MXPA96004731A - Use of an antagonist of peptidoleucotriene and una-anhistamine and composition that conti - Google Patents

Abstract

The invention relates to the use of a peptidoleukotriene antagonist and an antihistamine in the manufacture of compositions for the treatment of disease causes.

Description

USE OF AN ANTAGONIST OF PEPTIDOLEUCOTRIENE AND AN ANTIHIST AND ANY COMPOSITION THAT CONTAINS THEM SCOPE OF THE INVENTION The invention relates to the use of a μepti doleucotenon antagonist and an anhistamine in the manufacture of compositions for the treatment of diseases caused by a mRNA type T response in a mammal, including allergic rhinitis, and with a composition containing said idoleukotriene and anti hi stapu peptide antagonists BACKGROUND OF THE INVENTION e has shown that the "Slow Reaction Substance of flnaphylaxis" (SRS-O) is a highly potent bronchodilator substance, which is released mainly from mast cells and basophils by the antigenic stimulus. SRS-fl has been proposed as a principal mediator in human asthma. SRS-fl, in addition to its pronounced effects on pulsed tissue, also produces changes in skin permeability and may be involved in cutaneous, acute allergic reactions. Furthermore, it has been shown that SRS-0 effects the depression of the ventricular contraction and potentiation of the cardiovascular effects of histarnine. present in a natural way and its relationship with SRS-A has reinforced interest in SRS-ñ and other arachidonate netabolites. The SRS-A derived from the mouse, rat, guinea pig and man have all been characterized as mixtures of leukotpene-C4 (LTC4), leucotpene-D4 (LTD4) and leukotpene-E4 (LTE4). Leukotpenes are a group of eicosanoids formed from the metabolism of arachidonic acid via the lipoxygenase pathway. These lipid derivatives originate from LTA4 and are of two types: (l) those that contain a sulfidopeptide side chain (LTC4, LTD4 and LTE) and (2) those that are not peptide (LTB4). Leukotpenes consist of a group of naturally occurring substances that have the potential to significantly contribute to the pathogenesis of a variety of ischemic inflammatory disorders. The pathophysiological role of leucotens has been the focus of recent intense studies. t - Corno was summarized by Left, fl.M., Biochernical Pharnacology, 35, 2, 123-127 (1986) both peptidic and non-peptidic leukotrienes exert microcirculatory actions, promoting the leakage of fluid through the capillary endothelial membrane in most types of vascular beds. LTB4 has potent quirniotact actions that contribute to the recruitment and adherence of mobile sequester cells to the endothelial membrane. LTC4, LTD4 and LTE4 stimulate a variety of muscle types. LTC4 and LTD4 are potent bronchoconstinators and effective stimulators of vascular smooth fluid. This vasoconstrictor effect has been shown to occur in the pulmonary, coronary, cerebral, renal and rnesentheic vasculature. Leukotpenes have been implicated in many lung diseases. Be knows that leucoviruses are potent bronchodontists in humans. LTC4 and LTD4 have been shown to be potent and selective agonists of peripheral pathways, being more active than histamine. TVlease Drazen, J.M. et al., Proc. Nßt'l. flead. Sci. USA, 77, 7, 4354-4358 (1980)]. LTC4 and LTD4 have been shown to increase the mucus release of the human areas in vitro. [See Marom, Z. et al-, Om. Rev. Re'spir. Dis., 126, 449-451 (1982) 1. Leukotrienes have been identified in nasal secretions of allergic individuals, who undergo live stimulation with the specific antigen. The release of leucot rà © nos correlated with typical allergic signs and symptoms. [See Créticos, P.S. et al., New England J. of Med., 310, 25, 1626-1629 (1984)]. This suggests that allergic rhinitis is another useful area for leukotropic antagonists. The antihistatics used in this invention are antagonists of the Hl receptor. Other histamma receptors, namely H2 and H3 receptors, have been identified and the specific antagonists for these last two receptors, they have been found to have effects other than those of the compounds, which antagonize the Hl receptor. But the term "antihistarnina" still carries the connotation of an antagonist Hl. For purposes of simplicity, the word antihistarnina or the abbreviation flH will be used here to mean only the receptor antagonists Hl. Histamine hl receptor antagonists have been used and are used primarily for the treatment of symptomatic relief of hypersensitivity reactions such • as urticaria and angioedema, rhinitis and conjunctivitis and to control pruritus associated with skin disorders. Others were used to control nausea and vomiting or to treat vertigo. This work is related to the use of antihistamines to treat symptoms related to rhinitis, particularly allergic rhinitis. Regarding the treatment of allergic rhinitis s related, antihistamines act by blocking the action of the histarnma, which is released from mast cells mainly in the initial phase of an allergic reaction. They are useful for controlling nasal itching, sneezing, runny nose and eye symptoms such as conjunctivitis, but they are not optimal for controlling nasal congestion. It has been found that antagonizing a idoleukotriene peptide such as LTC4, LTD4 and LTE4, while concomitantly administering a non-sedating anti-histarnine, provides a superior method for the treatment of rhinitis and associated phenomena and particularly allergic rhinitis.

