IE914444A1 - Administering alpha interferon by oral inhalation to treat¹asthma and non-malignant proliferative pulmonary diseases - Google Patents
Administering alpha interferon by oral inhalation to treat¹asthma and non-malignant proliferative pulmonary diseasesInfo
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- IE914444A1 IE914444A1 IE444491A IE444491A IE914444A1 IE 914444 A1 IE914444 A1 IE 914444A1 IE 444491 A IE444491 A IE 444491A IE 444491 A IE444491 A IE 444491A IE 914444 A1 IE914444 A1 IE 914444A1
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- Prior art keywords
- alpha interferon
- mammal
- treating
- asthma
- interferon
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
-
- 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]
- A61K38/212—IFN-alpha
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Public Health (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A pharmaceutical composition, use or method of treating or preventing asthma or of treating or preventing a non-malignant proliferative pulmonary disease in a mammal by orally administering by inhalation to such a mammal afflicted with asthma or a mammal afflicted with such a pulmonary disease, i.e. a reversible obstructive airway passage disease and/or exercise-induced bronchospasm an effective amount of rhIFN- alpha via a nebulizer or metered dose inhaler are disclosed.
Description
ADMINISTERING ALPHA INTERFERON BY ORAL INHALATION TO TREAT ASTHMA AND NON-MALIGNANT PROLIFERATIVE PULMONARY DISEASES BACKGROUND OF THE INVENTION This invention relates to pharmaceutical compositions comprising human recombinant DNA alpha interferon (rhIFN-α) as an active ingredient to treat or prevent asthma or to treat non-malignant proliferative pulmonary diseases. The invention also relates to use of rhIFN-α for making a medicament for treating or preventing asthma or non-malignant proliferative pulmonary disease as well as to a method of treating and/or preventing asthma or a non-malignant proliferative pulmonary disease by orally administering to a mammal in need of such treating and/or preventing an amount of rhIFN-α effective for such treating.
Human alpha interferon is a naturally occurring mixture of at least eleven compounds including those designated alpha-1 interferon and alpha-2 interferon.
A number of alpha interferon species or components are known and are usually designated by a numeral and letter after the Greek letter alpha. Human alpha-1 interferon is one species contemplated for use in this invention as are the species designated human alpha2 interferons. Under USAN, recombinant DNA human alpha-2 interferons are designated Interferon Alpha-2a, which can -2be made as disclosed in Rubenstein, Biochem. Biophys.
Acta (1982), 695, 5-16, and Interferon Alfa-2b.
Interferon Alfa-2b is the preferred species for use in this invention and is a recombinant DNA human alpha interferon (hereinafter rhIFN-α). Another suitable rhIFN-α included in the acope of this invention is recombinant DNA human interferon alpha-2a.
Human interferon alfa-2b can be produced in bacteria and other microorganisms using recombinant DNA techniques including those disclosed in Nagata et al. Nature, (1980) 284, 316-329; European Patent 32,134 and U.S. Patent No. 4,289,690. Various alpha interferon species are disclosed in U.S. patent 4,503,035.
It is known to administer rhIFN-α parenterally to treat hairy cell leukemia, AIDS-related Kaposi's sarcoma, and hepatitis as well as intralesionally to treat condylomate acuminata. Several groups of investigators have documented that parenterally administered IFN-α does not accumulate in the nasopharyngeal, oropharyngeal, or airway mucosa or in the lung parenchyma in sufficient concentrations or for long enough time periods to be effective against respiratory virus infections.
Recently, it has been shown that nonrecombinant human leukocyte alpha-interferon (hereinafter hIFN-α) can be given to mammals by inhalation to provide high local concentrations in lung and airway mucosal tissue. The instillation of hIFN-α into the bronchi of perfused rabbit lungs has resulted in measurable serum concentrations [V. Bocci et al., Antiviral Res. (1984) Vol. 4, 211-220].
