have been brought to remission, this invention provides a prophylactic treatment against the recurrence of the active manifestations of eczema.
In accordance with this invention, any eczematoid condition can be treated by the method described. Examples of active or remissionable eczematoid condition conditions that are treated include chronic and acute irritant dermatitis, allergic contact dermatitis, ticklop or pontiform eczema, seborrheic eczema, asteatotic eczema, and discoid eczema.
The 9-cis retinoic acid can be administered orally in any amount that is effective to treat the eczematoid condition. For example, 9-cis retinoic acid or a precursor thereof whose supply is preferred from about 0.3 to about 0.9 milligrams of 9-cis retinoic acid per kilogram of body weight. This dose can be administered according to any program determined by the doctor according to the patient's requirements. According to specific modalities, daily oral doses of about 0.3 mg to about 0.9 mg per kg of body weight are administered either by any, a continuous program or an intermittent program, for example in repetitive cycles of 3 continuous days per week, and 4 days without treatment, or in cycles of 7 continuous days and 7 days without treatment alternately. Therapy with 9-cis retinoic acid may also consist of both a continuous treatment and an induction therapy, until a remission is achieved, and subsequently followed by a treatment following an intermittent program, such as maintenance therapy.
For the treatment of the eczematoid condition by oral administration of 9-cis retinoic acid, 9-cis retinoic acid is administered orally to the patient in a composition that includes 9-cis retinoic acid or a precursor thereof whose administration produces 9- cis acid. cis retinoic acid, 9-cis retinoic acid is administered orally to the patient in a composition that includes 9-cis retinoic acid or a precursor thereof that supplies or produces 9-cis retinoic acid. Examples of suitable precursors of 9-cis retipoic acid include pharmaceutically acceptable salts of 9-cis retinoic acid, hydrolysable esters of 9-cis retinoic acid, 9-cis retinal, hydrolysable esters of 9-cis retinal, 9-cis retinol and hydrolysable esters of 9-cis retinol.
In one embodiment of the oral treatment method of the eczematoid condition, the composition containing 9-cis retinoic acid or precursors thereof is presented in a unit oral dosage form. In a more specific embodiment the oral unit dosage form is a tablet, capsule, pill or pouch containing from five to fifty milligrams, preferably from 10 to 20 mg of 9-cis retinoic acid or a pharmaceutically acceptable salt or a hydrolysable ester of East.
The pharmaceutically acceptable salts include any chemically permissible salt for 9-cis retinoic acid and applicable to human patients in a pharmaceutically acceptable preparation. Any conventional pharmaceutically acceptable 9-cis retinoic acid salt can be used. Conventional salts that may be used include basic salts, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or alkyl ammonium salts. .
The pharmaceutically acceptable hydrolysable esters can be used in the compositions and methods of this invention. Among the esters are the aromatic esters such as benzyl (Obzl) or benzyl substituted with lower alkyls, halo, nitro, thio or thio substituted, that is lower alkyl (1-7 carbon atoms) thio; aliphatic esters such as those of lower alkyls, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, and 9-fluorenylmethyl.
In another embodiment, this invention provides a method for treating an eczematoid condition of the skin in a human patient in need of such treatment, comprising the topical application of 9-cis retinoic acid to the skin area of said patient subject to such condition , in an effective amount to alleviate the effects of the condition. A patient who has active eczema is treated to reduce the severity of the eczema lesion or other symptoms. In the case where a patient previously had active eczema lesions that were brought into a state of remission, this invention provides a prophylactic treatment against the reappearance of the active manifestations of eczema. According to this invention, any eczematoid condition can be treated by the described methods. Examples of the eczema condition in remission that are treated include irritant dermatitis, allergic contact dermatitis, ticklop or ponfólix eczema, seborrheic eczema, astheatotic eczema, and discoid eczema.
