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Home , Clobenpropit, Impromidine, Thioperamide

US005869479A United States Patent [19] [11] Patent Number: 5,869,479 Kreutner et al. [45] Date of Patent: Feb. 9, 1999

[54] TREATMENT OF UPPER AIRWAY J .W. ClitheroW et al., “Novel 1,24—Oxadiazoles as Potent ALLERGIC RESPONSES and Selective H3 Receptor Antagonists,” Bioor ganic and Medicinal Chemistry Letters, vol. 6, pp. 833—838 [75] Inventors: William Kreutner, West Paterson; (1996). John A. Hey, Nutley, both of NJ. CR. Ganellin et al., “Design of Potent Non—Thiourea [73] Assignee: Schering Corporation, Kenilworth, H3Receptor Histamine Antagonists,” Journal of Medicinal NJ. Chemistry, vol. 38, pp. 3342—3350 (1995). M. MisaWa et al., “Pharmacological Studies on the Respi [21] Appl. No.: 909,319 ratory Tract (Rept. 186): The Effects of Antagonists on Guinea Pig Rhinitis Model,” Japanese Jour [22] Filed: Aug. 14, 1997 nal of Pharmacology, vol. 64, No. S1, Abstract P—246 Related US. Application Data (1994). C]. Matson et al., “An Experimental Non—lnvasive Animal [60] Provisional application No. 60/023,416, Aug. 16, 1996. Technique for Measuring Nasal AirWay Resistance: I. Adr [51] Int. Cl.6 ...... A61K 31/44; A61K 31/55 energic and Antihistaminic Agents,” Archives Internation 52] US. Cl...... 514/212; 514/220; 514/226.2; ales de Pharmacoa'ynamie et de Therapie, vol. 232, pp. 514/255; 514/264; 514/290; 514/296; 514/322; 68—78 (1978). 514/324; 514/326; 514/343; 514/352; 514/357; N. Sakai et al., “Effects of , a Histamine H3 514/397; 514/400; 514/849 , on Locomotor Activity and Brain [58] Field Of Search ...... 514/290, 357, Histamine Content in Mast Cell—De?cient W/Wv Mice,” 514/212, 220, 226.2, 849, 255, 264, 296, Life Sciences, vol. 48, pp. 2397—2404 (1991). 322, 324, 326, 243, 352, 397, 400 F.E.R. Simons, “H1—Receptor Antagonists: Clinical Phar [56] References Cited macology and Therapeutics,” Journal of Allergy and Clini cal Immunology, vol. 84, pp. 845—861 (1989). US. PATENT DOCUMENTS A. Korte et al., “Characterization and Tissue Distribution of 2,567,245 9/1951 Sperber et al...... 260/296 H3 Histamine Receptors in Guinea Pigs by 4,282,233 8/1981 Vilani ...... 424/267 N°‘—Methylhistamine,”Biochemical and Biophysical 5,019,591 5/1991 Gardner et al. .. 514/461 5,217,986 6/1993 Pomponi et al. 514/400 Research Communications, vol. 168, pp. 979—986 (1990). 5,352,707 10/1994 Pomponi et al...... 514/651 FOREIGN PATENT DOCUMENTS Primary Examiner—Leonard Schenkman Attorney, Agent, or Firm—Robert A. Franks 2207865 2/1989 United Kingdom ...... A61L 15/03 WO 94/18961 9/1994 WIPO ...... A61K 31/13 [57] ABSTRACT OTHER PUBLICATIONS Relief from the symptoms of rhinitis is obtained by treat R.W.S. HeW et al., “Characterization of Histamine ment With: (a) an antihistaminic effective amount of a H3—Receptors in Guinea—Pig Ileum With H3—Selective antagonist; together With (b) a su?i Ligands,” British Journal of Pharmacology, vol. 101, pp. cient amount of a antagonist to 621—624 (1990). provide a nasal decongestant effect. The components may be CE. Tedford et al., “Pharmacological Characterization of administered together in a single dosage form, or separately GT—2016, A Non—Thiourea—Containing Histamine H3 in the same or different dosage forms to maintain therapeutic Receptor Antagonist: In Vitro and In Vivo Studies,” The systemic levels of both components. Journal of Pharmacology and Experimental Therapeutics, vol. 275, pp. 598—604 (1995). 8 Claims, No Drawings 5,869,479 1 2 TREATMENT OF UPPER AIRWAY allergic reaction. Thus, it has been common to concurrently ALLERGIC RESPONSES administer sympathomimetic amine decongestant drugs, such as phenylpropanolamine or pseudoephedrine Which This application claims bene?t of provisional application function as ot-adrenoceptor agonists; several combination 60/023,416 ?led Aug. 16, 1996. products containing both H1 receptor antagonists and sym The present invention relates to a composition for treat pathomimetic amine decongestants are commercially avail ing allergy-induced responses in the mammalian airWay, and able. HoWever, not all allergy sufferers should use these to a method of treating allergy-induced airWay responses. decongestants drugs, due to their frequently observed central Allergies are knoWn to affect a very large fraction of the nervous system and cardiovascular side effects Which population. The allergic response in a particular individual 10 include