BRIEF DESCRIPTION OF THE INVENTION This invention covers a method for the treatment of a disease caused by immune responses of type T in a mammal, which method comprises administering to an individual who is approximately exposed to or who already suffers from the disease an amount of an idoleucotopic peptide antagonist and a 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 peptidoleucotenne antagonist and an antihistamine in the manufacture of a medicament for use in the treatment of a disease caused by an immune response of the ipod T. Specific Modalities This method can be used prophylactically, as well as to treat an existing state. The scope of treatment encompasses the treatment of a type T immune response in a mammal. This type T immune response is related to or caused by the interaction of an antigen with TgE, which results in an exaggerated reaction to the antigen. This exaggerated immune response can be caused by antigenic materials that originate from many different sources. For example, plant and animal materials, for example dandruff and pollen, or food, dust, drugs and chemicals that are known to cause abnormal reactions in mammals. Such reaction causes physiological changes, which results in many disease states, all of which can be treated by the practice of this invention, including but not limited to, rhinitis including allergic and perennial rhinitis, atopic, dermatitis, eczema, allergic conjunctivitis, urticaria, systemic ampilaxis and hay fever. This list establishes only a few disease states, which may arise from the TgE / antigen interaction and is not intended to limit the practice of this invention in any way. An allergic response is initiated very quickly after an allergen binds to IgE antibodies on mast cells. This induces the cell to release chemicals that generate symptoms grouped in the phrase allergic rhinitis. Among the chemicals released there are two groups that cause symptoms collectively referred to as allergic mediators, ie, histamine and peptidoleucotnenes. For example, where rhinitis is related, the tihistis mines relieve sneezing, pustules and itching of the eyes, nose and throat. But they are not particularly effective against nasal congestion or when allergens are very abundant or when there is a long term exposure. In allergic rmíticos who are dual responders, the concentration of histamine during the early stage correlates with the severity of sneezing and itching, while the concentration of leucotpenoe during the late phase correlates with the severity of nasal congestion, a symptom that is also induced by the exogenous administration of leucotropins. The peptidoleukotriene (PTL) antagonists (PTLfl) which can be used in this invention are extracted from those compounds which regulate the action, production or release of the peptidoleucotrienes, particularly those of LTCi and LTD4. Included within this group of compounds are those compounds which antagonize the LTC4 and LTD4 receptor known in any other way as receptor antagonists, or compounds which inhibit PLT biosynthesis, for example: i) inhibition of 'biodi sphedability of the sus-t time such as the phosphate ipase 02 (inhibitors of PLA2) or transacilasa independent of Cofl (Cofl-TT inhibitors); n) direct inhibition of the enzyme such as 5-LO inhibitors; or m) inhibition of the translocation / activation of the enzyme such as the protein that activates 5-LO (FLflP inhibitors). Compounds which are competitive inhibitors or those which bind reversibly to a receptor are included in this invention. Of particular interest are antagonists of the LTC4 and LTD4 receptor with competitive binding.