For the treatment of the eczematoid condition by topical administrations of 9-cis retinoic acid, 9-cis retinoic acid is administered topically to the patient in a topical composition which includes a compound selected from 9-cis retinoic acid and dermatologically acceptable salts of East. In the formulation of these topical compositions, the compound of formula I, its pharmaceutically acceptable salts or pharmaceutically acceptable esters thereof are mixed with a pharmaceutically acceptable carrier for topical administration. Any conventional pharmaceutically acceptable carrier can be used according to this invention.
These topical compositions containing 9-cis retinoic acid as well as their salts may contain any of the conventional excipients and additives commonly used in the preparation of topical compositions. Among the conventional additives or excipients that can be used in the preparation of these compositions according to this invention are preservatives, thickeners, perfumes and the like. Additionally, conventional antioxidants, such as butylated hydroxyanisoles (BHA), ascorbyl palmitate, propyl gallate, citric acid, butylated hydroxytoluene (BHT), ethoxyquin tocopherol, and the like, may be incorporated in these compositions. These topical compositions may contain conventional carriers acceptable for topical applications that are generally used in these compositions. These compositions may contain thickeners, wetting agents, emulsifying agents and viscosity stabilizers, such as those commonly used. Additionally these compositions may contain dyes and perfumes which are conventional in the preparation of cosmetic compositions.
The compositions for topical administration may contain any concentration of 9-cis retinoic acid or a salt thereof, which is effective to treat the eczematoid condition. For example, a composition containing the compound in a concentration of about 0.001 to about 0.05 weight percent of the composition may be used.
More specific concentrations of the compound that are suitable in the method include from about 0.003 to about 0.03 weight percent of the composition, and from about 0.005 to about 0.01 weight percent of the composition. Other suitable concentrations of the compound are at least about 0.0005 weight percent; 0.0005 to 0.15 percent by weight; 0.0005 to 0.05 weight percent; and 0.001 to 0.01 weight percent of the composition.
The pharmaceutically acceptable salts include chemically permissible salts for 9-cis retinoic acid and applicable to human patients in a pharmaceutically acceptable preparation. Any conventional pharmaceutically acceptable salt of 9-cis retinoic acid which may be used includes the basic salts, for example, alkali metal salts, such as sodium and potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium salts. or alkyl ammonium.
The topical compositions may be in any form that is conventional for topical compositions. For example, the topical composition may be present in the form of an ointment, cream, gel, lotion, or shampoo. Other examples of suitable forms for topical compositions include dyes, solutions, suspensions, micronized powders, suspensions, soaps, perfumes and aerosols.
The invention can be better understood through the following example, which is illustrative of the invention and not restrictive.
Example 1
Activity of 9-cis retinoic acid in chronic eczema of the hands.
a) Methods Fifteen patients, eight men and seven women, with chronic eczema of the hands, resistant to conventional treatment, were treated with 9-cis retinoic acid. Their average age was 52.3 years, ranging from 21 to 83. Before starting therapy with 9-cis retinoic acid, their eczema had already lasted from 3 months to 8 years, with an average of 29 months. In addition to avoiding irritants and allergens, their previous treatment consisted of topical corticosteroids (the 15 patients), topical tar (2 patients), isotretinoin (2 patients), tretinoin (1 patient) and X-rays (3 patients). The response to these treatments was in all cases unsatisfactory, in 4 moderate patients, in three light patients and in 8 patients there was no response at all. The therapy consisted of a daily oral dose of 40 mg of 9-cis retinoic acid, with breakfast, given in the form of two soft gelatin capsules containing 20 mg of 9-cis retinoic acid. The side effects were recorded, particularly those belonging to syndrome A of hypervitaminosis: headache, dry lips, other mucocutaneous manifestations, musculoskeletal symptoms and laboratory abnormalities.
