BG107834A - Histamine receptor antagonists - Google Patents

Abstract

The invention relates to a combination of histamine H1 receptor antagonist and selective H4 histamine receptor antagonist for the treatment of diseases which can be treated by antagonism to one or both H1 and H4 receptors, including allergic diseases and disorders such as allergic rhinitis and asthma. The invention also relates to the use of this combination, to compositions, products and methods for the treatment wherein the combination is used, as well as to selective histamine H4 receptor antagonist. 13 claims

Description

The invention relates to a combination of a histamine Hi receptor antagonist and a selective histamine H2 receptor antagonist for the treatment of a number of diseases that can be treated by antagonism to either one or both of the Hi and Hd receptors, including allergic diseases and disorders such as allergic allergic allergic disorders , to their use, and to compositions, products, and methods of treatment using this combination. The invention also relates to a selective histamine Hd receptor antagonist.

BACKGROUND OF THE INVENTION

Allergies are widespread and affect a large proportion of the world's population. Essentially they can be seasonal and can be caused by various environmental factors such as pollen, particulate matter and dust particles.

Symptoms of allergic rhinitis, which may be seasonal or year-round, include rhinorrhea, nasal congestion and irritation, often accompanied by coughing or sneezing. Irritation and soreness in the throat and eyes are also common. The severity of any symptom manifested can range from a minor problem for the patient to a serious effect on the patient.

The use of a histamine H1 receptor antagonist in the treatment of allergic rhinitis has been well documented, but when administered alone, does not provide effective relief of nasal blockage and, therefore, such agent is often administered concomitantly with sympathomimetic amine decongestants such as phenylpropanolamine and phenylpropanolamine. However, such concurrent treatment is not appropriate for all patients, since cardiovascular and central nervous system problems are often reported as side effects. WO98 / 06394 discloses the use of a combination of a histamine Hi receptor antagonist and an H 3 receptor antagonist for the treatment of allergic-induced mammalian airway responses, including alleviation of nasal obstruction.

There is a need for additional effective treatments for allergic diseases and disorders such as allergic rhinitis and asthma. There is a particular need for alternative treatment to provide relief from most, if not all, symptoms of allergic rhinitis, including nasal congestion.

SUMMARY OF THE INVENTION

The present invention is based on that described in EP 1096009 A1 (European Patent Application No. 00309364.6), which inter alia describes and claims a polynucleotide encoding a polypeptide corresponding to a G protein coupled receptor (GPCR) recently named by others histamine LB receptor researchers. Although a compound that antagonizes or selectively antagonizes such a polypeptide has also been described in general terms, the meaning and selectivity are not defined or discussed. In addition, it is not mentioned that antagonists such as polypeptides can be used in combination with a histamine Hi receptor antagonist.

The contents of the document are included here for reference. In the document, the histamine H ₄ receptor is defined as a polypeptide comprising:

(a) a polypeptide having the traced amino acid sequence translated from the polynucleotide sequence in 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 DNA of NCIMB 41073 and variants, fragments, homologs, analogs and derivatives thereof.

The definitions of the above terms relating to the polypeptide should be understood to be in accordance with EP 1096009 A1 (European Patent Application No. 00309364.8), and in particular the terms "variant", "homolog", "fragment", "analogue" or " derivative "in connection with the amino acid sequence for a polypeptide include any substitution, variation, modification, replacement, dilution or addition of one (or more) amino acids from or to the sequence, providing the resulting polypeptide GPCR activity, preferably at least as biological ac IVEN as a polypeptide shown in attached SEQ ID N0: 2. In particular, the term "homologous" covers homology in terms of structure and / or function. In terms of sequential homology, there is at least 70%, preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and more preferably at least 95% sequence homology shown in SEQ ID NO: 2. Most preferably, there is at least 98% homology to the sequence shown in SEQ ID NO: 2.

This polypeptide corresponds to a single G-protein coupled receptor encoded by GPRv53 that was thought to be a new histamine Hd receptor, as described in The Journal of Biological Chemistry, 275 (47).

36781 - 36786 (November 2000), the contents of which are incorporated herein by reference.

