SK8572003A3 - Histamine receptor antagonists - Google Patents

Description

Technical field

The invention relates to a combination of a histamine H 1 receptor antagonist and a selective histamine H ₄ receptor antagonist for the treatment of a variety of diseases that can be treated by antagonizing one or both of the Hi and H ₄ receptors, including allergic diseases and disorders such as allergic rhinitis and asthma. it relates to their use and compositions, products and methods of treatment, including such a combination. The present invention also relates to a selective histamine H ₄ receptor antagonist.

BACKGROUND OF THE INVENTION

Allergies are widespread and affect a large part of the world's population. They may be seasonal in nature and may be caused by a variety of environmental factors such as pollen, dust mites and dust particles.

Symptoms of allergic rhinitis, which may be seasonal or persistent, may include rhinorrhea, nasal congestion and irritation, often accompanied by cough or sneezing. Irritation and pharyngeal and eye pain are also common. The level of criticality of survival of each symptom can vary from secondary problems to severe distress.

The use of a histamine H 1 receptor antagonist in the treatment of allergic rhinitis is well documented, but when administered alone does not provide effective relief from nasal congestion and such agents are therefore often administered concomitantly with sympathomimetic amine anti-nasal congestion medications such as phenylpropanolamine and pseudo-amine. Such concomitant therapy is not suitable for all patients, as side effects on the central nervous and cardiovascular systems are often reported. WO 98/06394 discloses the use of a combination of a histamine H 1 receptor antagonist and a histamine H ₃ receptor antagonist for treating allergic-induced responses in the mammalian airway, including releasing nasal congestion.

There remains a need for further effective treatment of allergic diseases and disorders such as allergic rhinitis and asthma. In particular, there remains a need for alternative therapy to provide relief from most, if not all, of the symptoms of allergic rhinitis, including nasal congestion.

The present invention is based on the teachings of EP 1096009 A1 (European Patent Application No. 00309364.8), which inter alia discloses and patentes a polynucleotide encoded for a polypeptide corresponding to a G-protein coupled receptor (GPCR) by other researchers newly called histamine H ₄ receptor. Although the general terms also describe a compound that antagonizes or selectively antagonizes such a polypeptide, there is no definition or discussion of the meaning of selectivity. Furthermore, there is no mention that antagonists of such a polypeptide may be useful in combination with a histamine H 1 receptor antagonist. The teachings of this document are incorporated herein by reference. Herein, the histamine H ₄ receptor is defined as a polypeptide comprising:

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

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

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

The definitions of the above terms relating to the polypeptide are to be understood to be in accordance with the teachings of EP 1096009 A1 (European Patent Application No. 00309364.8) and in particular the terms "variant," homolog, "fragment," analog or "derivative" amino acid sequences for a polypeptide include any substitution, modification, modification, replacement, deletion, or addition of one (or more) amino acid in the sequence, provided that the resulting polypeptide has GPCR activity, preferably being at least as active as the polypeptide shown in the appended sequence identification number 2. In particular, the term "homologue" covers homology with respect to structure and / or function. With respect to sequence homology, it is at least 70%, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, more preferably at least 95% homology to the sequence shown in SEQ ID NO. Most preferred is at least 98% homology to the sequence shown in SEQ ID NO: 2. Second

This polypeptide corresponds to GPRv53 encoded by an orphan G protein-coupled receptor, which is believed to be the novel histamine H ₄ receptor, as described in The Journal of Biological Chemistry, 275 (47), 36781-36786 (November 2000), findings which are incorporated herein by reference.

We have surprisingly found that histamine-induced chemotaxis (migration towards the chemical attractant) of human eosinophils appears to be mediated by the histamine H ₄ receptor and not the histamine H ₃ receptor, and therefore histamine H ₄ receptor antagonists prevent histamine-induced chemotaxis of human eosinophils. Eosinophils are involved in the pathogenesis of inflammatory and allergic diseases such as asthma and allergic rhinitis, and high concentrations of histamine are released in patients with these conditions. The use of histamine H <3 antagonists may be beneficial for the treatment of such conditions, since (i) they are likely to inhibit eosinophil infiltration into the nose, thereby releasing the nasal congestion through an additional or independent mechanism for histamine H ₃ receptor antagonism; into the lungs are likely to reduce asthma-associated inflammation and provide effective alternative treatments for the disease.

