EP1227831A2 - Interferon gamma pour le traitement de l'asthme - Google Patents

Interferon gamma pour le traitement de l'asthme

Info

Publication number
EP1227831A2
EP1227831A2 EP00976004A EP00976004A EP1227831A2 EP 1227831 A2 EP1227831 A2 EP 1227831A2 EP 00976004 A EP00976004 A EP 00976004A EP 00976004 A EP00976004 A EP 00976004A EP 1227831 A2 EP1227831 A2 EP 1227831A2
Authority
EP
European Patent Office
Prior art keywords
ifn
glucocorticoid
asthma
combination
dosage
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Withdrawn
Application number
EP00976004A
Other languages
German (de)
English (en)
Inventor
Lutz-Henning Block
Rolf Ziesche
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Relief Therapeutics International SA
Original Assignee
Mondobiotech AG
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.)
Filing date
Publication date
Application filed by Mondobiotech AG filed Critical Mondobiotech AG
Priority to EP00976004A priority Critical patent/EP1227831A2/fr
Publication of EP1227831A2 publication Critical patent/EP1227831A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/217—IFN-gamma
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention describes for the first time the successful clinical application of interferon gamma (IFN- ⁇ ) in human bronchial asthma therapy.
  • IFN- ⁇ interferon gamma
  • the clinical data show unambiguously that continuous application of IFN- ⁇ in relatively low doses can be successfully used for long-term treatment of severe asthma bronchiale, especially of glucocorticoid-resistant asthma.
  • the invention relates also to a combination therapy administering IFN- ⁇ and glucocorticoids, which alone are not or not sufficiently effective in asthma therapy.
  • Bronchial asthma has been defined by the WHO as "chronic inflammatory disease of the airways" and summarized by chronic infiltration and activation of several types of inflammatory cells in the bronchial mucosa, particularly CD4 + T lymphocytes, defined as helper type 2 phenotype (Th2), by their cytokine profile (Bousquet et al.,1990, N. Engl. J. Med. 323:1033-1039; Broide et al., 1991 , J. Allergy Clin. Immunol. 88:637-648; Robinson et al., 1992, N. Engl. J. Med. 326:298-304; Woodley et al., 1994, Eur. Resp. J.
  • Chronic inflammation of the respiratory mucosa plays a fundamental role in the pathogenesis of asthma, which affects as many as 10% of individuals in industrialized nations (Roche et al,1989, Lancet. 1 :520-523).
  • the inflammatory response in asthma is tightly associated with airway hyperresponsiveness, a hallmark of asthma, and involves a number of different cell types including eosinophils, basophils, mast cells, and, most importantly, Th2 lymphocytes, which can be isolated from the lungs of patients with asthma. When activated, these cells induce mediators of inflammation and cytokines, such as interleukin (IL)-4, IL-5, IL-10 and GM-CSF, which amplify the inflammatory response and may remodel lung architecture.
  • IL interleukin
  • IL-13 a pleotropic cytokine produced in large quantities by activated Th2 lymphocytes causes chronic airway inflammation, mucus hypersecretion, subepithelial fibrosis, and eotaxin production (Zhou et al., Z., 1999, J. Clin. Invest. 103:779-788), classical features of bronchial asthma. Even more important, abrogation of the IL-13-dependent immune response in IL-13 deficient mouse models led to the complete abolishment of bronchial hyperresponsiveness (Wills-Karp et al., 1998, Science 282: 2258-61 ; Gr ⁇ nig et al., 1998, Science 282:2261-63).
  • Th2 cells promote airway inflammation in asthma
  • Th1 cells which secrete IFN- ⁇
  • Th1 cells inhibit the proliferation, and therefore the development, of Th2 cells (Drazen et al, 1996, J. Exp. Med. 183:1-5)
  • IFN- ⁇ inhibits IgE synthesis in some instances (Derdak et al., 1992, Am. J. Physiol. 263:L283-L290).
  • conventional allergen immunotherapy which improves symptoms in allergic and asthmatic patients, reduces IL-4 production (Makhluf et al, 1996, J. Investig. Dermatol.
  • Interferon- ⁇ is a naturally glycoprotein having a molucular weight of about 17 kD which can be commercially produced today also by recombinant techniques.
  • IFN- ⁇ is, for example, known to be effective alone or in combination with other anti- inflammatory drugs in the treatment of rheumatic arthritis and in inducing production of additional surfactants in the lungs of individuals afflicted with respiratory distress syndrome (RDS).
  • RDS respiratory distress syndrome
