KR20030069216A - Histamine receptor antagonists - Google Patents

Abstract

The invention histamine H ₁ for the treatment of a series which can be treated by antagonism of either of, histamine H ₁ and H ₄ receptor comprising the allergic diseases and disorders such as allergic rhinitis and asthma, or both diseases A mixture of receptor antagonists and selective histamine H ₄ receptor antagonists, their use, and compositions, formulations and methods of treatment comprising the mixtures. The invention also relates to selective histamine H ₄ receptor antagonists.

Description

HISTAMINE RECEPTOR ANTAGONISTS

Allergies are widespread and affect most of the world's population. This can be caused by a variety of factors that are inherently seasonal and exist in the environment, such as pollen, mites and dust particles.

Symptoms of allergic rhinitis, which can be seasonal or persist throughout the year, often include runny nose, redness and irritation of the nose accompanied by coughing or sneezing. In addition, irritation and pain in the throat and eyes are common. The severity of each symptom experienced can vary from minor to severely affected.

The use of histamine H ₁ receptor antagonists in the treatment of allergic rhinitis has been widely demonstrated, but when administered alone does not effectively relieve nasal congestion and therefore these agents are often combined with sympathomimetic amine decongestants such as phenylpropanolamine and pseudoephedrine. Administered. However, this combination therapy is not suitable for all patients because side effects of the central nervous system and cardiovascular system are often observed. WO 98/06394 discloses the use of a mixture of histamine H ₁ receptor antagonists and histamine H ₃ receptor antagonists for the treatment of allergic induction responses in the airways of mammals, including the resolution of nasal congestion.

Further effective treatments for allergic diseases and disorders such as allergic rhinitis and asthma are desired. Although not all, alternative therapies that relieve most of the symptoms of allergic rhinitis, including nasal congestion, are particularly desirable.

The invention histamine H ₁ for the treatment of a series which can be treated by antagonism of either of, histamine H ₁ and H ₄ receptor comprising the allergic diseases and disorders such as allergic rhinitis and asthma, or both diseases A mixture of receptor antagonists and selective histamine H ₄ receptor antagonists, their use, and compositions, formulations and methods of treatment comprising the mixtures. The invention also relates to selective histamine H ₄ receptor antagonists.

The present invention is based on the teaching of EP 1096009 A1 (European Patent Application 00309364.8), which specifically discloses the G-protein coupled receptor (H), which is newly named by his investigators as histamine H ₄ receptor. Polynucleotides encoding polypeptides corresponding to GPCRs) are disclosed and claimed. Moreover, although compounds which antagonize or selectively antagonize such polypeptides are disclosed as general terms, there is no definition or consideration for the meaning of selectivity. Moreover, there is no mention at all that antagonists of such polypeptides may be combined with histamine H ₁ receptor antagonists. The teachings of this document are incorporated herein by reference. In this document the histamine H ₄ receptor is defined as a polypeptide comprising the components of (a)-(c):

(a) a polypeptide having a deduced amino acid sequence translated from the polynucleotide sequence of SEQ ID NO: 1, and variants, segments, homologs, analogs and derivatives thereof;

(b) a polypeptide of SEQ ID NO: 2 and variants, segments, homologs, analogs and derivatives thereof; or

(c) a polypeptide encoded by the cDNA of NCIMB 41073, and variants, fragments, homologs, analogs and derivatives thereof.

The definition of the term in relation to the polypeptide should be understood to comply with the teachings of EP 1096009 A1 (European Patent Application 00309364.8), in particular the terms "variants", "homologs" relating to amino acid sequences for polypeptides. , “Segment”, “analogue” or “derivative” means that if the resulting polypeptide has GPCR activity, preferably at least if it is biologically active, such as at least the polypeptide shown in attached SEQ ID NO: 2, And any substitutions, modifications, alterations, substitutions, deletions or additions of one or more amino acids. In particular, the term “homolog” encompasses homology related to structure and / or function. With regard to sequence homology, at least 70%, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and more, relative to the sequence shown in SEQ ID NO: 2 Preferably at least 95% homology. Most preferably, it has at least 98% homology to the sequence set forth in SEQ ID NO: 2.