The use of a combination of a selective histamine H ₄ receptor antagonist and a histamine H 1 receptor antagonist may be beneficial for the treatment of allergic rhinitis, as it would treat all the major symptoms of the disease, including nasal congestion. The use of a combination of a selective histamine H ₄ receptor antagonist and a histamine H 1 receptor antagonist may be beneficial for the treatment of asthma as lung function could be improved in a synergistic manner.

SUMMARY OF THE INVENTION

The present invention provides a combination of (a) a histamine H ₃ receptor antagonist and (b) an antagonist that is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor.

The present invention also provides a combination of (a) a histamine H ₃ receptor antagonist and (b) an antagonist that is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor for simultaneous, separate or sequential administration when used as a medicament. for the treatment of diseases or disorders that can be treated by antagonizing one or both of the histamine receptors aχ and H ₄ , such as allergic rhinitis or asthma.

The present invention further provides the use of a combination of (a) a histamine receptor antagonist Ηχ and (b) an antagonist which is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor for the manufacture of a medicament for simultaneous, separate or sequential administration. treating diseases or disorders that can be treated by antagonizing one or both of the histamine receptors aχ and H ₄ , such as allergic rhinitis or asthma.

The subject of the present invention of mammals, including humans, in treatment is further a method of treating diseases or disorders that can be treated by antagonizing one or both of the histamine receptors.

Ηχ and H ₄ , such as allergic rhinitis or asthma, comprising simultaneous, separate or sequential administration to a mammal of (a) an effective amount of a histamine receptor antagonist; and (b) an effective amount of an antagonist that is at least ten times more selective for a histamine receptor.

H ₄ compared to the histamine H ₃ receptor.

The present invention further provides a pharmaceutical composition comprising (a) a histamine H ₄ receptor antagonist and (b) an antagonist that is at least ten times more selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention further provides an article comprising (a) a histamine receptor antagonist Ηχ and (b) an antagonist that is at least ten times more selective for the histamine receptor

H ₄ as compared to the histamine H ₃ receptor, as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases or disorders that can be treated by antagonizing one or both of the histamine H ₁ and H ₄ receptors, such as allergic rhinitis or asthma.

The present invention further provides an antagonist which is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor, the use of compositions and methods of treatment comprising such an antagonist. Such a selective antagonist has not been previously described and thioperamide and clobenpropit, both H ₃ receptor antagonists, do not exhibit such a degree of selectivity.

Definition of an "antagonist that is at least ten times selective for the histamine receptor

H ₄ when compared to the histamine H ₃ receptor as used herein denotes an antagonist that is at least ten times selective over the histamine H ₄ receptor as defined in EP 1096009 A1 encoded in patent application no.

00309364.8) or as

GPRv53 orphan G-protein coupled receptor, The Journal of Biological Chemistry,

275 (47) how to

36781 when compared to the known histamine H ₃ receptor, using the bioassay described below.

The antagonist is preferably at least thirty times selective for the histamine H ₄ receptor as compared to the H ₃ receptor.

The antagonist is preferably at least fifty times selective for the histamine H ₄ receptor as compared to the H ₃ receptor.

The antagonist is preferably at least 100 times more selective for the histamine H ₄ receptor as compared to the H ₃ receptor.

