EP0755252A1 - Procede de traitement de la rhinite allergique - Google Patents
Procede de traitement de la rhinite allergiqueInfo
- Publication number
- EP0755252A1 EP0755252A1 EP95916942A EP95916942A EP0755252A1 EP 0755252 A1 EP0755252 A1 EP 0755252A1 EP 95916942 A EP95916942 A EP 95916942A EP 95916942 A EP95916942 A EP 95916942A EP 0755252 A1 EP0755252 A1 EP 0755252A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- antihistamine
- treating
- compounds
- peptidoleukotriene
- antagonist
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- 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.
- SRS-A 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.
- 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 ⁇ icosanoids 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.
- 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.
- LTC4 and LTD4 have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Draze ⁇ , 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 y ⁇ l ⁇ fi. fSee Marom. Z. et al.. Am. Rev. Respir. E>is .
- 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.
- 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.
- antihistamine still carries the connotation of an Hj antagonist.
- 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.
- 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.
- 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.
- 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.
- 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.
- riiinitis including allergic and perennial rhinitis, atopic dermatitis, exema
- allergic conjunctivitis urticaria
- systemic anaphylaxis and hay fever.
- 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.
- the released chemicals are two symptom-causing groups referred to collectively as allergic mediators, i.e., histamine and peptidoleukotrienes.
- allergic mediators i.e., histamine and peptidoleukotrienes.
- 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.
- the concentration of histamine during the early-phase correlates with the severity of sneezing and itching
- 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.
- peptidoleukotriene (PTL) antagonists 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).
- PLA2 inhibitors phospholipase A2
- CoA-IT inhibitors CoA-independent transacylase
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- compositions may be formulated in sustained release fo ⁇ n 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.
- 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.
- 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.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9407335A GB9407335D0 (en) | 1994-04-12 | 1994-04-12 | Method of treatment |
GB9407335 | 1994-04-12 | ||
PCT/US1995/004376 WO1995027487A1 (fr) | 1994-04-12 | 1995-04-10 | Procede de traitement de la rhinite allergique |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0755252A1 true EP0755252A1 (fr) | 1997-01-29 |
EP0755252A4 EP0755252A4 (fr) | 1997-07-30 |
Family
ID=10753480
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95916942A Withdrawn EP0755252A4 (fr) | 1994-04-12 | 1995-04-10 | Procede de traitement de la rhinite allergique |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0755252A4 (fr) |
JP (1) | JPH09511988A (fr) |
CN (1) | CN1149828A (fr) |
AP (1) | AP561A (fr) |
AU (1) | AU2381295A (fr) |
BR (1) | BR9507353A (fr) |
CZ (1) | CZ295396A3 (fr) |
GB (1) | GB9407335D0 (fr) |
HU (1) | HUT75940A (fr) |
IL (1) | IL113293A0 (fr) |
MA (1) | MA23503A1 (fr) |
NO (1) | NO964291L (fr) |
PL (1) | PL316850A1 (fr) |
WO (1) | WO1995027487A1 (fr) |
ZA (1) | ZA952932B (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5900421A (en) * | 1997-02-11 | 1999-05-04 | Sepracor Inc. | Methods and compositions for treating allergic asthma and dermatitis using descarboethoxyloratadine |
KR20050008391A (ko) * | 2003-07-15 | 2005-01-21 | 삼성전자주식회사 | 화질개선장치 및 그 방법 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993003723A1 (fr) * | 1991-08-14 | 1993-03-04 | Allergan, Inc. | Complexe antagoniste de recepteur de leucotrienes-antihistamine |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1261835A (fr) * | 1984-08-20 | 1989-09-26 | Masaaki Toda | Benz(thio) amides fusionnes |
-
1994
- 1994-04-12 GB GB9407335A patent/GB9407335D0/en active Pending
-
1995
- 1995-04-06 MA MA23830A patent/MA23503A1/fr unknown
- 1995-04-07 IL IL11329395A patent/IL113293A0/xx unknown
- 1995-04-10 BR BR9507353A patent/BR9507353A/pt not_active Application Discontinuation
- 1995-04-10 CN CN95193359A patent/CN1149828A/zh active Pending
- 1995-04-10 WO PCT/US1995/004376 patent/WO1995027487A1/fr not_active Application Discontinuation
- 1995-04-10 PL PL95316850A patent/PL316850A1/xx unknown
- 1995-04-10 HU HU9602786A patent/HUT75940A/hu unknown
- 1995-04-10 EP EP95916942A patent/EP0755252A4/fr not_active Withdrawn
- 1995-04-10 CZ CZ962953A patent/CZ295396A3/cs unknown
- 1995-04-10 AU AU23812/95A patent/AU2381295A/en not_active Abandoned
- 1995-04-10 ZA ZA952932A patent/ZA952932B/xx unknown
- 1995-04-10 JP JP7526484A patent/JPH09511988A/ja not_active Ceased
- 1995-04-11 AP APAP/P/1995/000729A patent/AP561A/en active
-
1996
- 1996-10-09 NO NO964291A patent/NO964291L/no not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993003723A1 (fr) * | 1991-08-14 | 1993-03-04 | Allergan, Inc. | Complexe antagoniste de recepteur de leucotrienes-antihistamine |
Non-Patent Citations (1)
Title |
---|
See also references of WO9527487A1 * |
Also Published As
Publication number | Publication date |
---|---|
CZ295396A3 (en) | 1997-08-13 |
AP9500729A0 (en) | 1995-04-30 |
PL316850A1 (en) | 1997-02-17 |
NO964291D0 (no) | 1996-10-09 |
NO964291L (no) | 1996-12-05 |
BR9507353A (pt) | 1997-09-23 |
HU9602786D0 (en) | 1996-11-28 |
ZA952932B (en) | 1995-12-20 |
AP561A (en) | 1996-11-15 |
GB9407335D0 (en) | 1994-06-08 |
JPH09511988A (ja) | 1997-12-02 |
HUT75940A (en) | 1997-05-28 |
CN1149828A (zh) | 1997-05-14 |
AU2381295A (en) | 1995-10-30 |
WO1995027487A1 (fr) | 1995-10-19 |
MA23503A1 (fr) | 1995-12-31 |
IL113293A0 (en) | 1995-07-31 |
EP0755252A4 (fr) | 1997-07-30 |
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