Surprisingly, we have found that the histamine-induced chemotaxis (migration to chemoattractant) of human eosinophils appears to be mediated by the histamine H ₃ receptor and not by the histamine H ₃ receptor, and therefore histamine H receptor antagonists prevent histaminases from histamines. Eosinophils are involved in the pathogenesis of inflammatory and allergic diseases such as asthma and allergic rhinitis, and high levels of histamine are released in patients in such conditions. Histamine H2 receptor antagonists may be advantageous in the treatment of such conditions because (I) they are likely to inhibit eosinophilic infiltration of the nose and thus alleviate nasal obstruction by additional and independent antagonism to the histamine H2 receptor or (II) eosinophilic infiltration into the lungs probably reduces asthma-related inflammation and provides an effective alternative treatment for the disease.

A combination of a selective histamine H1 receptor antagonist and a histamine H1 receptor antagonist may advantageously be used to treat allergic rhinitis as it would affect all significant symptoms of the disease, including nasal congestion. A combination of a selective histamine H1 receptor antagonist and a histamine H1 receptor antagonist may advantageously be used to treat asthma as it may improve lung function synergistically.

The present invention provides a combination of (a) a histamine H] receptor antagonist and (b) an antagonist that is at least 10-fold selective to the histamine H1 receptor compared to the histamine H ₃ receptor.

The invention also provides a combination of (a) a histamine H] receptor antagonist and (b) an antagonist that is at least 10-fold selective to the histamine H 3 receptor compared to the histamine H 3 receptor, for administration simultaneously, separately or sequentially, for use as a a medicament for treating a disease or disorder that can be treated by antagonism to one or both of the histamine Hi and Hd receptors, such as allergic rhinitis or asthma.

The invention further provides the use of a combination of (a) a histamine H1 receptor antagonist and (b) an antagonist that is at least 10 times more selective to the histamine H3 receptor than the histamine H3 receptor, for simultaneous, separate or sequential administration the manufacture of a medicament for the treatment of a disease or disorder that can be treated by antagonism to one or both histamine Hi and Hd receptors such as allergic rhinitis or asthma.

The invention further provides a method of treating a mammal, including a human, for the treatment of a disease or disorder that can be treated by antagonism to one or both histamine H 1 and H 2 receptors such as allergic rhinitis or asthma, involving the simultaneous, separate or sequential administration of (a) an effective amount of a histamine H1 receptor antagonist and (b) an effective amount of an antagonist that is at least 10 times more selective to the histamine H1 receptor compared to the histamine H3 receptor.

The invention further relates to a pharmaceutical composition comprising (a) a histamine H1 receptor antagonist and (b) an antagonist that is at least 10-fold more selective to the histamine H3 receptor compared to the histamine H3 receptor and a pharmaceutically acceptable excipient, diluent or carrier.

The present invention further provides a product comprising a combination of (a) a histamine Hi receptor antagonist and (b) an antagonist that is at least 10 times more selective to the histamine H2 receptor compared to the histamine H ₃ receptor as a combined concurrent preparation , separate or sequential use in the treatment of a disease or disorder that can be treated by antagonism to one or both histamine Hi and Hd receptors such as allergic rhinitis or asthma.

The invention further provides an antagonist that is at least 10-fold more selective to the histamine H ₃ receptor 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 described to date with both thioperamide and clobenpropite, both of which are histamine H ₃ receptor antagonists, and do not exhibit such a degree of selectivity.

The term "antagonist that is at least 10-fold more selective for the histamine Hg receptor as compared to the histamine H ₃ receptor" means an antagonist that is at least 10 times more selective for the histamine Hg receptor as defined in EP 1096009 A1 ( European Patent Application No. 00309364.8) or as a single G protein-coupled receptor encoded by GPRv53, as described in The Journal of Biological Chemistry, 275 (47), 36781 - 36786 (November 2000), compared to the known histamine H ₃ receptor, found of the biological tests described below.

Preferably, the antagonist is at least 30 times more selective to the histamine H ₃ receptor compared to the histamine H ₃ receptor.

Preferably, the antagonist is at least 50-fold more selective to the histamine H ₃ receptor compared to the histamine H ₃ receptor.

Preferably, the antagonist is at least 100 times more selective to the histamine H ₃ receptor compared to the histamine H ₃ receptor.

Preferably, the antagonist is at least 1000-fold more selective to the histamine H4 receptor than the histamine H ₃ receptor.

The definition of "histamine H] receptor antagonist" is well understood by one of skill in the art.