agitation, sleeplessness, tachycardia, angina pectoris may be caused by any of numerous environmental factors, and hypertension. some of Which are consistently present and others being US. Pat. Nos. 5,217,986 and 5,352,707 to Pomponi et al. more seasonal in nature. Although not alWays recogniZed, attribute an ability for treating conditions including rhintitis WorldWide losses in productivity due to allergic responses and airWay congestion to certain compounds apparently are economically very signi?cant. 15 having H3 receptor binding activity, but no H1 receptor Clinical symptoms of seasonal allergic rhinitis typically antagonist activity. HoWever, no clinical observation or include nasal itching and irritation, sneeZing and Watery other support is provided for this proposition. rhinorrhea, frequently accompanied by nasal congestion. It Would be desirable to have available a treatment for The perennial allergic rhinitis clinical symptoms are similar, allergic rhinitis Which provides relief from all of the com eXcept that nasal blockage may be more pronounced. Either 20 mon symptoms thereof, including nasal congestion, but type of allergic rhinitis may also cause other symptoms such Which does not exhibit adverse nervous system or cardio as itching of the throat and/or eyes, epiphora and edema vascular effects. around the eyes. These symptoms may vary in intensity from the nuisance level to debilitating. Other types of rhinitis SUMMARY OF THE INVENTION present the same types of symptoms. 25 The invention is a composition for the treatment of the At the cellular level, the mechanism of rhinitis has been symptoms of allergic rhinitis, comprising a combination of the subject of considerable study. In addition to other at least one histamine H1 receptor antagonist and at least one processes, the mechanism is Well knoWn to involve the histamine . Also included Within the release of histamine [2-(4-ImidaZolyl) ethylamine] Which is invention is a method for treating symptoms of allergic synthesiZed and stored in secretory granules of mast cells 30 rhinitis, comprising maintaining in the circulatory system an located throughout the body, such as the skin, lungs, gut and antihistaminic amount of at least one histamine H1 receptor the lining of blood vessels. Mast cell histamine is a mediator antagonist, together With suf?cient amounts of at least one in immediate hypersensitivity reactions. Following its histamine H3 receptor antagonist to provide a nasal decon release from mast cells in the nasal mucosa, and acting gestant effect. primarily through histamine H1 receptors, histamine evokes 35 mucous secretion and vasodilatation, increases vascular DETAILED DESCRIPTION OF THE permeability, induces pruritus and causes sneeZing by INVENTION sensory-nerve stimulation. The released histamine also can cause symptoms including hypotension, tachycardia, ?ush For purposes of the present invention, an “antihistaminic” ing and headache. Although histamine H2 receptors (Which 40 effect Will be considered that symptomatic relief Which has typically activate to increase gastric acid secretion) may also classically been considered as being obtainable by a sufferer be involved in the allergic response, their effects are not of rhinitis, resulting from the administration of H1 receptor presently considered to be signi?cant. antagonists, e.g., Without limitation thereto, attenuation of Histamine H3 receptors are found on sympathetic nerves, sneeZing, ocular and nasal itching, rhinorrhea and epiphora. Where they modulate sympathetic neurotransmission and 45 This antihistaminic effect speci?cally does not include sig attenuate a variety of end organ responses under control of ni?cant relief from nasal congestion symptoms. the sympathetic nervous system. Speci?cally, H3 receptor Numerous chemical substances are knoWn to have hista activation by histamine attenuates norepinephrine out?oW to mine H1 receptor antagonist activity. Many useful com resistance and capacitance vessels, causing vasodilatation. pounds can be classi?ed as ethanolamines, It is thought that the primary symptoms of rhinitis 50 ethylenediamines, alkylamines, or pip involve activity at H1 receptors. Indeed, relief has been eridines. Representative H1 receptor antagonists include, provided since the 1940’s by a succession of “” Without limitation: , , , H1 receptor antagonists including the Well-knoWn drug , , chlorpheniramine, chlorpheniramine