The antagonist is preferably at least a thousand times selective

Hist to the histamine H ₄ receptor as compared to the H ₃ receptor.

definition "antagonist histamine of the H 1 receptor in technology well known and used in compliance with this hers EEA. diseases or failure, that can to heal submitted combination or antagonist, include ú also diseases and

disorders that can be modulated by H ₄ receptor antagonism, for example those relating to signal transduction aspects. Beneficial therapeutic areas include, but are not limited to, obesity, diabetes and metabolic diabetes, neurological diseases, psychotherapy, urogenital diseases, reproductive and sexual medicine, inflammation, cancer, tissue repair, dermatology, skin pigmentation, light exposure, weakness, osteoporosis, cardiovascular diseases, gastrointestinal diseases, anti-infective effects, allergic and respiratory diseases, sensory organ disorders, sleep disorders and hair loss.

Advantageously, diseases and disorders such as allergic disorders such as external asthma, rhinitis (allergic or chronic), dermatitis response, onchocercous dermatitis, atopic dermatitis, drugs and NERDS (nodules, eosinophilia, rheumatism, vasculitis, vasculitis, vasculitis, vasculitis, vasculitis) can be treated. transient vasculitis, ChurgStrauss syndrome, polyarteritis, Wegner's granulomatosis and eosinophilic granulomatous prostatitis, immunological disorders, e.g. autoimmune response (e.g., multiple sclerosis), graft rejection and true asthma, interstitial and other pulmonary diseases such as chronic obstructive pulmonary disease (COPD), transient eosinophilic pleural effusion, pulmonary eosinophilic infiltrates (Loffler), histiositis, chronic eosinitis, preciositis pneumonitis, allergic bronchopulmonary aspergillosis, sarcoidosis, idiopathic pulmonary fibrosis and topical eosinophilia, infectious parasitic diseases such as toxocarosis, filariasis, schistosomosis, trichinosis, strongyloidiasis, tubariasis and echinococcosis, or cysticercidosis, other cysticercidosis, other cysticercidosis fever and chlamydial pneumonia in childhood, neoplastic and myeloproliferative diseases such as bronchogenic carcinoma, hypereosinophilic syndrome, T-cell lymphoma and Hodgkin's disease, inflammatory conditions such as intestinal inflammatory diseases (e.g., ulcerative colitis, Crohn's disease) and sinusitis and abdominal diseases, obstructive liver disease and herpetiform dermatitis.

Particularly preferred diseases and disorders that can be treated are selected from the group consisting of asthma (both external and true) rhinitis (allergic and chronic), COPD and intestinal inflammatory diseases or those consisting of allergic disorders, vasculititis granulomatous diseases, immune disorders, interstitial and other pulmonary diseases, infectious diseases, inflammatory diseases and neoplastic and myeloproliferative diseases, said allergic disorders are preferably external asthma or rhinitis (allergic or chronic), immunological disorders are true asthma, pulmonary diseases are COPD and inflammatory diseases are intestinal inflammatory diseases.

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

In a suitable cell line, for example HEK293 or CHO, cDNA for the human histamine receptor H ₃ and H ₁ may be expressed.

In addition, membranes can be prepared from tissues or cells that naturally express either the histamine H ₃ and / or H ₄ receptor. Affinity can be determined at any receptor by determining the ability of the ligands to inhibit the binding of a suitable radiolabeled ligand to membranes containing either the histamine H ₃ receptor or the H ₄ receptor. The activity of the compounds is compared by calculating their pKi values.

The functional activity of the ligands to determine agonist or antagonist activity is determined in whole cells expressing either the H ₃ receptor or the H ₄ receptor. Agonists (total or partial) are identified as agents that inhibit forskolin-stimulated production of cyclic AMP, which can be measured directly (as cyclic AMP) or indirectly, as a change in beta-lactamase activity in cells co-expressing the CREbeta-lactamase reporter system and the appropriate histamine receptor. The agonist activities can be expressed by IC 50 values.

Inverse agonists of basal inhibition

Reagents, cAMP activities can also be identified by (e.g.

in the absence of forskolin).

which have no effect on forskolin-stimulated cAMP or inhibition of basal cAMP may be antagonists and such activity may be measured in an assay where cells first incubate the ability to inhibit H ₃ forskolin-stimulated with the ligand of interest and their or H ₄ agonist induced the reduction in cyclic AMP is measured as described above. Experiments can be performed in one of two ways. First, increasing the concentration of the antagonist over a fixed concentration of the agonist and calculating the IC 50 for each antagonist. Second, increasing the concentration of the antagonist against increasing the concentration of the agonist and expressing the antagonist potency by pk _b or pA ₂ values as appropriate.