Intranasally administered rhIFN-α at a dose of 5 million units/day prevented rhinovirus transmission within families (Douglas, et al, NEJM (1986), Vol. 314, pp65-70. In one Chinese study, interferon-α (hIFN-a) -3given both intranasally and intraorally at a dose of 7001600 units/day was effective in the treatment of influenza, respiratory syncytial viral bronchiolitis, and asthmatic bronchitis (Jia-xiong, et al, Chin Med J. 100:162-166, 1987).
In man, hIFN-α has been inhaled by patents with advanced non-small cell lung cancer at doses up to 120 million International Units (IU). Kinnula et al. discloses in the J. Interferon Res. (1989), Vol 9, 419-23 that inhaled hIFN-α resulted in serum concentration and side effects (e.g. fever, headache, influenza-like symptoms and nausea) similar to those seen after systemic hIFN-α administration as well as reversible airflow obstruction but no activity against the lung cancer was observed. Inhaled hIFN-α has also been administered to patients suffering from bronchoalveolar carcinoma but no activity on the bronchoalveolar carcinoma has been demonstrated [V. Kinnula et al. J. Interferon Res, (1988) Vol 8, Suppl. 1 p 115].
C.W. White, Semin. Hematol., (1990) Vol. 27 (3, Suppl. 4), 15-22, discloses that parenteral rhINF-α has been successfully used to treat patients with pulmonary hemangiomatosis as well as other variants of hemangiomatous disease such as hemangioendoetheliomas.
J. Pene et al., Proc. Natl Acad. Sci USA (1988) Vol. 85, 6880-6884 disclose that IFN-α can suppress, in vitro, the IgE production from human peripheral blood mononuclear cells. G. Souillet et al. The Lancet, June 17, 1989 p 1384 disclose that the successful subcutaneous administration of IFN-α to a single patient with hyper IgE syndrome (i.e. markedly elevated IgE levels) indicates that such parenteral administration of IFN-a may have potential application in the treatment of severe cases of allergy associated with sharply increased serum IgE levels. B. Burrows et al., NEJM (1989) Vol. 320, -4271-276 disclose that asthma has an allergic basis and is invariably associated with elevaled levels of igE. However, none of the references disclose this invention.
There is still a need for pharmaceutical compositions of rhIFN-α for treating an/or preventing asthma and non-malignant proliferative pulmonary diseases.
SUMMARY OF THE INVENTION This invention provides pharmaceutical compositions for treating or preventing asthma or treating non-malignant proliferative pulmonary diseases which comprises an amount of recombinant DNA human alpha interferon effective for such purposes.
This invention also provides a use of recombinant DNA human alpha interferon for the manufacture of a medicament to treat or prevent asthma or to treat non-malignant proliferative pulmonary diseases.
This invention provides a method of treating asthma in a mammal afflicted with asthma which comprises orally administering via inhalation to such a mammal an amount of recombinant human DNA alpha interferon effective for such treating.
This invention also provides a method of preventing asthma in a mammal afflicted with reversible obstructive airway passage disease or exercise-induced bronchospasm which comprises orally administering via inhalation to such a mammal an amount of recombinant human DNA alpha interferon effective for such preventing.
This invention provides a method of treating a non-malignant proliferative pulmonary disease in a mammal afflicted with such a proliferative disease which comprises orally administering via inhalation to such a mammal an amount of recombinant human DNA alpha interferon effective for such treating. This invention also provides a method of preventing a non-malignant 5proliferative pulmonary disease in a susceptible mammal, which comprises orally administering via inhalation to such a mammal an amount of recombinant DNA human alpha interferon effective for such preventing.
DETAILED DESCRIPTION OF THE INVENTION The term asthma* as used herein includes any asthmatic condition marked by recurrent attacks of paroxysmal dyspnea (i.e. reversible obstructive airway passage disease*) with wheezing due to spasmodic contraction of the bronchi (so called bronchospasms). Asthmatic conditions which may be treated or prevented in accordance with this invention include allergic asthma and bronchial allergy characterized by manifestations in sensitized persons provoked by a variety of factors including exercise, especially vigorous exercise (exercise-induced bronchospasm), irritant particles (pollen, dust, cotton, cat dander) as well as psychologic stresses. The pharmaceutical compositions of this invention are particularly useful in preventing the onset of asthma in mammals e.g. humans afflicted with reversible obstructive airway passage disease and exercise-induced bronchospasm.