b) results, As can be seen in table 1, the fifteen patients responded markedly to 9-cis retinoic acid (9-cis-RA) and all lesions and symptoms improved by treatment. The total count of lesions and symptoms of 14 of the patients who responded was reduced to an average of 81.3% (in a range of 53 to 100%). The various lesions and symptoms such as erythema, papules and vesicles etc., were all favorably influenced and regressed to 62-100%. The 9-cis retinoic acid in a dose of 40 mg daily was very well tolerated. The only side effect noted in these 15 patients consisted of headache in 2, and dry lips in 5 patients. No other ucocutaneous manifestation or skeletal muscle was observed with high doses, nor were other symptoms observed. Such symptoms were observed at high doses by (Kurie et al., Clin Cancer Res. 2, 287-293 (1996);, Miller et al .. Clin Cancer Res. 2, 471-475 (1996)). The well-known laboratory abnormalities, such as the elevation of transaminases (ALAT, ASAT), alkaline phosphatase, triglycerides and cholesterol, frequently caused by retinoids were not observed with this low dose of 9-cis retinoic acid. The response to therapy with 9-cis retinoic acid in patients with chronic eczema of the hands resistant to normal treatment was evaluated by the doctor, as well as by the patient and was considered good or very good in 13 of the 15 patients or 87% of the patients (tables 1 and 2).
_J
w w
Table: 9-cis retinoic acid (9-cis RA) therapy of chronic eczema on the hands (summary)
No. of patients 15 Sex 8 male and 7 female Age 21-83 years, with an average of 52.3 years Duration of eczema 3-96 months with an average of 29 months Previous treatment Topical corticosteroids (15), tar (29 , isotretinoin (2), tretinoin (1), acitretin (1) Response to previous treatment Moderate (4), mild (3), no (8) Therapy with 9-cis RA Daily oral dose 40 mg Duration of treatment From 1 - 3 months, with an average of 2 months Efficiency w
Reduction of the lesion / simptom count, in% For all 15 patients 0-100, with a mean of 76.5 For the 14 responses of patients 53-100, with a mean of 81.8 Response of patients to therapy with 9- cis RA Evaluated by: Patient Doctor Very good 10 (67%) 6 (40%) Good 3 (20%) 7 (47%) Moderate 1 (6.5%) 1 (6.5%) Slight 0 (0%) 0 (= %) No 1 (6.5%) 1 (6.5%) Side effects Dry lips 5 (33.3%) Headache 2 (13.3%)
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following is claimed as property.
Claims (52)
1. The use of 9-cis retinoic acid and its pharmaceutically acceptable salts and the pharmaceutically acceptable hydrolysable esters thereof as well as prodrugs and metabolites thereof and their pharmaceutically acceptable salts and pharmaceutically acceptable hydrolysable esters for the manufacture of a medicament for the treatment of an immune disease mediated by T helper cells type 1.
2. - The use of a compound selected from the group consisting of 9-cis retinoic acid and its pharmaceutically acceptable salts and pharmaceutically suitable hydrolysable esters thereof, 9-cis retinal and its pharmaceutically acceptable acetals thereof, and 9-cis retinol and its pharmaceutically acceptable hydrolysable esters thereof as an active ingredient for the manufacture of a medicament for the treatment of an immune disease mediated by T helper cells type 1.
3. - The use according to claims 1 or 2, wherein the active ingredient is used in combination with a pharmaceutically suitable carrier.
4. - The use according to claims 1,2 or 3, wherein the drug is prepared for an oral or topical administration.
5. - The proper use of any of the claims 1 to 4, where the drug is manufactured as a tablet, capsule, pill, pouch, cream, or lotion.
6. - The appropriate use of any of the claims 1 to 5, wherein the drug is manufactured as a tablet, capsule, pill or bag containing 5 to 50 mg, preferably 10 to 20 mg, of active ingredient.
7. - The appropriate use of any of the reinvidiations from 1 to 6, where the drug is manufactured for a daily dose of 0.05 mg to 1.5 g., Preferably 0.3 mg. At 0.9 mg, per kg. Of body weight.
8 - The proper use of any of the claims 1 to 5, wherein the drug is manufactured as an ointment, cream or lotion containing 0.0005 to 0. 05 weight percent of the active ingredient. Preferably from 0_001 to 0.01 weight percent, of the active ingredient.
