WO2000015226A1 - Anti-histamines traitant la sinusite ou l'otite moyenne non infectieuse - Google Patents

Anti-histamines traitant la sinusite ou l'otite moyenne non infectieuse Download PDF

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Publication number
WO2000015226A1
WO2000015226A1 PCT/US1999/018839 US9918839W WO0015226A1 WO 2000015226 A1 WO2000015226 A1 WO 2000015226A1 US 9918839 W US9918839 W US 9918839W WO 0015226 A1 WO0015226 A1 WO 0015226A1
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WO
WIPO (PCT)
Prior art keywords
composition
antihistamine
pharmaceutically acceptable
substituted
otitis media
Prior art date
Application number
PCT/US1999/018839
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English (en)
Inventor
Alan G. Harris
Domenic G. Iezzoni
Melvyn R. Danzig
Richard R. Lorber
Original Assignee
Schering Corporation
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to AU60188/99A priority Critical patent/AU6018899A/en
Publication of WO2000015226A1 publication Critical patent/WO2000015226A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention generally relates to methods of treatment of sinusitis and
  • otitis media including otitis media with effusion and persistent middle ear effusion
  • descarboethoxyloratadine also referred to as desloratadine or "DCL"
  • DCL desloratadine
  • Sinusitis is an inflammation of the mucosa of
  • Sinusitis and otitis media are often typically treated as an infectious disease.
  • the treatment typically includes administration of an antibiotic along with a corticosteroid and an antihistamine, or a nasal decongestant, such as described in, for example, J. Braun et al, Allergy, 52 (6). 650-655 (1997).
  • a corticosteroid and an antihistamine or a nasal decongestant, such as described in, for example, J. Braun et al, Allergy, 52 (6). 650-655 (1997).
  • the sinusitis or otitis media is not necessarily accompanied by an infection. This is particularly true when the disease is associated with allergic rhinitis.
  • the above-noted desires and objectives are addressed by the present invention which, in one embodiment, provides methods and pharmaceutical compositions for the treatment of non- infectious sinusitis or otitis media or both.
  • the composition comprises in combination: (i) a therapeutically effective amount of one or more a':tihistamines with substantially reduced anticholinergiC activity or a pharmaceutically acceptable salt or solvate of such antihistamine(s) and (ii) a pharmaceutically acceptable carrier. While additional ingredient or ingredients may optionally be present, the antihistamine(s) is (are) the major active ingredient(s) in the composition. Antibiotics, however, are absent in the composition.
  • the antihistamines useful in the practice of the present invention correspond to the general Formula I:
  • X represents a halogen atom or a hydrogen atom
  • Y represents hydrogen, - COOR, or -SO 2 R 2 , wherein R, represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic ring; and R 2 represents a substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted aryl group.
  • the compounds of Formula I embrace optical isomers and mixtures thereof, racemic mixtures, enol forms and other such modifications.
  • Preferred compounds belonging to Formula I are those in which X is a halogen atom or a hydrogen atom, and Y is hydrogen or -COOR,, where R, is defined above. More particularly preferred compounds of this class are when X is Cl and R, is carboethoxy (the compound being commonly known as loratadine or SCH 29851) and when X is Cl and R, is hydrogen (the compound being commonly known as descarboethoxyloratadine or desloratadine or DCL or SCH 34117).
  • the antihistamine or its pharmaceutically acceptable salt or solvate is generally present in the composition in about 2.5-20 milligrams, preferably in about 5-10 milligrams and typically in about 7.5 milligrams per dosage. Additionally, a pharmaceutically acceptable carrier is present. As stated earlier, one or more other non- antibiotic ingredients may also be optionally present in the composition.
  • Such optional compounds may include, a decongestant (such as, for example, pseudoephedrine), a cough suppressant (such as, for example, dextromethorphan), an expectorant (such as, for example, guiaifenesin), a leukotriene antagonist (such as, for example, montelukast or a pharmaceutically acceptable salt or solvate thereof, and the like), an inhaled nasal steroid (such as, for example, mometasone furoate, NASONEX' (available from Schering-
  • a decongestant such as, for example, pseudoephedrine
  • a cough suppressant such as, for example, dextromethorphan
  • an expectorant such as, for example, guiaifenesin
  • a leukotriene antagonist such as, for example, montelukast or a pharmaceutically acceptable salt or solvate thereof, and the like
  • an inhaled nasal steroid such as, for example
  • the present invention additionally discloses a method for the treatment of non- infectious sinusitis and/or otitis media in a mammalian organism in need of such treatment, such treatment comprising administering a pharmaceutical composition described above.
  • this invention provides pharmaceutical compositions for the treatment of non-infectious sinusitis, otitis media or both.
  • otitis media also includes otitis media with effusion and persistent middle ear effusion in this invention.