Diseases and disorders that can be treated with the combination or antagonist include those that can be modulated by antagonism of the H4 receptor such as those affecting aspects of signal transduction. Useful treatment areas include, but are not limited to, obesity, diabetes and metabolic disease, neurological disease, psychotherapy, urogenital diseases, reproductive and sexual medicine, inflammatory conditions, cancer, tissue repair, dermatology, dermatology problems, weakness, osteoporosis, vascular diseases, gastrointestinal diseases, anti-infectious, allergic and respiratory diseases, disorders of the sensory organs, sleep disorders and hair loss.

Preferred diseases and disorders that can be treated are allergic disorders such as extrinsic asthma, rhinitis (allergic and chronic), onchocerchal dermatitis, atopic dermatitis, drug sensitivity and NERDS (nodal thickening, eosinophymatitis, rheumatitis, rheumatitis, rheumatitis, rheumatitis, rheumatitis, rheumatitis diseases such as temporary vasculitis, Churg-Strauss syndrome, polyarthritis, Wegner's granulomatosis and eosinophilic granulomatous prostatitis, immunological disorders such as autoimmune reactions (eg, multiple sclerosis), rejection of isadka and intrinsic asthma, interstitial and other pulmonary diseases like chronic obstructive pulmonary disease (COPD), eosinophilic pleural leaks, transient pulmonary eosinophilic infiltrates (Loffler), histiocytosis, chronic eosinophilic pneumonia, hypersensitivity pneumonitis, allergic bronchopulmonary aspergilozit, sarcoidosis, idiopathic pulmonary fibrosis and topical eosinophilia, infectious parasitic diseases such as toxocariasis, filariasis, schistosomiasis, trichinosis, strongyloid, ascariasis and echinococcosis / cysticercosis, others noncommunicable diseases such as acute coccidioidomycosis, cat scratch disease, afebrile tuberculosis and chlamydial pneumonia in the earliest, neoplastic and myeloproliferative diseases such as bronchogenic carcinoma, hyperosinophilic syndrome, T-cell inflammatory disease, T-cell disease colitis, Crohn's disease) and sinusitis, abdominal disease, obstructive hepatitis, and dermdtitis herpetiformis.

Particularly preferred treatable diseases and disorders are selected from the group consisting of asthma (both extrinsic and intrinsic), rhinitis (allergic and chronic), COPD and inflammatory bowel disease, or such consisting of allergic disorders, vascular disorders granulomatous diseases, immunological disorders and interstitial and other pulmonary diseases, infectious diseases, inflammatory diseases and neoplastic and myeloproliferative diseases. Preferred allergic disorders are extrinsic asthma or rhinitis (allergic or chronic), immunological disorders such as intrinsic asthma, pulmonary disease COPD, and inflammatory diseases such as inflammatory bowel diseases.

The selectivity of the antagonist to the histamine H ₃ or H ₂ receptor can be determined in the following ways.

The human histamine H ₃ and Hd receptor cDNAs can be expressed in a suitable cell line such as HEK293 or CHO. In addition, tissue or cell membranes can be prepared that naturally express either the histamine H ₃ and / or Hd receptor. The affinity can be evaluated at each receptor by evaluating the ability of ligands to inhibit the binding of a suitable radiolabeled ligand to membranes containing either the histamine H3 or Hd receptor. The activity of the compounds was compared by calculating their pKj values.

The functional activity of the ligands to determine agonist or antagonist activity is carried out in whole cells expressing the H3 or Hd receptor. Agonists (whole or partial) are identified as agents that inhibit forskolin-stimulated cyclic AMP production, which can be measured directly (as cyclic AMP) or indirectly as changes in beta-lactamase activity in cells co-expressing CRE-beta-lactamase reporter system and the corresponding histamine receptor. Agonist activity can be expressed as IC50 values. Inverse agonists can also be identified by inhibiting basal cAMP activity (i.e., in the absence of forskolin). Agents that have no activity on forskolin stimulated with cAMP or inhibit basal cAMP may be antagonists, and such activity can be measured in a test in which the ability to inhibit H3 or Hd agonist-induced can be measured on pre-incubated cells with a ligand of interest reduction of forskolin-stimulated cyclic AMP as described above. Experiments can be conducted in one of two ways. First, by increasing the concentration of antagonist relative to a fixed concentration of agonist and calculating IC50 for each antagonist. Second, by increasing the concentration of antagonist versus increasing the concentration of agonist and expressing the strength of the antagonist as a pKb or pA ₂ value, whichever is more appropriate.