9. - The appropriate use of any of the claims 1 to 8, wherein the active ingredient is selected from the group consisting of 9-cis retinoic acid and its alkali metal salts, and alkaline earth metal salts, benzyl esters, esters of lower alkyls and 9-fluorenimethyl esters thereof, 9-cis retinal and dialkyl acetals and their dibenzyl acetals, and 9-cis retinol and their esters formed with carboxylic acids of C? -C2o-
10. The suitable use of claims 1 to 9 wherein the active ingredient is 9-cis retinoic acid or a pharmaceutically acceptable salt thereof.
11. - The appropriate use of any of claims 1 to 7, 9 and 10, wherein the medicament is prepared for the treatment of autoimmune diseases, and other autoimmune diseases mediated by cells such as rheumatic arthritis, multiple sclerosis, uveoretinitis , thyroiditis, Crohn's disease, diabetes mellitus with insulin dependence, eczema, systemic lupus erythematosus, rejection of allogeneic grafts.
12. - The appropriate use of any one of claims 1 to 10, wherein the medicament is made for the treatment of exogenous eczema, such as irritant dermatitis, allergic contact dermatitis, tick-like eczema, ponfólix or endogenous eczema, such such as seborrheic eczema, asteatotic eczema and discoid eczema.
13. A method of treating an eczematoid condition in a human patient preferably affected by this condition, comprising an oral administration of 9-cis retinoic acid to said patient in an efficient amount to treat the condition of said patient.
14. The method of claim 13, wherein the condition consists of an active lesion of eczema.
15. - The method of claim 14, wherein the condition consists of an active lesion of eczema of: irritant dermatitis, allergic contact dermatitis, seborrheic eczema, asteatotic eczema or discoid eczema.
16. - The method of claim 13, wherein the conditions of preexisting eczema lesions which are in remission.
17. - The method of claim 16, wherein the conditions of the lesions consist of: irritant dermatitis, allergic contact dermatitis, tilotico eczema or pomfólix, seborrheic dermatitis, asteatotic eczema, or discoid eczema; injuries which are decreasing.
18. - The method of claim 13, wherein the effective amount of 9-cis-retinoic acid is about 0.3 to 0.9 milligrams per kilogram of body weight.
19. The method of claim 13, wherein the 9-cis-retinoic acid is administered in a composition comprised of 9-cis-retinoic acid or in a precursor thereof which creates 9-cis-retinoic acid.
20. The method of claim 19, wherein the precursor is selected from the pharmaceutically suitable group comprised of: salts of 9-cis-retinoic acid; hydrolysable esters of 9-cis retinoic acid; 9-cis retinal; hydrolysable esters of 9-cis retinol; 9-cis retinol; and hydrolysable esters of 9-cis retinol.
21. - The method of claim 19, wherein the composition is presented in a unit dose in oral form
22. - The method of claim 21, wherein the unit dose in oral form is a tablet, capsule, pill or pouch containing from twenty to sixty milligrams of acid 9-cis retinoic acid or a pharmaceutically suitable salt or thereof a hydrolysable ester.
23. - A method of treating an eczematoid condition of the skin of a human patient in need of such treatment, comprising a topical application on the skin area of said patient subject to the condition of 9-cis retinoic acid in an effective amount to relieve the effects of that condition.
24. - The method of claim 23, wherein the condition is comprised of an active eczema lesion.
25. The method of claim 24, wherein the condition is comprised of an active eczema lesion by: irritant dermatitis, allergic contact dermatitis, ticklick or ponfólix eczema, seborrheic eczema, asteatotic eczema, or discoid eczema.
26. - The method of claim, wherein the condition is comprised of a lesions of preexisting eczemas which are in decline.
27. - The method of claim 26, wherein the condition is comprised of preexisting lesions by: irritant dermatitis, allergic contact dermatitis, ticklick or ponfólix eczema, seborrheic dermatitis, asteatotic eczema, or discoidic eczema; such injuries are decreasing.