maleate. More recently developed drugs , , carebastine, , provide H1 receptor antagonist activity With loWer levels of 55 , descarboethoXyloratadine (also knoWn as undesirable side effects, among the most noteWorthy being SCH-34117), , dimethindene, , greatly reduced incidences of somnolence and anticholin , e?etiriZine, , , ergic effects. This is considered to result from the later , , , , drugs’ greater selectivity for H1 receptors, as Well as their , , noberastine, , reduced ability to cross the blood-brain barrier. In general, 60 norastemiZole, picumast, pyrilamine, , none of the H1 receptor antagonists are knoWn to have , , temelastine, trimepraZine and signi?cant effects on H2 or H3 receptors. . Other compounds can readily be evaluated to H1 receptor antagonists have been proven ef?cacious for determine activity at H1 receptors by knoWn methods, preventing and relieving sneeZing, itching, rhinorrhea and including speci?c blockade of the contractile response to other symptoms of the early allergic response, but have not 65 histamine of isolated guinea pig ileum. been found to be very effective for relief of the nasal The currently knoWn histamine H3 receptor antagonists blockage Which is characteristic of the later stages of an cannot be easily classi?ed chemically, but include, Without 5,869,479 3 4 limitation: thioperamide, , , about 1 and about 1000 milligrams of each compound Will , , mifetidine, S-sopromidine, be administered in a dose. The compounds may be combined R-sopromidine, 3-(imidaZol-4-yl)-propylguanidine (SKF in a single dosage formulation, or may be administered in 91486), 3-[(4-chlorophenyl)methyl]-5-[2-(1H-imidaZol-4yl) separate dosage forms, and these may be solid (such as ethyl] 1,2,3-oxadiaZole (GR-175737), 4-(1 tablets, capsules, sachets and the like), liquid (such as cyclohexylpentanoyl-4-piperidyl) 1H-imidaZole (GT-2016), solutions or suspensions) or inhalation aerosols for either or 2-{[2-[4(5)-imidaZolyl]ethyl]thio}-5-nitropyridine (UCL both compounds. While the solid compounds Will typically 1199) and . Other compounds can readily be be administered orally, the liquids may be administered evaluated to determine activity at H3 receptors by known orally or by injection. Other dosage forms, such as methods, including the guinea pig brain membrane assay 10 suppositories, are also useful. and the guinea pig neuronal ileum contraction assay, both of Appropriate amounts of the H1 receptor antagonists and Which are described in US. Pat. No. 5,352,707. Another H3 receptor antagonists for each dose, and the proper dosing useful assay utiliZes rat brain membranes and is described by regimen, must be determined for each combination by West et al., “Identi?cation of TWo H3 -Histamine Receptor suitable clinical trials. Ideally, each drug Will have a similar Subtypes,” Molecular Pharmacology, Vol. 38, pages 15 duration of action after dosing, frequently indicated by 610—613 (1 990). elimination half-life and by clinical observation of symptom Aparticularly useful screening assay measures binding to relief. HoWever, in the event that the individual drug dura sites in guinea pig brain membranes. This test is described tion of action is considerably different for members of a in detail by Korte et al., “Characterization and Tissue given combination, it Will be necessary to resort to alternate Distribution of H3 Histamine Receptors in Guinea Pigs by 20 formulation techniques, such as inhibiting the release kinet Na-Methylhistamine,” in Biochemical and Biophysical ics of a component from the formulation to prolong its Research Communications, Vol. 168, pages 979—986 (1990), activity. These techniques are Well knoWn in the pharma and quanti?es the displacement of bound radiolabeled ceutical formulation art. The least expensive dosing Na-methylhistamine from tissues by candidate compounds. regimen, hoWever, may involve separately administering the Results are expressed as “K” values, in nanoMolar (nM) 25 H1 and H3 receptor antagonists, using dose frequencies and units, Which values can be considered as being dissociation strengths as necessary to maintain therapeutic systemic constants for the H3 antagonist on the H3 receptor system, or levels of both agents. an index of antagonist af?nity for the receptor. The present The invention Will be further described by means of the inventors have evidence that decongestant activity in their folloWing examples, Which are not intended to limit