This polypeptide is an orphan G protein bound receptor assumed as a novel histamine H ₄ receptor, as described in The Journal of Biological Chemistry, 275 (47), 36781-36786 (Nov. 2000). Corresponding to coding GPRv53, the teachings of which are incorporated herein by reference.

We found that histamine-induced chemotaxis (migration towards chemical attractants) of human eosinophils is mediated by the histamine H ₄ receptor but not by the histamine H ₃ receptor, so that histamine H ₄ receptor antagonists are histamine-induced chemotaxis of human eosinophils. I found a surprising fact that it can prevent. Eosinophils are involved in the development of inflammatory diseases and allergic diseases such as asthma and allergic rhinitis, and high levels of histamine are released in patients with these symptoms. Histamine H ₄ receptor antagonists (i) inhibit eosinophil infiltration into the nose and thus can relieve nasal congestion as an additional or independent mechanism for antagonism of the histamine H ₃ receptor, or (ii) prevent infiltration of eosinophils into the lung. It can be advantageously used to treat such symptoms because suppressing reduces inflammation associated with asthma, thereby providing an effective alternative treatment for this disease.

Mixtures of selective histamine H ₄ receptor antagonists and histamine H ₁ receptor antagonists can be advantageously used in the treatment of allergic rhinitis because they treat all major symptoms of these diseases including nasal congestion. Mixtures of selective histamine H ₄ receptor antagonists and histamine H ₁ receptor antagonists can be advantageously used in the treatment of asthma because they improve lung function in a synergistic manner.

The invention (a) provides a histamine H ₁ receptor antagonist and (b) a mixture of at least 10-fold selective for the histamine H ₄ receptor antagonist as compared to the histamine H ₃ receptor.

The present invention also provides simultaneous, separate or sequential administration for use as a medicament for the treatment of diseases or disorders that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors such as allergic rhinitis or asthma. for (a) providing a mixture of a histamine H ₁ receptor antagonist and (b) histamine at least 10 fold selective for the histamine H ₄ receptor antagonist as compared to the H ₃ receptor.

In addition, the present invention provides simultaneous, separate or sequential for the manufacture of a medicament for treating a disease or disorder that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors such as allergic rhinitis or asthma. (a) for administration provides a histamine H ₁ receptor antagonist and (b) use of a mixture of at least 10-fold selective for the histamine H ₄ receptor antagonist as compared to the histamine H ₃ receptor.

Furthermore, the present invention is (a) histamine H ₁ receptor antagonist in an effective amount and (b) at the same time an effective amount of at least 10-fold selective antagonists to histamine H ₄ receptor as compared to the histamine H ₃ receptor to a mammal, including a human, but separately, or Provided is a method of treating a disease or disorder in said mammal that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors, such as allergic rhinitis or asthma, comprising administering sequentially. .

In addition, the present invention is (a) Histamine H ₁ receptor antagonists, (b) histamine A pharmaceutical containing at least 10-fold selective antagonists, and pharmaceutically acceptable excipients, diluents or carriers for the histamine H ₄ receptor compared with the H ₃ receptor To provide a composition.

In addition, the present invention provides a combination for use simultaneously, separately or sequentially in the treatment of a disease or disorder that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors such as allergic rhinitis or asthma. as a formulation, (a) providing a preparation comprising at least 10-fold selective for the histamine H ₄ receptor antagonist as compared to the histamine H ₁ receptor antagonist and (b) a histamine H ₃ receptor.

Furthermore, the present invention provides an at least 10-fold selective antagonists, the use of such antagonists, compositions and therapeutic methods for the histamine H ₄ receptor as compared to the histamine H ₃ receptor. Such selective antagonists have not been disclosed previously, and both histamine H ₃ receptor antagonists, thioperamide and clobenpropit, do not exhibit this degree of selectivity.