As regards PTL antagonists, there are many compounds under clinical investigation, which are useful in this invention. It is expected that some or all of these antagonists may be used in the treatment regimen set forth herein. For example, the following examples have been reported in the literature to be in development as receptor antagonists: Zileuton (Abbott Laboratories); Accolate, ZD 2138, and ZD 3523 (Zeneca); MK-476 (Merck); BflY x-1005, BflY y-1015, and BAY x-7195 (Bayer); A78773 (flbbott Laboratories); AS- 35 (Tanabe); DS-4574 (Diiachl); SK & F 104353, SK &F 106203 and SB 205312 (Srm t hKli ne Beecharn, foot); RG 12525 (Rhone-Poulenc Rorer); and CGP45715 and CGS 25019C (Ciba Geigy). These compounds and their related analogues are available from the respective companies, or can be prepared by means of the chemistry established in different published patent applications and issued patents that describe and claim these compounds. This is only a short list and is set forth only to exemplify the compounds which may be used in this invention; This list is not intended to limit the scope of the invention in any way. PTL receptor antagonists are more preferred. The PTLA of greater interest is L 8- [p- (4-feml utiloxi) benzo? L arnmo-2- (tetrazol-5 '-? L) -4-oxo-4H-i-benzoprão and its salts, isomers , polymorphs and the like. This compound and its useful analogs are described in U.S. Patent 4,780,469 issued October 25, 1988, which is incorporated herein by reference. Any of the histamines can be used in this invention, while retaining their Hl receptor antagonist activity, when used in conjunction with a PTLA. Preferred AH compounds are those which used in this invention are those which are not sedatives, which retain their effect on the symptoms associated with rhinitis. CNS depression is a common effect of many antihistamines. Although this feature may have use in certain therapies, it is not observed with an advantageous object in the treatment of diseases where the purpose of the treatment is to eliminate the phenomena which interfere with normal activity patterns. Therefore, the antihista calls "more sedatives" have been developed. The approach has led to the preparation of compounds, which i) have little > enet ration through the blood / brain barrier or n) have greater selectivity for or greater affinity for peripheral receptors in place of the Hl histoiners of the CNS. Examples of this group of compounds include acrivas-t ina, asternizol, cetirizi a, loratadma, terfenadm and its carboxylic acid metabolite. Loratadma is a preferred antihistamine. These exemplary compounds are set forth for the technical or practicing practitioner of this invention, the characteristics of the anti-stains which are intended to be covered by the term "anti-sedative non-sedating".