Another functional test for the histamine Hd receptor determines the ability of histamine to induce chemotaxis in eosinophils isolated from human blood. In this assay, cells are initiated with interleukin 5 and the ability of histaminergic ligands to promote eosinophil migration across a permeable membrane is examined. The number of migrating cells per period is counted. The agonist activities are expressed as EC50 values. Antagonists may also be tested by pre-incubating eosinophils with the compound and then evaluating the inhibitory effects on histamine (or other suitable ligand) on eosinophil chemotaxis. Experiments can be conducted in one of two ways. First, by increasing the antagonist concentration relative to the fixed agonist concentration and calculating the IC50 for each antagonist. Second, by increasing the concentration of antagonist versus increasing the concentration of agonist and expressing the antagonist activity as pKb or pA ₂ value, whichever is more appropriate. Using this assay, we have shown that the histamine-induced chemotaxis of human eosinophils appears to be mediated by the histamine H3 receptor and not by the histamine H3 receptor.

The present combination (or any active ingredient thereof) or antagonist may be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected for intended use and standard pharmaceutical practice.

For example, the present combination or antagonist may be administered orally, buccally, or in the tongue in the form of tablets, capsules, in the fragmented state, such as gels, films, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate, delayed, modified, holding, pulsing or controlled-release applications. The present combination or antagonist may also be administered as a fast-dispersing or rapidly dissolving dosage form, either in the form of a high-energy dispersion or as coated particles. Suitable formulations of the present combination or antagonist may be as desired in a form that is coated or uncoated.

Such solid pharmaceutical compositions, for example, tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably maize, potato or tapioca starch), disintegrators, glycol croscarmellose sodium and certain complex silicates and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behanate and talc may be included.

Examples of carrying out the invention

A common example

A tablet formulation may contain from 0.01 mg to 500 mg of any active substance of the combination or the antagonist, while the weight of the fillers may range from 50 to 1000 mg. An example of a 10 mg tablet formulation is given below:

Ingredient % w / w Pharmaceutically active substance (s) 10,000 * Lactose 64.125 Starch 21.375 Croscarmellose sodium 3,000 Magnesium stearate 1,500

* the amount is adjusted according to the activity of the drug.

The tablets are manufactured according to standard methods, for example by direct compression or by wet or dry granulation. The cores of the tablets may be coated with suitable coatings.

Solid compositions of a similar type can also be used as fillers in gelatin or HPMC capsules. Preferred fillers for this are 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 sweetening or flavoring agents, coloring agents or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerol and a combination thereof.

The present combination or antagonist may also be administered parenterally, for example intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethally, intrasternally, intracranially, intramuscularly or subcutaneously, or may be administered by infusion or needle-free injection. For such parenteral administration, they are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solution should be appropriately buffered (preferably to a pH of 3 to 9) if necessary. Preparations representing suitable parenteral formulations under sterile conditions are prepared by standard pharmaceutical techniques well known in the art.

For oral and parenteral administration to humans, the daily dosage levels for each active substance of the present combination or of the present antagonist are typically from 0.01 to 50 mg / kg of body weight of the patient, preferably from 0.1 to 20 mg / kg (overnight or divided by several doses), or may be administered by intravenous infusion at a dose of 0.001 to 10 mg / kg / hour.

For oral, parenteral, buccal or sublingual administration to the patient to be treated, the daily dosage for each active ingredient of the combination or antagonist may be 10 to 500 mg (single or multiple doses).

Thus, tablets or capsules of the present combination or antagonist may contain from 5 to 100 mg of each active substance of the combination or by the antagonist for administration alone or on two or more of them simultaneously, as appropriate. The physician will determine in each case the current dosage that will be most appropriate for the individual patient and will vary according to the age, weight and response of the individual patient. The above dosages are exemplary of the average case. Naturally, there may be individual cases of higher or lower dosages and these are also within the scope of the invention.