The definition "at least 10-fold selective antagonists to histamine H ₄ receptor as compared to the histamine H ₃ receptor" is Unexamined European Patent Publication, the foregoing as compared to the histamine H ₃ receptor known as biological assay described below The EP 1096009 as used herein Histamine H ₄ receptors defined in A1 (European Patent Application 00309364.8) or the mispan G protein bound as disclosed in The Journal of Biological Chemistry, 275 (47), 36781-36786 (November 2000). By at least 10-fold selective antagonist such as receptor encoding GPRv53.

Preferably, this antagonist is at least 30-fold selective for the histamine H ₄ receptor over the histamine H ₃ receptor.

Preferably, the antagonist is at least 50 fold selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor.

Preferably, this antagonist is at least 100-fold selective for the histamine H ₄ receptor over the histamine H ₃ receptor.

Preferably, this antagonist is at least 1000-fold selective for the histamine H ₄ receptor over the histamine H ₃ receptor.

Definitions "Histamine H ₁ receptor antagonists" are widely recognized in the art and accordingly.

Diseases or disorders that can be treated with the mixtures or antagonists of the invention include those that can be modulated by antagonism of H ₄ receptors, such as diseases or disorders associated with aspects of signal transduction. Useful therapeutic areas include obesity, diabetes and metabolic diseases, neurological diseases, psychotherapy, genitourinary diseases, reproductive and sexual medicine, inflammation, cancer, tissue repair, skin disease, skin deposition, photoaging, frailty, osteoporosis, Cardiovascular diseases, gastrointestinal diseases, infection prevention, allergic and respiratory diseases, sensory organ disorders, sleep disorders and hair loss.

Preferred diseases or disorders that can be treated include exogenous asthma, rhinitis (allergic and chronic), nematode dermatitis, atopic dermatitis, drug reactions and allergic disorders such as NERDS (nodules, eosinophilia, rheumatism, dermatitis and swelling), Vascular granulomatous diseases such as transient vasculitis, Chug-Strauss syndrome, multiple arteritis, Wegener's granulomatosis and eosinophil granulomatous prostatitis, autoimmune reactions (e.g., multiple sclerosis), graft rejection and endogenous Immunological disorders such as asthma, chronic obstructive pulmonary disease (COPD), eosinophil pleural effusion, transient pulmonary eosinophil infiltration (Loffler), histiocytosis, chronic eosinophilic pneumonia, irritable pneumonia, allergic bronchopulmonary aspergillosis ), Interstitial and other lung diseases such as sarcoidosis, idiopathic pulmonary fibrosis and focal eosinophilia, toxocaratosis, filaria disease, schistosomiasis, adenocarcinoma Other infectious diseases such as disease, nematodes, roundworms, and infectious parasitic diseases such as cysticitis / cystitis, acute coccidioidomycosis, cat scratch disease, afebrile tuberculosis and childhood chlamydial pneumonia , Neoplastic and myeloproliferative diseases such as tracheal carcinoma, hypereosinophilic syndrome, T-cell lymphoma and Hodgkin's disease, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease) and sinusitis Inflammatory symptoms and celiac disease, obstructive liver disease and herpes dermatitis.

Particularly preferred diseases or disorders that can be treated are in the group consisting of asthma (both exogenous and endogenous), rhinitis (allergic and chronic), COPD and inflammatory bowel disease, or allergic disorders, vasculogenic granulomatous disease, immunological disorders , Interstitial and other lung diseases, infectious diseases, inflammatory diseases, and neoplastic and myeloproliferative diseases. Preferably, the allergic disorder is exogenous asthma or rhinitis (allergic or chronic), the immunological disorder is endogenous asthma, the lung disease is COPD, and the inflammatory disease is inflammatory bowel disease.

