METHOD OF TREATING ALLERGIC RHINITIS

Abstract: This invention relates to treating a disease caused by a type I immune response using a peptidoleukotriene antagonist and an antihistamine.

Description: Method of Treating Allerfic Rhinitis Scope of the Invention This invention relates to treating diseases caused by a type I immune responses in a Tnammal, including allergic rhinitis, using a peptidoleukotriene antagonist and an antihistamine. Background of the Invention "Slow Reacting Substance of Anaphylaxis" (SRS-A) has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine. The discovery of the naturally occurring leukotrienes and their relationship to SRS-A has reinforced interest in SRS-A and other arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig and man have all been characterized as mixtures of leukotriene-C4 (LTC4), leukotriene-D4 (LTD4) and leukotriene-E4 (LTE4). Leukotrienes are a group of εicosanoids formed from arachidonic acid metabolism via the lipoxygenase pathway. These lipid derivatives originate from LTA4 and are of two types: (1) those containing a sulfidopeptide side chain (LTC4, LTD4, and LTE4), and (2) those that are nonpeptidic (LTB4). Leukotrienes comprise a group of naturally occurring substances that have the potential to contribute significantly to the pathogenesis of a variety of inflammatory and ischemic disorders. The pathophysiological role of leukotrienes has been the focus of recent intensive studies. As Summarized by Left, A.M., Biochemical Pharmacolog y . 21, 2, 123-127 (1986) both the peptide and non-peptide leukotrienes exert micrc irculatory actions, promoting leakage of fluid across the capillary endothelial membrane in most types of vascular beds. LTB4 has potent chemotactic actions and contributes to the recruitment and adherence of mobile scavenger cells to the endothelial membrane. LTC4, LTD4 and LTE4 stimulate a variety of types of muscles. LTC4 and LTD4 are potent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vasculatures. Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in humans. LTC4 and LTD4 have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazeπ, J.M. et al., Proc. Nat'l. Acad. Sci. USA. 77, 7, 4354-4358 (1980).] LTC4 and LTD4 have been shown to increase the release Of mucus from human airways JQ yάl∑fi. fSee Marom. Z. et al.. Am. Rev. Respir. E>is . 126, 449-451 (1982).] Leukotrienes have been identified in the nasal secretions of allergic subjects who underwent jn vivo challenge with specific antigen. The release of the leukotrienes was correlated with typical allergic signs and symptoms. [See Creticos, P.S. et al., New England J. of Med.. 310.25, 1626-1629 (1984).] This suggests that allergic rhinitis is another area of utility for leukotriene antagonists. The antihistamines used in this invention are Hj receptor antagonists. Other histamine receptors, namely H2 and H3 receptors, have been identified and antagonists specific to these latter two receptors have been found to have effects distinct from that of compounds which antagonize the Hj receptor. But the term "antihistamine" still carries the connotation of an Hj antagonist. For sake of simplicity, the word antihistamine or abbreviation AH will be used here to mean only Hj receptor antagonists. Histamine Hj -receptor antagonists have been and are used primarily for treating symptomatic relief of hypersensitivity reactions such as urticaria and angioedema, rhinitis, and conjunctivitis and to control pruritis associated with skin disorders. Others are used to control nausea and vomiting or to treat vertigo. That work is concerned with the use of antihistamines for treating symptoms related to rhinitis, particularly allergic rhinitis. In so far as treating allergic rhinitis is concerned, antihistamines act by blocking the action of histamine which is released from the mast cells mainly in the early phase of an allergic reaction. They are useful for controlling nasal itching, sneezing, rhinorrhoea and ocular symptoms such as conjunctivitis but are not optimally effective for controlling nasal congestion. It has been found that antagonizing a peptidoleukotriene such as LTC4, LTD4 and LTE4 while concomitantly administering an non-sedating antihistamine provides a superior method of treating rhinitis and associated phenomena, and particularly allergic rhinitis. Summary of the Invention This invention covers a method for treating disease caused by a type I immune responses in a mammal, which method comprises administering to a subject about to be exposed to or who is already suffering from said disease an amount of a peptidoleukotriene antagonist and an amount of an antihistamine which in combination are sufficient to treat the disease. In a second aspect this invention relates to the use of a peptidoleukotriene antagonist and an antihistamine in the manufacture of a medicament for use in treating