The present combination or antagonist may also be administered intranasally or by inhalation, in which case they are in the form of a dry powder for inhalation or as an aerosol spray coupled to a pressurized container, such as a pump, spray, atomizer or nebulizer, with or without the use of suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3heptafluoropropane (HFA 227EA] ), carbon dioxide or other suitable hectare with. In the case of a pressurized aerosol, the dosage unit may be determined by the use of a valve which gives a measured amount. The pressurized container, pump, spray, atomizer or nebulizer may contain a solution or suspension of the active compound (s), for example using a mixture of ethanol and propellant as solvent, which may contain an additional lubricant, for example sorbitan trioleate. Capsules and cartridges (made from, for example, gelatin) for use in an inhaler or insufflator, may

Pharmacological data

A) Selectivity of antagonists for histamine H ₃ and H ₆ receptors

WO98 / 06394 describes histamine H ₃ receptor antagonists, including thioperamide and clobenpropit, without mentioning any antagonistic activity against the histamine H ₃ receptor.

Thioperamide, clobenpropit and iodophenpropit were tested for (I) binding affinity to the histamine H ₃ receptor using the method described on page 7 using the HEK293 cell line and (II) binding affinity to the histamine H ₃ receptor using human brain tissue using human brain tissue naturally expresses the histamine H ₃ receptor.

The results are given below.

compound Sun binding affinity (pK0 H ₃ binding affinity No.) thioperamide 7.26 +/- 0.06 6.79 +/- 0.04 clobenpropit 8.18 +/- 0.02 8.63 +/- 0.04 iodophenpropyl 7.87 +/- 0.04 7.94 +/- 0.10

(a difference of 1.0 log units will mean 10x selectivity for the receptor for which the highest pKj value is obtained)

These data clearly indicate that thioperamide, clobenpropit and iodophenpropit are both histamine H ₃ and H ₁ receptor antagonists but have little selectivity for the histamine H ₃ receptor over that of the histamine H ₃ receptor. They are certainly not 10 times more selective.

B) Histamine-induced chemotaxis to human eosinophils

Using the interleukin 5 initiation method from page 8, it has been demonstrated that histamine promotes the chemotaxis of human isolated eosinophils at a concentration range of 10 ' ⁸ to ΙΟ' ⁵ M. However, agonists individually selective for Hi (NTMT), H ₂ ( dimaprite) and H ₃ (imethite) are formulated to contain a powder mixture of the present combination or antagonist and a suitable powder base such as lactose or starch.

Aerosols or dry powder formulations are preferably so designed that each metered dose or "down" contains from 10 μg to 1 mg of each active ingredient of the present combination or antagonist for administration to the patient. The average daily dose of aerosol will be in the range of 10 µg to 10 mg of each active ingredient of the present combination or of the antagonist, which may be administered as a single dose or more frequently in divided doses throughout the day.

Alternatively, the present combination or antagonist may be administered in the form of suppositories or pessaries, or they may be administered externally in the form of gel, hydrogel, lotion, solution, cream, ointment or powder for powder. The present combination or antagonist may also be administered dermally or transdermally, for example when using a pat on the skin. They may also be administered by pulmonary or rectal routes.

They may also be administered by the ocular route, in particular for the treatment of allergic conditions of the eyes. For ophthalmic administration, the compounds may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline solutions or, preferably, solutions in isotonic, pH-adjusted, sterile saline solutions, optionally in combination with a preservative such as benzylalkonium chloride. Alternatively, they may be formulated in an ointment as paraffin.

For external application to the skin, the present combination or antagonist may be formulated as a sterile ointment containing the active compound or compounds or dissolved in an exemplary mixture of one or more of the following substances: mineral oil, liquid paraffin, white oil, propylene glycol, polyoxyethyl polyoxypropylene compound, emulsifying wax and water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved, for example, in a mixture of one or more of the following substances: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters, cetaryl alcohol, 2-octyldode , benzyl alcohol and water.

Each element of the present combination or antagonist may also be used in combination with cyclodextrin. Cyclodextrins are known to form included and not included complexes with drug molecules. The formation of drug-cyclodextrin complexes can alter the solubility, rate of dissolution, bioavailability and / or stability of the drug molecule. Drug cyclodextrin complexes are generally suitable for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrin may be used as an adjunct, for example, as a carrier, diluent or solubilizer.

The most commonly used are alpha, beta and gamma cyclodextrins and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WOA-98/55148.

The present invention encompasses all other suitable formulations and routes of administration described in EP 1096009 A1 (European Patent Application No. 00309364.8).

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

The present combination, antagonist or composition may be used to treat the above-mentioned conditions in humans or animals.

It should be understood that all treatments here include the treatment itself as well as palliative and prophylactic treatment.

Pharmacological data

A) Selectivity of antagonists for histamine H ₃ and H ₆ receptors

WO98 / 06394 discloses histamine H 3 receptor antagonists, including thioperamide and clobenpropite, without mentioning any antagonistic activity against the histamine H 3 receptor.