Another histamine H ₄ receptor functional assay determines the ability of histamine to induce chemotaxis in eosinophils isolated from human blood. In this assay, cells are prepared with interleukin 5 and the ability of histamine-activated ligands to promote migration of eosinophils across the permeable membrane is studied. It is then calculated at a defined time interval.

number of migrants

The agonist activity is expressed by the cells

IC50. Antagonists can also be studied by pre-incubating eosinophils with the compound then assessing the inhibitory effects on histamine (or other suitable ligand) on eosinophil chemotaxis. Experiments can be performed in one of two ways. First, by increasing the concentration of the antagonist over a fixed concentration of the agonist and calculating

IC ₅₀ for each antagonist. Second, by increasing the concentration of antagonist versus increasing concentrations of agonist and expressing the antagonist potency values pts _pts appropriate. Using this assay, we have demonstrated, or pÄ ₂ , that histamine-induced chemotaxis of human eosinophils appears to be mediated by the histamine H ₄ receptor and not the histamine H ₃ receptor.

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

For example, the present combination or antagonist may be administered orally, buccally or sublingually in the form of tablets, capsules, multiparticulates, gels, ovules, elixirs, solutions or suspensions, which may contain flavoring and coloring agents, for immediate, delayed, modified, continuous, pulsatile or controlled release formulations.

The present combination or antagonist may also be administered as a rapidly dispersing or rapidly dissolving dosage form or in the form of a high energy dispersion or as coated particles. If desired, formulations of the present combination or antagonist, with or without a coating, may be suitable.

Such solid compositions may contain, for example, excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine and starch (preferably corn, potato or topioc), disintegrants such as sodium starch glycolate, sodium croscarmellose

and certain silicate complexes and binders granules, for example

polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxy-

propylcellulose (HPC), sucrose, gelatin and gum arabic.

In addition, lubricants such as magnesium stearate, stearic acid, glyceryl bahenate and talc may be included.

DETAILED DESCRIPTION OF THE INVENTION

General example

Tablets may typically contain from 0.01 mg to 500 mg of each active element of the combination or antagonist, while the tablet fill weight may range from 50 mg to 1000 mg. An example of a preparation for a 10 mg tablet is given below:

component % by weight Pharmaceutical active ingredient (s) 10,000 * lactose 64.125 starch 21,375 croscarmellose sodium 3,000 Magnesium stearate 1,500

Amounts set according to drug activity.

Tablets are produced in a standard way, for example, direct

by compression or granulation in wet or dry conditions.

The tablet cores may be coated with a suitable coating agent.

Solid compositions of a similar type may also be employed as fillers in gelatin or HPMC capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the present combination or antagonist may be combined with various sweeteners or flavors, coloring or coloring agents, emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The present combination or antagonist may also be administered parenterally, for example, intravenously, intraarterially, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or may be administered by infusion or needle-free injection. For such parenteral administration, it is best to use a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to render the solution isotonic with blood. If necessary, aqueous solutions should be suitably buffered (to a pH of from 3 to 9). The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

For oral and parenteral administration to human patients, the daily dose of each active element of the present combination or the present antagonist will usually be from 0.01 to 50 mg / kg body weight of the subject to be treated, preferably from 0.1 to 20 mg / kg (in one or in divided doses), or may be administered by intravenous infusion at a dosage of from 0.001 to 10 mg / kg / hour.

For oral, parenteral, buccal or sublingual administration to a subject to be treated, a typical daily dose of each active element of the combination or antagonist may be from 10 to 500 mg (in single or divided doses). The tablets or capsules of the present combination or antagonist may thus contain from 5 to 100 mg of each active element of the combination or antagonist for a single administration or for two or more doses at a reasonable time. In any case, the actual dose most appropriate for any individual patient will be determined by the physician, and will vary with the age, weight and response of the particular patient. The sizes of said dose are given as an example of the average case. Of course, there may be individual instances where higher or lower dosage ranges are preferred and are included within the scope of the invention.