a disease caused by a type I immune response. Specific Embodiments This method can be used piophylactically as well as to treat an existing condition. The scope of treatment encompasses treating a type I immune response in a mammal. This type I immune response is related to or caused by the interaction of an antigen with IgE which results in an exaggerated reaction to the antigen. This exaggerated immune response can be caused by antigenic materials originate from many different sources. For example plant and animal materials, e.g., dander and pollen, or foods, dust, drugs, and chemicals are known to cause abnormal reactions in mammals. Such reaction cause physiological changes which result in a number of disease states, all of which can be treated by the practice of this invention, including but not limited to, riiinitis including allergic and perennial rhinitis, atopic dermatitis, exema, allergic conjunctivitis, urticaria, systemic anaphylaxis, and hay fever. This list sets out only a few of the disease states which can arise from the IgE antigen interaction and is not intended to limit the practice of this invention in any manner. An allergic response is initiated quite rapidly after an allergen binds to IgE antibodies on mast cells. This induces the cell to release chemicals that generate symptoms lumped into the phrase allergic rhinitis. Among the released chemicals are two symptom-causing groups referred to collectively as allergic mediators, i.e., histamine and peptidoleukotrienes. For example, where rhinitis is concerned, antihistamines relieve the sneezing, rhinorreah, and itching of the eyes, nose and throat But they are not particularly effective against nasal congestion or when allergens are quite abundant or when there is long term exposure. In allergic rhinitics that are dual responders, the concentration of histamine during the early-phase correlates with the severity of sneezing and itching, whereas the concentration of peptidoleukotrienes during the late-phase correlates with the severity of nasal congestion, a symptom that is also induced by the exogenous administrtion of leukotrienes. The peptidoleukotriene (PTL) antagonists (PTLA) which can be used in this invention are drawn from those compounds which regulate the action, production or release of peptidoleukotrienes, particularly that of LTC4 and LTD4. Included within this group of compounds are those compounds which antagonize the LTC4 and LTD4 receptor otherwise known as receptor antagonists, or compounds which inhibit the biosynthesis of PLT, for example: i.) inhibition of availability of substrate such as phospholipase A2 (PLA2 inhibitors) or CoA-independent transacylase (CoA-IT inhibitors); ii) direct inhibition of enzyme such as 5-LO inhibitors; or iii) inhibition of translocation/activation of enzyme such as 5-LO activating protein (FLAP inhibitors). Compounds which are competitive inhibitors or those which bind irreversibly to a receptor are included in this invention. Of particular interest are the competitive binding LTC4 an d LTD4 receptor antagonists. In so far as PTL antagonists are concerned, there are a number of compounds undergoing clinical investigation which are useful in this invention. It is expected that some or all of these antagonists could be used in the treatment regime set forth herein. For example the following compounds have been reported in the literature to be under development as receptor antagonists: Zileuton (Abbott Laboratories); Accolate, ZD 2138, and ZD 3523 (Zeneca); MK-476 (Merck); BAY x-1005, BAY y-1015, and BAY x-7195 (Bayer); A78773 (Abbott Laboratories); AS-35 (Tanabe); DS-4574 (Diiachi); SK&F 104353, SK&F 106203 and SB 205312 (SmithKline Beecham, pic); RG 12525 (Rhone- Poulenc Rorer); and CGP45715 and CGS 25019C (Ciba Geigy). These compounds and their related analogs are available from the respective companies, or can be prepared via the chemistries set forth in the various published patent applications and issued patents disclosing and claiming these compounds. This is but a brief list and is set forth only to exemplify the compounds which can be used in this invention; this list is not intended to limit the scope of the invention is any manner. PTL receptor antagonists are most preferred. The PTLA of greatest interest is 8- [p -(4-phenylbutyloxy)ben__oyl]__-mno-2-(tetrazol-5'-yl)-4-oxo-4H- 1-benzopyran and its salts, isomers, polymorphs and the like. This compound and useful analogs are disclosed in U.S. patent 4,780,469 issued on 25 October 1988 which is incorporated herein by reference. Any antihistamines can be used in this invention so long as it retains its native Hj receptor antagonist activity when used in conjunction with a PTLA. The preferred AH compounds are those which used in this invention are those which are non-sedating but which retain their effect on the symptoms associated with