The selectivity of the antagonist for the histamine H ₃ or H ₄ receptor can be determined by the following procedure.

CDNA for human histamine H ₃ and H ₄ receptors can be expressed in a suitable cell line such as HEK293 or CHO. In addition, membranes can be prepared from tissues or cells that naturally express histamine H ₃ and / or H ₄ receptors. Affinity at both receptors can be assessed by assessing the ligand's ability to inhibit binding of a suitable radiolabeled ligand to a membrane comprising either the histamine H ₃ or H ₄ receptor. The efficacy of the compounds is compared by calculating the pK ₁ values.

The functional activity of a ligand that determines agonist or antagonist activity is measured in all cells that express either H ₃ or H ₄ receptor. Agents (in whole or in part) can be measured either directly (as cyclic AMP) or indirectly as changes in beta-lactamase activity in cells co-expressing the CRE-beta-lactamase receptor system and the appropriate histamine receptor. (forskolin) It is identified as an agent that inhibits the production of stimulated cyclic AMP. Agent activity can be expressed as an IC ₅₀ value. In addition, agonists can also be identified as inhibition of basal cAMP activity (ie, in the absence of forskolin). Agents that have no effect or inhibit basal cAMP on phospholine stimulated cAMP may be antagonists, and such activity is pre-cultured with the ligand of interest and the H ₃ or H ₄ agonist of phospholine stimulated cyclic AMP. Their ability to inhibit the induced reduction can be measured by assays measuring as described above. This experiment can be performed in one of two ways. First, increasing the antagonist concentration for a fixed concentration of agonist and how to calculate the IC ₅₀ for each antagonist, or increasing the concentration of antagonist, it increases the second agent concentration of and suitably the efficacy of the antagonist pK _b or pA It can be carried out by the method represented by ₂ .

Further functional assays for the histamine H ₄ receptor determine the ability of histamine to induce chemotaxis in eosinophils isolated from human blood. This assay investigates the ability of histamine-activated ligands to first sensitize cells with interleukin 5 and to promote the migration of eosinophils across the permeable membrane. Subsequently, the cells migrated for a defined time are counted. The efficacy of the agent is expressed as an EC ₅₀ value. In addition, antagonists can be investigated by pre-incubating eosinophils with compounds, assessing the inhibitory effect on histamine (or other suitable ligand) on eosinophil chemotaxis. This experiment can be performed in one of two ways. First, increasing the antagonist concentration for a fixed concentration of agonist and how to calculate the IC ₅₀ for each antagonist, or increasing the concentration of antagonist, it increases the second agent concentration of and suitably the efficacy of the antagonist pK _b or pA It can be carried out by the method represented by ₂ . The assay using the present inventors have found appears to be mediated as a histamine induced chemotaxis The histamine H ₃ receptors in human eosinophils by histamine H ₄ receptor.

The present mixture (or each active ingredient thereof) or antagonist may be administered alone, but generally in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. have.

For example, this mixture or antagonist may comprise a flavor or colorant, for immediate release, delayed release, controlled release, sustained release, pulsed release or controlled-release applications, It may be administered orally, buccal or sublingual in the form of capsules, multiparticulates, gels, coatings, ovules, elixirs, solutions or suspensions. In addition, the present mixtures or antagonists may be administered as a quick dispersible or quick dissolving dosage form, or as a high energy dispersant or as coated particles. Suitable formulations of the present mixtures or antagonists are in coated or uncoated form, as desired.

Such solid pharmaceutical compositions, such as tablets, include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and excipients such as starch (preferably corn, potato or tapioca starch), starch glycolate, cross Disintegrants such as carmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and gum arabic Can be. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

General example

Typically tablet formulations may comprise from 0.01 to 500 mg of each active ingredient of the present mixture or antagonist, and the tablet fill amount may range from 50 to 1000 mg. Examples of 10 mg tablet formulations are illustrated below:

ingredient % w / w Pharmaceutically active ingredients 10.000 * Lactose 64.125 Starch 21.375 Croscarmellose sodium 3.000 Magnesium stearate 1.500 Amount adjusted according to drug activity

Tablets are prepared by standard methods, such as direct compression, or by wet or dry granulation methods. The tablet nucleus may be coated with a suitable protective film.