  • interferone-gamma was successfully applied in interstitial lung, respectively idiopathic pulmonary fibrosis, disease in combination with prednisolone: the mechanisms that regulate the selected form of immune biology in bronchial asthma are unknown. From investigations performed in the comparable setting of a chronic inflammatory reaction, idiopathic pulmonary fibrosis, which is also characterized by a Th2-polarized immune response, it is known that the clinical application of IFN-g both improves pulmonary function and changes the immune response by reverting the Th2 response( Ziesche et al., 1996, Chest 110:25S, EP-A1-0795 332).
  • lnterferon- ⁇ is usually applicable via parenteral, preferably via subcutaneous, injection. Maximum serum concentrations have been found after seven hours, half life in plasma is six hours.
  • the main adverse effects consist of fever, chills, sweating, headache, myalgia and drowsiness. These effects have been observed within the first hours after injection. Rare side effects are local pain and erythema, elevation of liver enzymes, reversable granulo- and thrombopenia and cardiotoxicity. No specific antibodies against recombinant interferon- ⁇ have been observed up to now.
  • glucocorticoid-resistant asthma relates, according to this invention, to asthma forms and asthma-like disorders which are completely or essentially resistant against treatment with glucocoticoids as monotherapy.
  • the treatment according to the invention shows significant advantages in contrast to the traditional treatment with high-dosage glucocorticoids or immun-suppressive drugs alone or in combination.
  • the invention shows that - using the drugs mentioned above and below - the symptoms of the disease can be distinctly reduced or mitigated, respectively, the life quality improved. Hard and severe asthma attacks can be diminshed and finally stopped. This can be achieved by applying interferon- ⁇ in low doses and for a long-term period.
  • the simultaneous application of glucocorticoids although not effective as monotherapy of glucocorticoid-resistant asthma, causes a positive effect.
  • IFN- ⁇ which are usually applied in the treatment of viral infections or tumors (approximately 100 ⁇ g - 5 mg per M 2 of body surface per single dose and per day, up to 7-times per week, e.g. WO 87/07842)
  • using the drugs indicated below that a long-term treatment is possible which improves distinctly the health and the condition of the patient.
  • IFN- ⁇ interferon gamma
  • glucocorticoids for the manufacture of a medicament or a combination of medicaments for the long-term treatment of bronchial asthma.
  • IFN- ⁇ can be used successfully in acute as well as in long-term therapy of bronchial asthma.
  • IFN- ⁇ interferon gamma
  • interferon- ⁇ is effective in a dose of 5 - 100 ⁇ g, 1- 5 times, preferably 2 - 3 times per week during a period of 4 - 24 months, preferably 10 - 15 months.
  • the above-indicated single dosages of interferon- ⁇ are administered parenteral, preferably subcutaneously to the patient three times per week.
  • a weekly dosage for a patient is between approximately 15 and 300 ⁇ g interferon.
  • an object of the invention to provide a use and method for a long- term treatment of bronchial asthma in a patient comprising administering low- dosage interferon gamma (IFN- ⁇ ) or a combination of low-dosage of IFN- ⁇ with a glucocorticoid, wherein a single dose of 5 - 100 ⁇ g IFN- ⁇ is administered 1 - 5 times per week.
  • IFN- ⁇ interferon gamma
  • IFN- ⁇ low-dosage interferon gamma
  • Suitable glucocorticoids are, for example, cortisol, prednisone, cortisone, prednisolone, and 6- ⁇ -methylprednisolone.
  • the preferred compound according to the invention is prednisolone.
  • the doses of glucocorticoids which should be administered to a patient vary according to the invention from 10 - 100 mg / single dose and more preferably from 15 - 80 mg.
  • the initial application is preferably 75 mg.
  • the glucocorticoid is administered in an initial phase of 1- 4 weeks, preferably 2 - 3 weeks.
  • the dose during this initial dose varies between 20 and 100 mg, preferably 50 - 75 mg. After this initial phase the dose can be reduced to 10 - 5 mg. During the following months of therapy this dose can be continuously cut down and finally stopped.
  • the optimum therapeutically acceptable dosage and dose rate for interferon- ⁇ and glucocorticoids for a given patient within the above-said ranges depends on a variety of factors, such as the activity of the specific active material employed, the age, body weight, general health, sex, diet, time and route of administration, rate of clearance or the object of treatment.
  • parenteral as mentioned above and below includes subcutaneous, intravenous, intra-articular and intratracheal injection and infusion techniques. Oral administration is applicable only in the case of glucocorticoids. This application is not suitable for polypeptides like interferones since they are not bio- available after passing the gastro-intestinal tract.