Thioperamide, clobenpropit and iodophenpropit were tested for (I) binding affinity to the histamine H ₃ receptor using the method described on page 7 using the HEK293 cell line and (II) binding affinity to the histamine H ₃ receptor using human brain tissue using human brain tissue naturally expresses the histamine H ₃ receptor. The results are given below.

compound Sun binding affinity (PK0 H3 binding affinity (pK0 thioperamide 7.26 +/- 0.06 6.79 +/- 0.04 clobenpropit 8.18 +/- 0.02 8.63 +/- 0.04 iodophenpropyl 7.87 +/- 0.04 7.94 +/- 0.10

(a difference of 1.0U & units will mean 10x selectivity for the receptor for which the highest pK is obtained;)

These data clearly indicate that thioperamide, clobenpropit and iodophenpropit are both histamine H3 and H2 receptor antagonists, but have little selectivity for the histamine H2 receptor over that of the histamine H3 receptor. They are certainly not 10 times more selective.

B) Histamine-induced chemotaxis to human eosinophils

Using the interleukin 5 initiation method of page 8, it is demonstrated that histamine promotes the chemotaxis of human isolated eosinophils at a concentration range of 10 'to 10' M. However, agonists individually selective for Hi (NTMT), H ₂ (dimaprite) and H ₃ (imitate)

Claims (13)

Claims 1. A combination of (a) a histamine Hi receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine Hg receptor as compared to the histamine H ₃ receptor. 2. A combination of (a) a histamine H1 receptor antagonist and (b) an antagonist that is at least 10-fold more selective to the histamine H1 receptor compared to the histamine H ₃ receptor for use as a medicament. 3. A combination of (a) a histamine Hi receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine Hg receptor as compared to the histamine H ₃ receptor implementing ednovrmenno, separately or sequentially, for use as a medicament for treating a disease or disorder that can be treated by antagonism to either or both histamine H 1 or H 2 receptors such as allergic rhinitis or asthma. 4. Use of a combination of (a) a histamine Hi receptor antagonist and (b) an antagonist that is at least 10-fold selective for the histamine Hg receptor as compared to the histamine H ₃ receptor implementing ednovrmenno, separately or sequentially, for the manufacture of a medicament for treating a disease or disorder that can be treated by antagonism to either or both of the histamine Hi or Hd receptors such as allergic rhinitis or asthma. 5. Use of (a) an effective amount of a histamine H1 receptor antagonist and (b) an effective amount of an antagonist that is at least 10-fold more selective to the histamine H1 receptor compared to the histamine H ₃ receptor for the preparation of a medicament for the treatment of a disease or disorder that can be treated by antagonism to either or both of the histamine Hi or Hd receptors such as allergic rhinitis or asthma. A pharmaceutical composition comprising (a) a histamine H1 receptor antagonist and (b) an antagonist that is at least 10-fold more selective to the histamine H1 receptor compared to the histamine H ₃ receptor and pharmaceutically acceptable filler, diluent or carrier. A product comprising (a) a histamine Hi receptor antagonist and (b) an antagonist that is at least 10-fold selective to the histamine H ₃ receptor compared to the histamine H ₃ receptor as a combination composition for administration concurrently, separately or sequentially in the treatment of a disease or disorder that can be treated by antagonism to either or both of the histamine Hi or Hd receptors such as allergic rhinitis or asthma. An antagonist that is at least 10-fold more selective for the histamine H ₃ receptor than the histamine H ₃ receptor. A pharmaceutical composition comprising an antagonist according to claim 8 and a pharmaceutically acceptable excipient, diluent or carrier. The antagonist of claim 8 or the composition of claim 9 for use as a medicament. The antagonist of claim 8 or the composition of claim 9 for use as a medicament for the treatment of a disease or disorder that can be treated by antagonism to the histamine Hd receptor such as allergic rhinitis or asthma. The 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 to the histamine H2 receptor such as allergic rhinitis or asthma. Use of an antagonist or composition according to claim 8 or 9 for the preparation of a medicament for treating a human or animal of a disease or disorder that can be treated by antagonism to the histamine Hd receptor such as allergic rhinitis or asthma, which includes administration to a mammal. an effective amount of an antagonist according to claim 8 or a composition according to claim 9.