the invention for a given H3 antagonist concentration can be 30 scope of the claimed invention in any manner. In the predicted to increase as the Ki value obtained from the assay examples, compositional percentages are Weight for an antagonist decreases. In general, K- values less than percentages, unless the context clearly indicates otherWise. about 200 nM are considered necessary for an agent to be useful as an H3 antagonist in the invention. More preferably, EXAMPLE 1 35 the agent Will exhibit K- values of 100 nM or less. An objective measurement of nasal airWay resistance to Any of the foregoing drugs may be used in the form of a air How is used to demonstrate the induction and relief of pharmaceutically suitable salt, ester or other form, Where nasal congestion.. solubility or other characteristics of the drug should desir Adult cats are anesthetiZed With intraperitoneal injections ably be modi?ed, such as for formulation convenience. 40 of sodium pentobarbital. The right femoral artery and vein While it is not desired to be bound to any particular theory are cannulated for measurement of blood pressure With a of operation, it is normally expected that sympathetic inner pressure transducer, and for the administration of drugs. The vation of airWay blood vessels leads to vasoconstriction, animals are paralyZed With intravenous gallamine triethio Which Would oppose airWay resistance and congestion. dide and subsequently mechanically ventilated With room HoWever, during conditions of mast cell activation and the 45 air, using an animal ventilator. After isolation of the cervical release of histamine, such as in allergic diseases, the released esophagus, a cuffed endotracheal tube is advanced rostrally histamine acts on H3 receptors located on sympathetic nerve into the posterior nasopharynx and in?ated to form an terminals to inhibit sympathetic neurotransmission and air-tight seal, alloWing continuous measurement of pressure opposes the decongestant effect of norepinephrine, as Well as changes Within the nasal cavity. The right nasal airWay is activating H1 receptors that produce other symptoms of 50 occluded With dental impression compound, and humidi?ed allergic diseases. air is passed through the left nasal airWay at about 1.7 liters that block H1 receptors do not antagoniZe per minute. By means of pressure transducers, nasal airWay the H3 receptor-mediated inhibition of norepinephrine pressure and insuf?ation pressure can be derived and elec release and, therefore, are generally Without activity against tronically recorded. the effects of histamine in promoting air?oW limitation and 55 Nasal airWay resistance (N is determined by dividing the congestion. pressure Within the nasal cavity (expressed in centimeters of The decongestant effect of the combination of the present Water) by the air ?oW rate (expressed in liters per minute). invention is thought to reside in the anti-H3 activity Which Measurements With 18 subject animals yield an average enhances the release of norepinephrine, a natural endog baseline NAR of 2.6. enous decongestant, at the site of congestion in the nose, but 60 The knoWn histamine releaser “Compound 48/80” (the not elseWhere in the body, so no systemic cardiovascular condensation product of N-methyl-p effects are observed. The antiallergic effects reside primarily methoxyphenethylamine With formaldehyde, sold by Sigma in the anti-H, activity of the treatment. Chemical Company, St. Louis, Mo., USA), as a 1.0 percent Amounts of H1 receptor antagonists and H3 receptor solution in 0.9 percent aqueous saline solution, is aero antagonists Which are administered to achieve antihista 65 soliZed into the air stream for 2 minutes to induce an minic and decongestant effects Will vary, depending on the increased NAR. This effect is used to study the decongestant activities of the exact compounds used. In general, betWeen effects of various test substances, administered to the ani 5,869,479 5 6 mals intravenously 10 minutes prior to the introduction of and chlorpheniramine are effective to prevent congestion. Compound 48/80. These substances include 0.9 percent The results for 0.3 and 1.0 mg/Kg clobenpropit, adminis aqueous saline (normal saline “Vehicle”), phenylpropanola tered together With 0.8 mg/Kg chlorpheniramine, are statis mine hydrochloride at 1.0 mg/Kg of the free drug, thiop tically different from those for the vehicle. eramide maleate at 10 mg/Kg of the