  • Interferon is administered preferably in pharmaceutical compositions and formulations which contain beside interferon- ⁇ suitable carriers, excipients, diluents etc.
  • pharmaceutically acceptable carrier or excipient means an inert, non toxic liquid filler, diluent, solvent or solution, not reacting adversely with the active compounds or with the patient.
  • suitable liquid carriers are well known in the art such as steril water, saline, aqueous dextrose, sugar solutions, ethanol, glycols and oils, including those of petroleum, animal, vegetable, or synthetic origin.
  • the formulations may also contain adjuvants or vehicles which are typical for parenteral administration.
  • interferon- ⁇ and glucocorticoids may eventually form pharmaceutically acceptable salts with any non-toxic, organic or inorganic acid showing changed solubility.
  • Inorganic acids are, for example, hydrochloric, sulphuric or phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • organic acids are the mono, di and tri carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, salicylic and sulfonic acids.
  • Salts of the carboxy terminal amino acid moiety include the non- toxic carboxylic acid salts formed with any suitable inorganic or organic bases. These salts include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and organic primary, secondary and tertiary amines such as trialkylamines.
  • IFN- ⁇ in combination with other therapeutically effective agents such as anti-allergic agents, non-steroidal anti-inflammatory or anti-pyretic agents such as phenylbutazone, acetyl salicylic acid, ibuprofen or lipocortins.
  • agents such as anti-allergic agents, non-steroidal anti-inflammatory or anti-pyretic agents such as phenylbutazone, acetyl salicylic acid, ibuprofen or lipocortins.
  • agents can be administered in doses and pharmaceutical formulations which are per se known in the art.
  • It is another object of the present invention to provide a use and method for preventing redevelopment and continuous growths after surgical removal of nasal polyps associated to asthma and asthma-like diseases comprising administering to a patient IFN- ⁇ or a combination of IFN- ⁇ with a glucocorticoid as indicated above.
  • TGF- ⁇ 1 and IL-13 Investigating the transcription of genes related to the inflammatory mediators TGF- ⁇ 1 and IL-13 reveals that there is an increased level of these mediators and a decreased level and even a lack of IFN- ⁇ in tissue of bronchial mucosa of asthma patients. Since these factors are known to be associated with the epithelial growth and its regulation the use with IFN- ⁇ can be speculated to be successful for disorders which show overexpression of said factors.
  • IFN- ⁇ treatment IFN- ⁇ -1b, Boehnnger Ingelheim, Germany
  • IFN- ⁇ -1b IFN- ⁇ -1b
  • Boehnnger Ingelheim, Germany IFN- ⁇ -1b
  • Additive glucocorticoid treatment was reduced to 7,5 mg per day after three weeks.
  • Figure 2 demonstrates the course of his disease over a period of 12 months under continuous treatment with IFN- ⁇ (300 ⁇ g per week) and 7,5 mg prednisolone per day. Meanwhile, the patient has been under IFN- ⁇ treatment for 25 months.
  • the changes in lung volumes (total lung capacity (TLC), functional exspiratory vital capacity (FVC) and functional exspiratory volume (FEV)) and partial pressures of blood gases (pO 2 , pCO 2 ) of the patient during the above-specified treatment are given in Table 1 and Table 2.
  • the FEV1 value increases during the first 12 months from 3,1 I to ca. 4,5 I (+ 48,4 %), the FVC value increases from ca. 4,4 I to 6,5 I (+ 47,7%) and the TLC value increases from 7,1 to 7,6 (+ 7%).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pulmonology (AREA)
  • Zoology (AREA)
  • Rheumatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pain & Pain Management (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'application clinique réussie et inédite de l'interféron gamma (IFN-η) dans la thérapie de l'asthme bronchique humain. Les données cliniques montrent sans ambiguïté que l'application continue d'IFN-η à doses relativement faibles permet de traiter à long terme l'asthme bronchique grave avec succès, spécialement l'asthme résistant aux glucocorticoïdes. L'invention concerne également une thérapie combinant IFN-η et glucocorticoïdes, qui, administrés seuls, ne sont pas ou pas assez efficaces dans la thérapie de l'asthme.
EP00976004A 1999-11-10 2000-11-06 Interferon gamma pour le traitement de l'asthme Withdrawn EP1227831A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00976004A EP1227831A2 (fr) 1999-11-10 2000-11-06 Interferon gamma pour le traitement de l'asthme