The present combination or antagonist may also be administered intranasally or by inhalation and is practically supplied in the form of a dry inhaler or in the form of an aerosol spray and pump, spray, pressurized container, nebulizer without or with a suitable propellant atomizer, such as dichlorodifluoromethane. , trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane such as

1,1,1,2-tetrafluoroethane (HFA 134Ά trade mark) or

1,1,1,2,3,3,3heptafluoropropane (HFA

227EA (trademark), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by means of a connected valve to release a metered amount. The pressurized container, pump, spray, atomizer or nebulizer may contain a solution or suspension of the active ingredient or ingredients, e.g. using a mixture of ethanol and propellant as solvents, which may additionally contain a lubricant, e.g.

sorbitan trioleate. Capsules and cartridges of, for example, gelatin) for use in an inhalation device or insulflator may be formulated containing a powder mix of the present combination or antagonist and a suitable powder base such as lactose or starch.

The aerosol or dry powder formulations are preferably arranged such that each metered dose or spray contains from 10 µg to 1 mg of each active element of the present combination or antagonist administered to a patient. The total daily dose administered by aerosol will range from 10 µg to 10 mg of each active element of the present combination or antagonist, which can be administered in a single dose or, more usually, in divided doses throughout the day.

Alternatively, the present combination or antagonist may be administered in the form of a lace or pessary, or may be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The present combination or antagonist may also be administered dermally or transdermally, for example using a skin patch. They can also be administered by pulmonary or rectal routes.

They can also be applied to the eyes, especially in the treatment of ocular allergic conditions. For ophthalmic use, the compounds may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline or preferably as solutions in isotonic, pH adjusted sterile saline, optionally in combination with a preservative such as benzylalkonium chloride. Alternatively, they may be formulated as ointments such as petrolatum.

For topical application to the skin, the present combination or antagonist may be formulated as a suitable ointment containing the active compound or compounds suspended or dissolved in, for example, a mixture of one or more of mineral, oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene-polyoxypropylene compound, emulsifying agent. wax and water.

Alternatively, they may be formulated as suitable lotions or creams, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetaryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Each element of the present combination or the present antagonist may be used in combination with a cyclodextrin.

Cyclodextrins are known to form inclusion or non-inclusion complexes with drug molecules with cyclodextrin dissolution, biologicals. Complexing can modify the solubility and / or stability of the drug substance. Complexes beneficial to the medicament generally do most of the administration.

An alternative with the drug substance may be the drug rate of the cyclodextrin substance molecule are dosage forms for the direct formation and pathway of the complex using cyclodextrin as an external ingredient, e.g. as a carrier, diluent or solubilizing agent. Alpha-, beta- and gamma-cyclodextrins are most commonly used, and suitable examples are described in WO-A-91/11172, WOA-94/02518 and WO-A-98/55148.

The present invention includes any other suitable formulation and route of administration described in EP 1096009 A1 (European Patent Application No. 00309364.8).

The present combination or antagonist may be co-administered with a steroid, a beta-adrenoceptor agonist, a muscarinic antagonist or a mucolytic.

The present combination, antagonist or composition can be used to treat the above conditions in humans or other animals.

It should be appreciated that all references herein to treatment include therapeutic, soothing, and prophylactic treatments.

PHARMACOLOGICAL PARTICULARS

a) Selectivity of antagonists for histamine H ₃ and H ₄ receptors.

WO 98/06394 discloses a histamine H ₃ receptor antagonist including thioperamide and clobenpropit without mentioning any histamine H ₄ receptor antagonist activity.

Thioperamide, clobenpropit and iodfenpropit were tested for (i) histamine H ₄ receptor binding affinity using the method described on page 8 using the HEK293 cell line and (ii) histamine H ₃ receptor binding affinity using the method described on page 8 s utilizing human brain tissue that naturally expresses the histamine H ₃ receptor. The results are shown below.