rhinitis. CNS depression is a common effect of many antihistamines. While this characteristic may have use in certain therapies, it is not viewed as a desirable effect in the treatment of diseases where the purpose of treatment is to remove phenomena which interfere with normal activity patterns. Consequently, so called "non-sedating" antihistamines have been developed. The approach has been to make compounds which i) have poor penetration across the blood/brain barrier or ii) have a higher selectivity for or a greater affinity for peripheral rather than CNS histamine-Hj receptors. Examples of this group of compounds includes acrivastine, astemizole, cetirizine, loratadine, terfenadine and its carboxylic acid metabolite. Loratadine is a preferred antihistamine. These exemplary compounds are set forth to give the practitioner of this invention the characteristics of the _mtihist__mines which are intended to be covered by the term "non-sedating antihistamine." Known .mtihistamines can be obtained from commercial sources or made by published methods. The syntheses of antihistamines approved for human consumption have been published either in the patent literature or in professional journals. More information on antihistamines which are approved for human use can be such compendia as The Merck Index, 9th Edition, Merck and Company, Rahway, New Jersey (1976), Cutting's Handbook of Pharmacology, 6th Edition, Ed. T. Z. Czacky, M.D., Appleton- Century-Crofts, New York, 1979, Chapter 49:538-550, and Goodman and Gilman, The Pharmacological Basis of Therapeutics, 7th Ed. Editors A. G. Gilman, et al, 1985 Macmillan Publishing Co., New York. All of these references also provide information on the pharmacology of these compounds or reference relevant research in the area. As regards specific drugs, acrivastine is manufactured by Boroughs Wellcome. In the Chemical Abstracts System (CAS) it has been given number CAS-87848-99-5. Astemizole is produced by Janssen and has the CAS number CAS-68844-77-9. Cetirizine is available from Pfizer as the hydrochloride salt; it has been assigned two CAS numbers: CAS-83881-52-1 and CAS-83881-51-0. Loratadine, another Schering-Plough product has been assigned the number CAS-79794-75-5. Terfenadine (Seldane) and its carboxylic acid metabolite are available from Marion Merrell Dow. Terfenadine's CAS number is CAS-50679-08-8. Information about all aspects of these several drugs can be had by searching the Chemical Abstracts System data base using the numbers indicated. Because the combination of PTLA and antihistamine more effectively treats or alleviates the symptoms caused by the IgE/antigen interaction than either compound administered alone, it is expected that a combination product can or will contain less of each of the two actives than what would normally be administered. Thus a effective dose of the antihistamine can be lower than the dose which would be given if it was being administered without a PTLA. It is expected that a low end dose of the antihistamine when combined with a PTLA will be about one-half of what it would be if administered alone. There will not necessarily be any need to reduce the dose at the high end of the range, but it is contemplated that one will not need to use a dose equal to that of the highest dose currendy approved sale of the antihistamine alone. As a matter of convenience, it is expected that one will use a dose of antihistamine which has been approved for sale by a regulatory agency or body which oversees the sale and marketing of antihistamines. For example loratadine has been approved for sale in some countries as tablets containing lOmg, u.i.d.. Terfenadine has been approved for a sale in tablets containing 60mg of drug b.i.d. An effective dose of the PTLA will be some dose between about 10 to 500 mg/kg body weight per day. It is expected that the PTLA will be administered from one to four times a day. A preferred treatment regimen involving the PTLA will be a b.i.d. regimen involving an oral dose of 75 mg to 450 mg. The foregoing active ingredients may be combined in a single composition or provided as separate preparations. Any pharmaceutically acceptable vehicle can be used in preparing compositions containing these two actives, so long as the preparation has the requisite stability and patient acceptability. The most preferred formulation type is a solid or liquid dosage form which is taken orally. It is contemplated, a preferred embodiment, that both actives will be combined in one composition for simultaneous administration and use. However, the actives can be separately formulated and separately administered, such as were one of the actives is administered fewer times per day than is the other. If the actives are administered separately, it is contemplated that they will be administered close in time, that is within a couple minutes of each other. In