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99122357 1999-11-10
EP99122357 1999-11-10
PCT/EP2000/010941 WO2001034180A2 (fr) 1999-11-10 2000-11-06 Interferon gamma pour le traitement de l'asthme
EP00976004A EP1227831A2 (fr) 1999-11-10 2000-11-06 Interferon gamma pour le traitement de l'asthme

Publications (1)

Publication Number Publication Date
EP1227831A2 true EP1227831A2 (fr) 2002-08-07

Family

ID=8239362

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00976004A Withdrawn EP1227831A2 (fr) 1999-11-10 2000-11-06 Interferon gamma pour le traitement de l'asthme

Country Status (5)

Country Link
EP (1) EP1227831A2 (fr)
JP (1) JP2003513933A (fr)
AU (1) AU1392301A (fr)
CA (1) CA2387089A1 (fr)
WO (1) WO2001034180A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPR381601A0 (en) * 2001-03-19 2001-04-12 Monash University Method of treating respiratory conditions
US6911198B2 (en) 2001-09-17 2005-06-28 Yeda Research And Development Co. Ltd. Method and pharmaceutical composition for treating inflammation
AU2002347182A1 (en) * 2001-12-18 2003-06-30 Mondobiotech Licensing Out Ag Pharmaceutical composition of interferon gamma or pirfenidone with molecular diagnostics for the improved treatment of interstitial lung diseases
EP1430902A1 (fr) * 2002-12-20 2004-06-23 Mondobiotech Laboratories Anstalt Composition pharmaceutique comprenant l'interferon gamma avec diagnostic moléculaire pour un meilleur traitment de l'asthme
CA2519313A1 (fr) * 2003-03-28 2004-10-07 Katrien Lorre Traitement de la pneumopathie inflammatoire mediee par la reponse immunitaire de type 1, par la modulation de l'activite de l'ifn-gamma
EP1516627A1 (fr) * 2003-09-17 2005-03-23 CONARIS research institute AG Interferon-gamma pour le traitement de maladies associées au gène NOD2
US11135223B2 (en) 2016-01-22 2021-10-05 Yale University Compositions and methods for inhibiting Dkk-1

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007842A1 (fr) * 1986-06-17 1987-12-30 Biogen N.V. Combinaisons d'interferons gamma et d'agents anti-inflammatoires ou anti-pyretiques et procede de traitement de maladies

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL76591A0 (en) * 1984-10-05 1986-02-28 Bioferon Biochem Substanz Pharmaceutical compositions containing ifn-ypsilon and processes for the preparation thereof
DK0502997T3 (da) * 1989-12-01 1995-07-17 Childrens Medical Center Behandling af atopiske sygdomme med gamma-interferon
EP0795332B1 (fr) * 1996-03-14 2005-06-01 Mondobiotech Interferon SA Utilisation médicale de gamma interféron dans les maladies pulmonaires interstitielles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987007842A1 (fr) * 1986-06-17 1987-12-30 Biogen N.V. Combinaisons d'interferons gamma et d'agents anti-inflammatoires ou anti-pyretiques et procede de traitement de maladies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0134180A3 *

Also Published As

Publication number Publication date
JP2003513933A (ja) 2003-04-15
WO2001034180A2 (fr) 2001-05-17
AU1392301A (en) 2001-06-06
WO2001034180A3 (fr) 2001-11-08
CA2387089A1 (fr) 2001-05-17

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