Similar forms of solid compositions can also be used as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, cellulose, lactose and high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the present mixtures or antagonists include various sweetening or flavoring agents, colorants or dyes, emulsifying and / or suspending agents, diluents such as water, ethanol, propylene glycol and glycerin, or It can be mixed with the mixture.

In addition, the present mixtures or antagonists may be administered parenterally, such as intravenous, intraarterial, intraperitoneal, intradural, intraventricular, urethral, intrasternal, intracranial, intramuscular or subcutaneous, or they may be infused or acupuncture It can be administered by infusion technique without using. For such parenteral administration, they are most widely used in the form of sterile aqueous solutions which may contain sufficient amounts of salts or glucose to make other substances such as isotonic solutions with blood. This aqueous solution should be appropriately buffered if desired (preferably to pH 3-9). Formulations of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

For oral and parenteral administration to human patients, the daily dosage level of each active ingredient of this mixture or antagonist is usually from 0.01 to 50 mg, preferably from 0.1 to 20 mg (single or divided doses) per kg of body weight of the treated patient. Amount), or they may be administered by intravenous infusion at a dosage of 0.001 to 10 mg / kg / hour.

For oral, parenteral, buccal or sublingual administration to the treated patient, the daily dosage of each active ingredient of the present mixture or antagonist is typically 10 to 500 mg (single or divided doses).

Thus, tablets or capsules of the present mixture or antagonist may comprise from 5 to 100 mg of each active ingredient of the present mixture or antagonist for administration once or twice as needed. In any case, the physician will determine the actual dosage best suited for any individual patient, which will depend on the age, weight and response of the particular patient. The dosage is an example of an average case. Of course, more or less dosage ranges may be beneficial and such cases are also within the scope of the present invention.

In addition, the present mixtures or antagonists may be administered nasally or by inhalation, and include suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkali (e.g., 1,1, 1,2-tetrafluoroethane (HFA 134 A ™ or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA ™)), carbon dioxide or other suitable gas It may be conveniently delivered in the form of a dry spray inhaler using a pressurized vessel, pump, nebulizer, atomizer or nebulizer or with or without aerosol spray. In the case of a pressurized aerosol, a unit dose may be determined by providing a valve to deliver a metered amount. Pressurized vessels, pumps, nebulizers, atomizers or nebulizers may comprise solutions or suspensions of the active compounds, for example using mixtures of ethanol and propellant as solvents, which may further comprise lubricants such as sorbitan trioleate. Can be. Capsules or cartridges (eg, made of gelatin) for use in an inhaler or insufflator can be formulated to include the present mixture or antagonist and a powder mixture of a suitable powder base such as lactose or starch.

Preferably, the aerosol or dry powder formulation is adjusted to include 10 μg to 1 mg of each active ingredient of the mixture or antagonist of the present invention for each metered dose, ie a “puff” to be delivered to a patient. . The total daily dose with aerosol is in the range of 10 μg to 10 mg of each active ingredient of the present mixture or antagonist and may be administered in a single dose or more usually in divided doses throughout the day.

Alternatively, the present mixtures or antagonists may be administered in the form of suppositories or pessaries, or may be applied topically in the form of gels, hydrogels, lotions, solutions, creams, ointments or spray powders. In addition, the present mixtures or antagonists may be administered to the skin or transdermally, such as using skin patches. In addition, they may be administered by the pulmonary or rectal route.