free drug and chlor maleate at 0.8 mg/Kg of the free drug, all of the EXAMPLE 4 drug compounds being in solution in 0.9 percent aqueous Blood pressure data from the experiments of the preced saline. ing examples are examined, to determine the effects of Results are obtained, as shoWn beloW: certain congestion-preventing treatments. These data are as 10 shoWn beloW, Wherein the change from baseline is shoWn for various drugs (“CPA” being chlorpheniramine, administered Treatment NAR as the maleate): Vehicle 9.1 Thioperamide 6.7 Chlorpheniramine 6.0 15 Treatment mm Hg Phenylpropanolamine 2.9 Vehicle —16 Thioperamide 10 mg/Kg + CPA 0.8 mg/kg —10 It can be seen that the sympathomimetic amine signi? Phenylpropanolamine 1 mg/Kg +31 cantly prevents congestion, but the H1 and H3 receptor antagonists, administered singly, are decidedly inferior at The data shoW that treatment With the thioperamide and preventing nasal congestion. Only the phenylpropanolamine chlorpheniramine combination has little adverse effect on gives a statistically different result from that for the vehicle. blood pressure, While the phenylpropanolamine treatment EXAMPLE 2 (Which yields an approximately equivalent nasal congestion preventing effect) signi?cantly increases blood pressure. The experiment of the preceding example is repeated, but 25 Only the results for phenylpropanolamine are statistically the intravenous drugs are varying amounts of thioperamide different from those for the vehicle. (administered as the maleate), in solution together With a constant 0.8 mg/Kg of chlorpheniramine (“CPA,” adminis EXAMPLE 5 tered as the maleate). 30 The affinity of various histamine H3 receptor antagonists Results are obtained, as shoWn beloW: for binding sites is determined by a guinea pig brain mem brane assay, according to the procedure of Korte et al., Biochemical and Biophysical Research Communications, Treatment NAR Vol. 168, pages 979—986 (1990). Vehicle 9.1 35 Results are as shoWn beloW: Thioperamide 1.0 mg/Kg + CPA 6.1 Thioperamide 3.0 mg/Kg + CPA 4.3 Thioperamide 10 mg/Kg + CPA 2.2 Compound Ki, nM Verongamine 280 There is a signi?cant congestion prevention response to 40 Thioperamide 12 increasing doses of thioperamide in the presence of Clobenpropit 0.1 chlorpheniramine, although the combination of 1 mg/Kg thioperamide and 0.8 mg/Kg chlorpheniramine is not statis These results predict that verongamine, having a Ki value tically different from the vehicle. Comparison of the maxi higher than 200 nM, Will not be useful in the practice of the mum response results shoWn in this example, to the results 45 invention. in Example 1 for administration of 1.0 mg/Kg phenylpropanolamine, indicates that the combination of 0.8 To test the statement in Us. Pat. No. 5,217,986 that mg/kg chlorpheniramine and 10 mg/Kg thioperamide is at verongamine itself has decongestant activity, an experiment least as effective at preventing nasal congestion. similar to that of preceding Example 1, but With a different vehicle, is conducted. The folloWing results are obtained: EXAMPLE 3 50 The experiment of preceding Example 1 is repeated, but the intravenous drug administered is clobenpropit in varying Treatment NAR amounts, either alone or in solution together With a constant Vehicle 7.8 Verongamine 10 mg/Kg 7.3 0.8 mg/Kg of chlorpheniramine (“CPA,” administered as the 55 maleate). Results are obtained, as shoWn beloW: Contrary to the prediction of the patent, the result for verongamine is not statistically different from that for the vehicle. Treatment 60 EXAMPLE 6 Vehicle 9.1 Clobenpropit 1.0 mg/Kg 5.5 The experiment of preceding Example 3 is conducted, Clobenpropit 0.3 mg/Kg + CPA 2.9 using loratadine as the antihistaminic compound at 3 mg/Kg, Clobenpropit 1.0 mg/Kg + CPA 3.4 administered in a solution (“Vehicle”) Which is 30 percent 65 Dimethylsulfoxide, 40 percent Ethanol and 30 percent nor Clobenpropit alone does not exhibit signi?cant prevention mal saline, and using thioperamide as the H3 receptor of nasal congestion, but the combinations of clobenpropit antagonist at 10 mg/Kg. 5,869,479 7 8 Results are obtained, as follows: injection, U.S.P. or bacteriostatic Water for injection, U.S.P. Suitable pH buffers and/or preservatives may be added, as needed. Treatment NAR