28. The method of claim 23, wherein the 9-cis retinoic acid is applied in a present composition comprised of a compound selected from the group consisting of 9-cis retinoic acid and dermatologically suitable salts thereof.
29. - The method of claim 28, wherein the composition of the composition contains an amount of about 0.001 to about 0.05 weight percent of the composition.
30. - The method of claim 29, wherein the composition of the composition contains an amount of 0.003 to 0.03 weight percent of the composition.
31. - The method of claim 30, wherein the composition of the compound contains an amount of about 0.005 to about 0.01 weight percent of the composition.
32. - The method of claim 31, wherein the composition is presented in the form of an ointment, cream, gel, lotion, or shampoo.
33. - A method of treating an immune disease mediated by T-helper cells type 1 in a human patient, is performed by administering to the patient a compound in an amount effective to treat the disease; wherein the compound is selected from the group consisting of 9-cis retinoic acid, exits and pharmaceutically acceptable esters thereof, precursors and metabolites of 9-cis retinoic acid with pharmaceutically acceptable salts and esters thereof hydrolyzable.
34. - The method of claim 33, wherein the 9-cis retinoic acid or a pharmaceutically acceptable salt is administered.
The method of claim 33, wherein a precursor of 9-cis retinoic acid is selected from the group consisting of the 9-cis retinal, pharmaceutically acceptable acetal of the 9-cis retinal, retinol 9-cis, hydrolyzable pharmaceutically acceptable esters of 9-cis retinol, and pharmaceutically acceptable salts thereof, are administered.
36. - The method of claim 33, wherein the compound is administered orally.
37. - The method of claim 36, wherein the effective amount of the compound is 1.5 milligrams per kilogram of body weight per day.
38. - The method of claim 37, wherein the effective amount of the compound is from 0.3 to 0.9 milligrams per kilogram of body weight per day.
39. The method of claim 33, wherein the disease is an eczematoid condition and the compound is administered topically.
40. The method of claim 33, wherein the compound is administered in a composition comprised by the compound and a pharmaceutically acceptable carrier.
41. - The method of claim 40, wherein the composition is in the form of a tablet, capsule, pill or pouch.
42. - The method of claim 41, in each tablet, capsule, pill or pouch contains five to fifteen milligrams of the compound.
43. The method of claim 42, wherein each tablet, capsule, pill or pouch contains ten to twenty milligrams of the compound.
44 - The method of claim 40, wherein the composition is in the form of an ointment, cream or lotion.
45. - The method of claim 44, wherein the composition of the composition contains an amount of 0.0005 to 0.05 weight percent of the composition.
46. - The method of claim 45, wherein the composition of the composition contains an amount of 0.001 to 0.1 weight percent of the composition.
47. The method of claim 33, wherein the compound is selected from the group consisting of 9-cis retinoic acid and alkali metal salts, alkaline earth metal salts, benzyl esters, low alkaline esters and 9-fluorenylmethyl esters thereof , 9-cis retinal and dialkaline acetals of these, acetal dibenzil, and 9-cis retinol with their same esters formed with C-C20 carboxylic acids.
48. The method of claim 36, wherein said disease is rheumatic arthritis, multiple sclerosis, uveoretinitis, thyroiditis, Crohn's disease, diabetes mellitus with insulin dependence, eczema, systemic lupus erythematosus or rejection of alogenic grafts.
49. - The method of claim 33, 36 or 39, wherein the disease is an exogenous eczema.
50. The method of claim 49, wherein the exogenous eczema is an irritant dermatitis, allergic contact dermatitis, tilotic eczema or ponfólix.
51. - The method of claims 33, 36 or 39, wherein the disease is an endogenous eczema.
52. - The method of claim 51, wherein the endogenous eczema is a seborrheic eczema, asteatotic eczema or discoid eczema.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP97114651 | 1997-08-23 |
Publications (1)
Publication Number | Publication Date |
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MXPA00001803A true MXPA00001803A (en) | 2001-03-05 |
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