In addition, they may be administered by the ocular route, in particular to treat allergic conditions of the eye. For ophthalmic use, the compounds may be formulated as undifferentiated suspensions in isotonic, pH adjusted sterile saline, preferably as solutions in isotonic, pH adjusted sterile saline, optionally mixed with preservatives such as benzylalkonium chloride. Can be. Alternatively, they may be formulated as an ointment such as petrolatum.

For topical application to the skin, the present mixture or antagonist is suspended or dissolved in, for example, one or more mixtures selected from mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. It may be formulated into a suitable ointment comprising the compound. Alternatively, they may be, for example, one or more selected from mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water It may be formulated in a suitable lotion or cream suspended or dissolved in the mixture.

In addition, each component of the present mixture or antagonist may be used in admixture with cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of the drug-cyclodextrin complex can change the solubility, dissolution rate, bioavailability and / or stability properties of the drug molecule. In general, drug-cyclodextrin complexes are useful for most dosage forms and routes of administration. As an alternative to direct complexation of the drug, cyclodextrins can be used as auxiliary additives, such as carriers, diluents or solubilizers. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/11172, WO 94/02518 and WO 98/55148.

The present invention includes any other suitable formulation and route of administration as described in EP 1096009 A1 (European Patent Application 00309364.8).

In addition, the present mixtures or antagonists may be administered with steroids, beta-adrenergic receptor agonists, muscarinic antagonists or mucolytic agents.

The present mixtures, antagonists or compositions can be used to treat the aforementioned symptoms in humans or other animals.

All references herein to treatment should be understood to include healing, palliative and prophylactic treatments.

Pharmacological data

a) histamine H ₃ And H ₄ Selectivity of antagonists to receptors

International Publication No. WO98 / 06394 discloses histamine H ₃ receptor antagonists, including thioperamide and clobenpropit, without mention of any antagonist activity on histamine H ₄ receptor.

Binding affinity to histamine H ₄ receptor for thioperamide, clobenpropit and iodophenpropit using the method described in (9) page 9 using the HEK293 cell system, and (ii) histamine by the H ₃ receptor expression using the original method described in claim 9, if the specification using the human brain to analyze the binding affinity for the histamine H ₃ receptor. The results are shown in Table 1 below:

compound H ₄ binding affinity (pKi) H ₃ binding affinity (pKi) Thioperamide 7.26 ± 0.06 6.79 ± 0.10 Cloveben Profit 8.18 ± 0.02 8.63 ± 0.04 Iodofenpropit 7.87 ± 0.04 7.94 ± 0.10 1.0 logarithm indicates 10-fold selectivity for the receptor with the highest pKi value.

These data clearly show the tee opera mid, close-Ben Prophet and iodo pen Prophet of this selectivity for the histamine H ₄ receptor as compared to the histamine H ₃ and H _4, but both the receptor antagonist of histamine H ₃ receptor is low. These are certainly not 10 times selective.

b) Histamine-induced chemotaxis of human eosinophils

It has been demonstrated that histamine promotes chemotaxis of human eosinophils isolated over a concentration range of 10 ⁻⁸ to 10 ⁻⁵ M using the Interleukin 5 first sensitization method of page 10 of the specification. However, agonists that are selective for H ₁ (HTMT), H ₂ (dimaprit) and H ₃ (imetit) receptors, respectively, are capable of chemotaxis of human eosinophils at concentrations of 10 ⁻⁸ to 10 ⁻⁵ M. Did not promote.

Using the eosinophil preculture method of page 10, the non-selective H ₄ / H ₃ antagonist thioperamide maleate and clobenpropite dihydrobromide were histamine of human eosinophils at IC ₅₀ of 0.83 and 1.50 μM, respectively, in a concentration-related manner. It has been demonstrated to inhibit induced chemotaxis. In contrast, antagonists selective to the H ₁ receptor (mepyramine maleate) and the H ₂ receptor (cimetidine) respectively had little or no effect on histamine induced chemotaxis at concentrations of 10 μM.