Compound H ₄ Binding Affinity (pKJ) ___ H ₃ Binding Affinity (pKJ)

thioperamide 7.26 + about, 06 6.79 ± 0.10 clobenpropit 8, 18 + 0 02 8, 63 + 0, 04 iodophenpropit 7, 87 + 0 04 7.94 + 0, 10

(A difference of one logarithmic unit would indicate ten-fold selectivity to the receptor for which the highest pKJ value was obtained.

These data clearly show that tioperamide, clobenpropit and iodfenpropit are both H ₃ receptor and receptor antagonists.

H ₄ , but have little selectivity for the histamine H ₄ receptor over the histamine H ₃ receptor. They are not ten times more selective.

b) Histamine-induced chemotaxis of human eosinophils

Using the method of adding interleukin 5 on page 9, histamine has been shown to promote chemotaxis of human isolated eosinophils in a concentration range of 10 ^-8 to 10 ^-5 M. However, at a concentration of 10 ⁸ to 10 ^-5 M, no H 1 -selective antagonist (HTMT), The H ₂ (dimaprite) and H ₃ (imetite) receptors do not promote chemotaxis of human eosinophils.

Using the eosinophilic preincubation method on page 9, the non-selective H ₄ / H ₃ antagonists tioperamide maleate and clobenpropit dihydrobromide were shown to inhibit histamine-induced chemotaxis of human eosinophils in a concentration-dependent manner with respective micromolar IC 50 values of 0.83 and 1.50. In contrast, antagonists individually selective for H 1 receptor (mepyramine maleate) and H ₂ receptor (cimetidine) have no or little effect on histamine-induced chemotaxis at micromolar concentrations 10.

These data indicate that histamine-induced chemotaxis of human eosinophils must be mediated through histamine receptor activation

H ₄ .

As such, histamine receptor antagonists can be used

H ₄ advantageously used in the treatment of asthma and allergic rhinitis, since (i) they are likely to inhibit eosinophilic infiltration into the nose and thereby release nasal congestion by an additional or independent mechanism for histamine receptor antagonism

H ₃ or (ii) by inhibiting eosinophil infiltration into the lung, is likely to reduce the inflammation associated with asthma and provide an effective alternative treatment for this disease.

Combination of a selective histamine receptor antagonist

H ₄ and the histamine H ₁ receptor antagonist can therefore be advantageously used for the treatment of allergic rhinitis as it will treat all the main symptoms of the disease, including nasal congestion.

The combination of a selective histamine H ₄ receptor antagonist and a histamine H 1 receptor antagonist can also be advantageously used for the treatment of asthma, as it can improve lung function in a synergistic manner.

Claims (5)

PATENT CLAIMS A combination of (a) a histamine H 1 receptor antagonist and (b) a receptor characterized in that it is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor. 2. A combination of (a) a histamine H _x and (b) a receptor that is at least ten-fold selective for the histamine receptor Shih H ₄ as compared to the histamine H ₃ receptor, wherein it is used as a medicine. A combination of (a) a histamine H 1 receptor antagonist and (b) an antagonist which is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor, characterized in that it is used for simultaneous, separate or sequential administration as a medicament for the treatment of a disease or disorder that can be treated by antagonizing one or both of the histamine H _x and H ₄ receptors, such as allergic rhinitis or asthma. Use of a combination of (a) a histamine H 1 receptor antagonist and (b) an antagonist that is at least ten times selective for the histamine H ₄ receptor as compared to the histamine H ₃ receptor, for simultaneous, separate or sequential administration, for the manufacture of a medicament for treating a disease or a disorder that can be treated by antagonizing one or both of the histamine H 1 and H ₄ receptors, such as allergic rhinitis or asthma. A method of treating a mammal, including a human, in the treatment of a disease or disorder that can be treated by antagonizing one or both of the histamine H 1 and H ₄ receptors, such as allergic rhinitis or asthma,