  • the composition comprises a therapeutically effective amount of one or more antihistamines with substantially reduced anticholinergiC activity or a pharmaceutically acceptable salt or solvate of such antihistamine, in combination with a pharmaceutically acceptable carrier. While additional ingredients may optionally be present, the antihistamine is the major active ingredient in the composition. Antibiotics, however, are absent in the composition.
  • the amount of the antihistamine which can be employed in a unit dosage form of the present compositions ranges generally from about 2.5 to about 20 mg, preferably from about 5 to about 10 milligrams and typically in about 7.5 milligrams.
  • the antihistamines useful in the practice of the present invention correspond the general Formula I shown above.
  • the various elements in Formula I are also described above.
  • the compounds of Formula I can be prepared in accordance with processes known in the art, for example, that disclosed in U.S. Patent 3,326,924. Preferred compounds are those in which X is a halogen atom or a hydrogen atom, and Y is hydrogen or -COOR,, where R, is defined above.
  • More particularly preferred compounds of this class are when X is Cl and R, is carboethoxy (the compound being known as loratadine) and when X is Cl and R, is hydrogen (the compound being known as descarboethoxyloratadine or DCL).
  • Loratadine is an antagonist of the H-l histamine receptor protein.
  • the histamine receptors H-l and H-2 are two well-identified forms.
  • the H-l receptors are those that mediate the response antagonized by conventional antihistamines. H-l receptors are present, for example, in the nose, sinus, ocular conjunctiva and tissues, ileum, the skin, and the bronchial smooth muscle of man and other mammals.
  • Descarboethoxyloratadine is a non-sedating antihistamine, whose technical name is 8-chloro-6,l 1-dihydro-l l-(4-piperidylidene)-5H- benzo[5,6]cyclohepta[l,2]pyridine. This compound is described in Quercia et al., Hosp. Formul, 2__ 137-53 (1993), in U.S. Patent 4,659,716, and in WO 96/20708. DCL is also an antagonist of the H-l histamine receptor protein. DCL is a metabolic derivative of loratadine.
  • a pharmaceutically acceptable carrier which includes diluents, excipients or carrier materials
  • the carrier is suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component 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, disinfectants and coloring agents may 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, and the like.
  • Disintegrants include starch, methylcellulose, guar gum and the like.
  • Disinfectants include benzalkonium chloride and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • non-antibiotic ingredients may also be optionally present in the composition.
  • Such optional compounds may include a decongestant (such as, for example, pseudoephedrine), a cough suppressant (such as, for example, dextromethorphan), an expectorant (such as, for example, guiaifenesin), a leukotriene antagonist (such as, for example, montelukast or a pharmaceutically acceptable salt thereof), an inhaled nasal steroid (such as, for example, mometasone furoate, NASONEX * and the like), a non-steroidal anti-inflammatory (such as, for example, ibuprofen, naproxen and the like), a non-narcotic analgesic (such as, for example, acetaminophen and the like) and suitable combinations thereof, such as, for example, a nasal spray with a combination of ingredients including loratadine, DCL, mometasone furoate and other suitable ingredients.
  • the present invention discloses a method of preparing a composition for the treatment of sinusitis and or otitis media, with the composition comprising a therapeutically effective amount of one or more antihistamines represented by Formula I, or a pharmaceutically acceptable salt or solvate of such antihistamine, in combination with a pharmaceutically acceptable carrier.
  • the present invention discloses a method of administering an effective treatment for sinusitis and/or otitis media.
  • the pharmaceutical compositions of the present invention can be administered depending upon the patient's age, sex, weight and severity of the condition being treated.
  • the human oral dosage form containing the antihistamine and the carrier can be administered 1 or 2 times per day.
  • this invention discloses a method for the treatment of non-infectious sinusitis and or otitis media in a mammalian organism in need of such treatment, such treatment comprising administering a pharmaceutical composition described above.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic 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.
  • Dosage form - refers to composition containing the antihistamine and the carrier formulated into a delivery system, i.e., tablet, capsule, oral gel, powder for constitution or suspension in association with inactive ingredients.
  • Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the antihistamine and the carrier.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet- refers to a compressed or molded solid dosage form containing the ingredients (the antihistamine and the carrier) with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
  • Oral gels refers to the antihistamine and the carrier dispersed or solubilized in a hydrophilic semi-solid matrix.