The known antihistarnins can be obtained from commercial sources or prepared by published rne-all. The synthesis of the most approved antihista for human consumption have been published either in the patent literature or in professional journals. More information about ant ihist amines which are approved for human use, such as the Mercl * 'Index, 9th Edition, Merck and Company, Rahway, New Dersey (1976), Cutting's Handbook, - Pharrnacology, 6th Edition, Ed. T.Z. Czac and, MD, Appleton-Century-Crofts, New York, 1979, Chapter 49: 538-550 and Goodman and Gilnan, The Phar acological Basis of Therapeutics, 7th Ed. AG Gilrnan, et al, 1985 Macmillan Publishmg Co., New York All these references also provide information on the pharmacology of these compounds or important investment reference in the area. With respect to specific drugs, acpvastma is manufactured by Boroughs Wellcome. In the Chemical Abstracts System (CAS) the number CAS- 97848-99-5 has been given. Asternizol is produced by 3anssen and has the CAS number CAS-68844-77 -9. Cetirizma is available from Pfizerco or the hydrochloride salt; Two CAS numbers have been assigned: CAS-83881-51-1 and CAS-83881-51-0. The loratadma, other product of Schering-Plow has been assigned the number CAS- 79794-75-5. Terfenadma (Seldane) and its carboxylic acid rnetabolite are available from Manon Merrell Dow. The CAS number of terfenadine is CAS-50679-08-8. Information about all aspects of these various drugs can be found in the Chemical Abstracts System database using the numbers indicated. Because the combination of PTLA and antihistamma are more effective treatments or alleviate the symptoms caused by the TgE / antigen interaction than any compound administered alone, it is expected that a combination of the product can or will contain less than each of the assets that could normally be be administered Thus, an effective dose of antihistamine may be less than the dose which could be given if administered without a PTLA. It is expected that a final dose of antihistamine, when combined with PTLA, would be about one-half of what it would be if administered alone. Necessarily there is no need to reduce the dose to the high end of the range, but it is contemplated that one does not need to use a dose equal to that of the highest dose currently approved in the sale of the antihistamine alone. As a convenience material, it is expected that a dose of antihistamine will be used, which has been approved for sale by an agency or regulatory body, which oversees the sale and marketing of antihistamines. For example, loratadine has been approved for sale in some countries as tablets containing 10 rng, u.i.d. Terfenadine has been approved for sale in tablets containing 60 mg of the drug b.i.d. An effective dose of PTLA will be some dose between L2 approximately 10 to 500 rng / kg of body weight per day. It is expected that PTLA will be administered one to four times a day. A preferred treatment regimen implies the PTLA will be a b.i.d. regimen. which implies an oral dose of 75 rng to 450 rng. The above active ingredients can be combined in a single composition or provided as separate preparations. Any pharmaceutically acceptable carrier can be used in preparing compositions containing these two active substances, while the preparation has the requirement of patient stability and acceptability. The most preferred type of formulation is a solid or liquid dosage form which is orally treated. A preferred embodiment is contemplated that both assets will be combined in a combination for simultaneous administration and use. However, assets can be formulated separately and administered separately, such as where one of the assets is administered less times a day than the other. If the assets are administered separately, it is contemplated that they will be administered close in time, which is within a couple of minutes of each other. In addition, the dose can be varied such that a time point at a higher dose of an active is administered. For example, it may be more effective to administer a higher dose of an active in the morning against a night dose of that ingredient, or some variation of this regimen. If a compound is usually administered a few times a day, the treatment regimen must be done to allow an addition in the dosing regimen. For example, if an antihistamine is normally administered once a day, such as loratadine, but PTLA is administered twice a day, then two, or three different formulations will be necessary to be prepared and packaged separately with specific instructions for use. . These compositions can take the form of tablets, capsules (hard or soft), elixirs, syrups, suppositories, etc., consistent with conventional pharmaceutical practices for treating cold or catarrh symptoms. For example, for oral administration in the form of tablets or capsules, the components of the active drug can be combined with any inert pharmaceutically acceptable, non-toxic, oral carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, phosphate. dicalcic, calcium sulfate, mamthol, alcohol etai co (liquid forms) and the like. In addition, when suitable binders, lubricants, disintegrating agents and coloring agents are desired or necessary, they can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia gum, sodium alginate, carboxymethylene cellulose, polyethylene glycol and waxes. Among the lubricants may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, without limitation, starch, rnetiicellulose, agar, bentomat, guar gum, etc. Sweetening and flavoring agents and preservatives may also be included where appropriate. fldi, these compositions can be formulated in sustained release form to provide controlled rate release of any or more of the components to optimize the therapeutic effects, while minimizing undesirable side effects. Suitable dosage forms for the included release include layered tablets containing layers of varying disintegration rates or controlled release polymerase matrices impregnated with the active components and formed into a tablet or capsules containing such impregnated or encapsulated porous polyrneral matrices. An example of a sustained release preparation is a partial or fully transparent soft gelatin capsule preparation, wherein the internal volume is filled with a pharmaceutically acceptable liquid and the granules in the form of tablets (beadlets) in an amount which comprises partial filling of the empty capsule space, or in which the beadlets fill the entire capsule and the interstices between the granules are filled with liquid. Such a preparation can be found in United States Application USSN 08/080851, filed on June 18, 1993, co-pending and USSN 08/089361 filed July 9, 1993, which are incorporated herein by reference. The technology for making beadlets was initiated by R. H. Blythe in U.S. Patent 2,738,303. Describe a therapeutic preparation in dosage form of prepared unit of seeds without panel (granules of sugar), sieve, place in a tray of coating, moisten with syrup, then treat with an 80:20 mixture of sulphate of Dextroamphetamine and calcium sulfate dihydrate, then dry. This procedure is repeated several times until the drug is formed in a seed without a panel; It is treated with talc to create the core granule. These granules are then treated with a wax-fat coating solution one or more times to create the granules with one or more fatty layers surrounding the core granule. Subsequent developments include placing an osmotic wall around the core granule and preparations where the drug dissolves in the material that forms the particle wall and passes through it to the outside when exposed to water. Reference to such particles can be found in the literature, for example in U.S. Patent 4,434,153; the important parts are incorporated herein by reference. See also U.S. Patent 4,961,932, which contains a substantial list of patents to relate to tiny or small pills and dosage forms comprising them. Alternatively, these preparations may be presented in the form of troches, lozenges and the like where the active ingredients are either dissolved 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 the beadlets are trapped in a material that forms the solid matrix. In yet another modality, the beadlets can be filled in a hard cover gelatin film. The representative preparations of the formulations described in the two preceding paragraphs can be found in the United States Patent Application Serial No. 08/090387 filed July 12, 1993, co-pending, the contents of which are incorporated herein. for reference.

Claims (2)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a peptidoleukotriene antagonist and an antihistamine in the manufacture of a medicament for the treatment of the type I immune response in a mammal.

2. A pharmaceutical composition for use in the treatment of the type I immune response in a mammal, characterized in that it comprises an effective amount of a peptidoleukotriene antagonist, an antihistamine and a pharmaceutically acceptable excipient.