addition, the doses may be varied so that at one time point a higher dose of one active is being administered. For example it may be most efficacious to administer a higher dose of one active in the morning versus an evening dose of that ingredient, or some variation of this regimen. If one compound is normally administered fewer times per day, the treatment regimen must make accomodate a split in the dosing regimen. For example if an antihistamine is normally administered once a day, such as loratadine, but the PTLA is administered twice daily, then two, or three, different formulations will need to be prepared and packaged separately with specific instructions for use. These compositions may take the form of tablets, capsules (hard or soft), elixirs, syrups, suppositories, etc. consistent with conventional pharmaceutical practices for treating cold or flu symptoms. For instance, for oral administration in the form of tablets or capsules, the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, guar gum, etc. Sweetening and flavoring agents and preservatives can also be included where appropriate. Additionally, these compositions may be formulated in sustained release foπn to provide the rate controlled release of any one or more of the components to optimize the therapeutic effects while minimizing undesirable side effects. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. One example of a sustained release preparation is a partially or wholly transparent soft gelatin capsule preparation wherein the internal volume is filled with a pharmaceutically acceptable liquid and beadlets in an amount which comprise a partial fill of the soft capsule void, or in which the beadlets fill all the capsule and the interstices between the beads are filled with said liquid. Such a preparation can be found in co¬ pending U.S. applications USSN 08/080851 filed 18 June 1993 and USSN 08/089361 filed 09 July 1993, which are incorporated herein by reference. The technology for making beadlets was pioneered by R. H. Blythe as per U.S. patent 2,738,303. He describes there a therapeutic preparation in unit dosage form prepared from non-pariel seeds (sugar pellets), screened, placed in a coating pan, wetted with syrup, then treated with a 80:20 mixture of dextro-amphetamine sulfate and calcium sulfate dihydrate, then dried. This process was repeated several times to build up drug on the non-pariel seed; it is treated with talc to create the core pellet These pellets were then treated with a wax-fat coating solution one or more times to create pellets with one or more fatty layers surrounding the core pellet Later developments include placing an osmotic wall around the core pellet and preparations where the drug dissolves in the wall-forming material of the particle and passes through it to the exterior on exposure to water. Reference to such particles can be found in the literature, for example in U.S. patent 4,434,153; the relevant parts are incorporated herein by reference. See also U.S. patent 4,961,932 which contains a substantial list of patents said to relate to tiny or small pills, and dosage forms comprising same. Alternatively these preparations can be presented in the form of troches, lozenges and the like where the active ingredients are either dissolves or suspended in the matrix or are presented in a beadlet form. These preparations may be opaque or semi-transparent or transparent. A preferred formulation is one where beadlets are entrapped in a solid matrix- forming material. In yet another embodiment beadlets may be filled into a hard-shelled gelatin skin. Representative preparations of the formulations described in the two preceding paragraphs can be found in co-pending U.S. patent application serial number 08/090387 filed 12 July 1993, the contents of which are incorporated herein by reference.

Claims: What is claimed is: 1. A method for treating a disease caused by a type I immune response in a mammal, which method comprises administering to a subject about to be exposed to or who is already suffering from said disease an amount of a peptidoleukotriene antagonist and an amount of an antihistamine which in combination are sufficient to treat the disease. 2. The use of a peptidoleukotriene antagonist and an antihistamine in the manufacture of a medicament for the treatment of type I immune response in a mammal. 3. A pharmaceutical composition for use in treating type I immune response in a mammal, which comprises an effective amount of a peptidoleukotriene antagonist and an antihistamine and a pharmaceutically acceptable excipient

Inventors: DEJONG EGBERT, TORPHY THEODORE J, DEJONG, EGBERT, TORPHY, THEODORE, J.
Applicants: DEJONG EGBERT, SMITHKLINE BEECHAM CORP, TORPHY THEODORE J, DEJONG, EGBERT, SMITHKLINE BEECHAM CORPORATION, TORPHY, THEODORE, J.
Application year: 1995
Main classification: A61K31
IPC codes: A61K45, A61P37