  • Powders for constitution refers to powder blends containing the antihistamine and the carrier and suitable diluents which can be suspended in water or juices.
  • Diluent - refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn rice and potato; and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
  • Disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
  • Binders - refers to substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidinone; and inorganics such as magnesium aluminum silicate.
  • sugars such as sucrose
  • starches derived from wheat, corn rice and potato natural gums such as acacia, gelatin and tragacanth
  • derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate
  • the amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'1-leucine.
  • Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Coloring agents - excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
  • Bioavailability - refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control, as well as to topical bioavailability.
  • the antihistamine/ carrier combination and the optional ingredient or ingredients may be administered in combination or separately in the method of treating the non- infective sinusitis or otitis media. For example, they may be administered concurrently or sequentially, i.e. they may be administered in combination either concurrently or by the sequential administration of the ingredients in a suitable order.
  • terapéuticaally effective amount means that amount of the antihistamine which provides a therapeutical benefit in the treatment or management of the non-infective sinusitis or otitis media.
  • a prophylactic or therapeutic dose of the antihistamine in the acute or chronic management of the targeted disease or condition will vary with the severity of the condition to be treated and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according the age, body weight, and response of the individual patient.
  • Suitable total daily dose ranges can be readily determined by those skilled in the art.
  • the dose may be administered in single or divided doses orally, topically, transdermally, or locally by inhalation.
  • a preferred oral daily dose range of decongestant, such as pseudophedrine should be from about 50 mg to about 300 mg, more preferably, about 120 mg to about 240 mg.
  • suitable oral daily dosage ranges of leukotriene inhibitor can be readily determined by those skilled in the art.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of the antihistamine according to the methods of the present invention.
  • oral, intraoral, rectal, parenteral, epicutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, intradural, intraocular, intrarespiratory, oral or nasal inhalation and like forms of administration may be employed.
  • pharmaceutically acceptable salt refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids or bases or organic acids or bases. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric.
  • Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succi ic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic.
  • inorganic bases include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Appropriate organic bases may be selected, for example, from N,N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylgulcaine), lysine and procaine.
  • dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, syrups, elixirs, gels, powders, magmas, lozenges, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal or oral sprays, aerosols and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desirable, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the composition for use in the methods of the present invention may also be administered by controlled release means and/or delivery devices. Such skills are well known to those skilled in the art.
  • compositions for use in the methods of the present invention may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient and any optional ingredient or ingredients with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • the antihistamines particularly preferred in the practice of the invention are loratadine and its metabolite, DCL.
  • Loratadine may be synthesized by methods disclosed in U.S. Patent No. 4,282,233.
  • the metabolite DCL may be prepared similarly, by reaction steps conventional in the art, as described in U.S. Patent No. 4,659,716 which is incorporated here by reference in its entirety.
  • One common method of preparing DCL is to reflux loratadine in the presence of sodium hydroxide and ethanol.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention a trait à des compositions sans antibiotique et des méthodes de traitement de la sinusite et/ou de l'otite moyenne non infectieuse. Les compositions contiennent une dose thérapeutique efficace d'une anti-histamine anticholinergique ou d'un sel ou d'un solvate pharmaceutiquement acceptable de celle-ci; et (ii) un excipient pharmaceutiquement acceptable, et les méthodes consistent en leur administration.
PCT/US1999/018839 1998-09-10 1999-09-09 Anti-histamines traitant la sinusite ou l'otite moyenne non infectieuse WO2000015226A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60188/99A AU6018899A (en) 1998-09-10 1999-09-09 Antihistamines for treating non-infective sinusitis or otitis media