Vehicle 12.6 EXAMPLE 11 Loratadine 10.2 Loratadine + Thioperamide 2.1 An oral liquid is prepared by dissolving and/or suspend ing effective amounts of an H1 receptor antagonist and an H3 receptor antagonist in a solution made from Water, contain Only the results for the combination of loratadine and ing desired amounts of the folloWing safely ingestible ingre thioperamide are statistically different from those for the 10 dients: sWeetening agents, ?avorants, colorants, vegetable vehicle. oil and suspending agents and/or thickeners. It should be noted that, in any of the formulations of EXAMPLE 7 preceding Examples 8—1 1, either of the H1 receptor antago The experiment of the preceding example is repeated, 15 nist or the H3 receptor antagonist can be omitted if the active using 1 mg/Kg descarboethoxyloratadine as the histamine compounds are to be separately administered. It is not . Similar results are obtained. necessary to administer the drugs in the same dosage forms. What is claimed is: EXAMPLE 8 1. A method of relieving symptoms of rhinitis in a Tablets containing a combination of H1 receptor antago mammal, comprising simultaneously maintaining in the nist and H3 receptor antagonist are prepared by combining circulatory system: (a) an antihistaminic effective amount of the folloWing ingredients (per tablet to be prepared): one or more histamine H1 receptor antagonists; and (b) a suf?cient amount of one or more histamine H3 receptor H1 antagonist effective amount antagonists having a K- value less than about 200 nanoMolar H3 antagonist effective amount 25 in a guinea pig brain membrane assay to provide a nasal Lactose 100 mg decongestant effect. Corn starch, 10% paste 5 mg 2. The method of claim 1, Wherein the H1 receptor antagonist and the H3 receptor antagonist are present in a Corn starch, dried 25 mg single dosage form. Magnesium stearate 1.25 mg 3. The method of claim 1, Wherein the H1 receptor The ?rst, second, third, and a portion of the ?fth, ingre antagonist and the H3 receptor antagonist are administered dients are thoroughly blended in a suitable mixer for at least in separate dosage forms. 10—15 minutes. The mixture is granulated With the fourth 4. The method of claim 1, Wherein the histamine H1 ingredient and, if necessary, passed through a sieve having receptor antagonist is selected from the group consisting of openings about 0.6 mm. After drying, the granules are mixed 35 astemiZole, aZatadine, aZelastine, acrivastine, With the sixth ingredient and the remaining portion of the brompheniramine, chlorpheniramine, clemastine, cycliZine, ?fth ingredient in a mixer until uniform and compressed into carebastine, cyproheptadine, carbinoxamine, tablets of a desired shape in a tablet press, using suitable descarboethoxyloratadine, doxylamine, , dies. If desired, the tablets may be coated, such as With sugar , , dimethindene, ebastine, and/or With a Wax. epinastine, e?etiriZine, fexofenadine, hydroxyZine, EXAMPLE 9 ketotifen, loratadine, levocabastine, miZolastine, mequitaZine, mianserin, noberastine, mecliZine, Capsules containing a combination of H1 receptor antago norastemiZole, picumast, pyrilamine, promethaZine, nist and H3 receptor antagonist are prepared by combining terfenadine, tripelennamine, temelastine, trimepraZine, the folloWing ingredients (per capsule to be prepared): 45 triprolidine and mixtures of any tWo or more of the forego H1 antagonist effective amount ing. H3 antagonist effective amount 5. The method of claim 1, Wherein the histamine H3 receptor antagonist is selected from the group consisting of Lactose 125 mg thioperamide, impromidine, burimamide, clobenpropit, Corn starch, dried 25 mg impentamine, mifetidine, S-sopromidine, R-sopromidine, Magnesium stearate 2.5 mg SKF-91486, GR-175737, GT-2016, UCL-1 199, cloZapine The ?rst four ingredients are mixed thoroughly in a and mixtures of any tWo or more of the foregoing. suitable mixer for 10—15 minutes, then the ?fth ingredient is 6. The method of claim 1, Wherein the histamine H1 added and mixing continued for another 5 minutes. Prede receptor antagonist comprises loratadine. termined amounts of the mixture are ?lled into tWo-piece 55 7. The method of claim 1, Wherein the histamine H1 hard gelatin capsules of appropriate siZe. receptor antagonist comprises descarboethoxyloratadine. 8. The method of claim 1, Wherein the histamine H3 EXAMPLE 10 receptor antagonist has a Ki value not exceeding about 100 A parenteral solution formulation is prepared by dissolv nanoMolar. ing effective amounts of the H1 receptor antagonist and H3 receptor antagonist sterile poWders in sterile Water for