These data show that histamine-induced chemotaxis of human eosinophils is clearly mediated by the activation of histamine H ₄ receptor. As such, the histamine H ₄ receptor antagonist (i) inhibits eosinophil infiltration into the nose and thus can relieve nasal congestion as a mechanism additional or independent of the antagonism of the histamine H ₃ receptor, or (ii) eosinophils to the lung It can be advantageously used in the treatment of asthma and allergic rhinitis because it inhibits the penetration of, thereby reducing inflammation associated with asthma, thereby providing an effective alternative treatment for this disease. Therefore, a mixture of selective histamine H ₄ receptor antagonists and histamine H ₁ receptor antagonists can be advantageously used in the treatment of allergic rhinitis because it treats all major symptoms of these diseases including nasal congestion. Mixtures of selective histamine H ₄ receptor antagonists and histamine H ₁ receptor antagonists can be advantageously used in the treatment of asthma because they improve lung function in a synergistic manner.

Claims (13)

(a) histamine H ₁ receptor antagonist and (b) a mixture of selective antagonists to histamine H ₄ receptor 10 times or more as compared to the histamine H ₃ receptor. A mixture of (a) a histamine H ₁ receptor antagonist and (b) a antagonist at least 10-fold selective to the histamine H ₄ receptor as compared to the histamine H ₃ receptor for use as a medicament. For simultaneous, separate or sequential administration for use as a medicament for the treatment of diseases or disorders that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors such as allergic rhinitis or asthma (a) histamine H ₁ receptor antagonist and (b) a mixture of selective antagonists to histamine H ₄ receptor 10 times or more as compared to the histamine H ₃ receptor. For simultaneous, separate or sequential administration of a medicament for the treatment of a disease or disorder that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors such as allergic rhinitis or asthma (a) histamine H ₁ receptor antagonist and (b) the use of mixtures of selective antagonists to histamine H ₄ receptor 10 times or more as compared to the histamine H ₃ receptor. (a) an effective amount of the histamine H ₁ receptor antagonist effective amount and (b) a histamine H ₃ receptor selective antagonists than 10 times the histamine H ₄ receptor compared to the same time to a mammal, including humans, administering separately or sequentially A method of treating a disease or disorder comprising a antagonism of either or both of histamine H ₁ and H ₄ receptors, such as allergic rhinitis or asthma, in a mammal. (a) Histamine H ₁ receptor antagonists, (b) Histamine H ₃ A pharmaceutical composition comprising a 10-fold or more selective antagonists, and pharmaceutically acceptable excipients, diluents or carriers for the histamine H ₄ receptor than the receptor. As a combination formulation for use simultaneously, separately or sequentially in the treatment of a disease or disorder that can be treated by antagonism of either or both histamine H ₁ and H ₄ receptors such as allergic rhinitis or asthma, A formulation comprising a) a histamine H ₁ receptor antagonist and (b) a antagonist at least 10-fold selective to the histamine H ₄ receptor over the histamine H ₃ receptor. Antagonist 10 times more selective to histamine H ₄ receptor as compared to histamine H ₃ receptor. A pharmaceutical composition comprising an antagonist according to claim 8 and a pharmaceutically acceptable excipient, diluent or carrier. 10. An antagonist according to claim 8 or a composition according to claim 9 for use as a medicament. An antagonist according to claim 8 or a composition according to claim 9 for use as a medicament for the treatment of diseases or disorders that can be treated by antagonism of histamine H ₄ receptors such as allergic rhinitis or asthma. Use of an antagonist according to claim 8 or a composition according to claim 9 for the manufacture of a medicament for the treatment of a disease or disorder that can be treated by antagonism of histamine H ₄ receptors such as allergic rhinitis or asthma. A mammal that can be treated by antagonism of histamine H ₄ receptors, such as allergic rhinitis or asthma, comprising administering to a mammal, including humans, an effective amount of an antagonist according to claim 8 or a composition according to claim 9. How to treat a disease or disorder.