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15084298A 1998-09-10 1998-09-10
US09/150,842 1998-09-10

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WO2000015226A1 true WO2000015226A1 (fr) 2000-03-23

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AR (1) AR022378A1 (fr)
AU (1) AU6018899A (fr)
CO (1) CO5271713A1 (fr)
PA (1) PA8481801A1 (fr)
PE (1) PE20001070A1 (fr)
WO (1) WO2000015226A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009656A1 (fr) * 1987-06-08 1988-12-15 Abraham Sunshine Melanges contre la toux et le rhume comprenant des medicaments a base d'antihistaminiques sans effets sedatifs
EP0396404A1 (fr) * 1989-05-03 1990-11-07 Schering Corporation Composition pharmaceutique contenant de la loratadine, de l'ibuprofène et de la pseudoéphédrine
WO1994009761A1 (fr) * 1992-10-23 1994-05-11 Schering Corporation Composition stable de dose administree oralement et a liberation prolongee
WO1996020708A1 (fr) * 1994-12-30 1996-07-11 Sepracor, Inc. Procedes et composition de traitement de la rhinite allergique et d'autres troubles au moyen de descarboethoxyloratadine
EP0780127A1 (fr) * 1995-12-19 1997-06-25 The Procter & Gamble Company Pulvérisateur nasale contenant un stéréoide et un antihistamine
WO1997028797A1 (fr) * 1996-02-08 1997-08-14 Merck & Co., Inc. Procede de traitement et composition pharmaceutique
WO1998018470A1 (fr) * 1996-10-31 1998-05-07 Schering Corporation Composition destinee au traitement de l'asthme et contenant de la loratadine et un decongestionnant

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009656A1 (fr) * 1987-06-08 1988-12-15 Abraham Sunshine Melanges contre la toux et le rhume comprenant des medicaments a base d'antihistaminiques sans effets sedatifs
EP0396404A1 (fr) * 1989-05-03 1990-11-07 Schering Corporation Composition pharmaceutique contenant de la loratadine, de l'ibuprofène et de la pseudoéphédrine
WO1994009761A1 (fr) * 1992-10-23 1994-05-11 Schering Corporation Composition stable de dose administree oralement et a liberation prolongee
WO1996020708A1 (fr) * 1994-12-30 1996-07-11 Sepracor, Inc. Procedes et composition de traitement de la rhinite allergique et d'autres troubles au moyen de descarboethoxyloratadine
EP0780127A1 (fr) * 1995-12-19 1997-06-25 The Procter & Gamble Company Pulvérisateur nasale contenant un stéréoide et un antihistamine
WO1997028797A1 (fr) * 1996-02-08 1997-08-14 Merck & Co., Inc. Procede de traitement et composition pharmaceutique
WO1998018470A1 (fr) * 1996-10-31 1998-05-07 Schering Corporation Composition destinee au traitement de l'asthme et contenant de la loratadine et un decongestionnant

Non-Patent Citations (6)

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Title
BRAUN J J W: "Adjunct effect of loratadine in the treatment of acute sinusitis in patients with allergic rhinitis.", ALLERGY (COPENHAGEN), vol. 52, no. 6, 1997, pages 650 - 655, XP002127893 *
COOK P.R. ET AL: "Allergic rhinosinusitis in the pediatric population", OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA, (1996) 29/1 (39-56), United States, XP002127889 *
FIREMAN P: "Treatment strategies designed to minimize medical complications of allergic rhinitis", AMERICAN JOURNAL OF RHINOLOGY, vol. 11, no. 2, 1997, pages 95 - 102, XP002127890 *
PELIKAN Z.: "The role of allergy in sinus disease: Children and adults", CLINICAL REVIEWS IN ALLERGY AND IMMUNOLOGY, (1998) 16/1-2 (55-156), United States, XP002127887 *
SKONER D.P.: "Control of allergic rhinitis with antihistamines may prevent the onset or recurrence of otitis media.", PEDIATRIC ASTHMA, ALLERGY AND IMMUNOLOGY, (1997) 11/4 (193-205)., XP002127892 *
SOLOW I A ET AL: "II. ALLERGIC SEROUS OTITIS MEDIA TREATMENT AND RESULTS.", ANNALS OF ALLERGY, (1965 JUN) 23, 285-7., XP002127891 *

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AU6018899A (en) 2000-04-03
CO5271713A1 (es) 2003-04-30
PE20001070A1 (es) 2000-10-19
AR022378A1 (es) 2002-09-04

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