The recombinant DNA human alpha interferon (rhIFN-α) administered orally via inhalation to treat asthma in accordance with this invention may be used as monotherapy or as adjunctive therapy with other treatments, e.g., bronchodilators to treat asthma.
The term non-malignant proliferative disease as used herein in reference to the pulmonary system means one or more of (1) Alveolitis, such as Extrinsic Allergic Alveolitis, and Drug toxicity such as caused by e.g. cytotoxic and/or alkylating agents; (2) Vasculitis such as Wegenerzs granulomatosis, Allergic granulomatosis, Pulmonary hemangiomatosis and Pulmonary hemosiderosis; -6(3) Immunologic diseases such as Goodpasture's Syndrome; and (4) Interstitial diseases such as Collagen Vascular Disease (e.g., SLE, rheumatoid arthritis, seleroderma and dermatomyositis, Idiopathic Pulmonary Fibrosis, Chronic Eosinophilic pneumonia, Eosinophilic granuloma and saroidosis.
The effectiveness of the interferon therapy of this invention can be shown clinically in mammals, e.g. human beings afflicted with or suspectible to a nonmalignant proliferative disease or using patients with the following entry criteria: (1) a Karnofsky performance status of 60%; (2) adequate pulmonary function for undergoing the required inhalation treatment satisfactorily as evidenced by (a) forced expiration volume in one second (FEV1) of greater than or equal to 50% and (b) a forced vital capacity (FVC) of greater than or equal to 50% of the predicted value and; (3) no serious systemic infections and/or fever.
The recombinant DNA human alpha interferon (rhIFN-α) administered orally via inhalation with this invention may be used as monotherapy or as adjunctive therapy with other treatments e.g., chemotherapy or immunotherapy to treat non-malignant proliferative diseases.
The recombinant DNA human alpha interferon (rhIFN-α) is administered orally by inhalation in accordance with this invention as a pharmaceutical composition for treating and/or preventing asthma or non-malignant pulmonary diseases containing rhIFN-α which may be dissolved or dispersed in a pharmaceutically acceptable carrier suitable for use in a nebulizer and/or a metered dose inhaler. Pharmaceutically acceptable carriers include, for example, water, saline, ethanol and the like which form a rhIFN-α solution or suspension -7suitable for oral administration via inhalation in accordance with this invention. If desired, the rhIFN-a pharmaceutical compositions useful in this invention may also contain minor amounts of non-toxic auxiliary substances such as melting agents, emulsifying agents, preservatives, stabilizers, and pH buffering agents. The preparation of these pharmaceutical compositions is well known to those skilled in the art; see for example Remington's Pharmaceutical Sciences Mack Publishing Co., Easton PA 15th Edition (1975).
A preferred rhIFN-α pharmaceutical composition for use in accordance with this invention is the Intron® A brand of interferon available as a solution from Schering-Plough Corporation, Kenilworth, New Jersey.
This commercially available Intron A rhIFN-α composition contains glycine, di- and mono- basic sodium phosphate as a buffer and serum albumin. Other preferred rhIFN-a pharmaceutical compositions include any sterile isotonic aqueous solution, e.g. physiological phosphate-buffered saline at pH 7.3 which may also contain pharmaceutically acceptable non-toxic auxiliary agents such as stabilizers and/or a surfactants and the desired amount of rhIFN-a. The concentration of rhIFN-α in the pharmaceutical composition may be adjusted by dilution with 0.9% saline solution before orally administration via inhalation.
The inhalation of drugs by use of nebulizers and metered dose inhalers is well known. See for example Remington, ibid, at chapter 99, pages 1910-1912. Useful nebulizers include the Spira Electro 4 nebulizer, manufactured by Hameenlinman Tyoeskus, Hameenlinna, Finland, whose use is disclosed by Kinnula et al. in the J. of Interferon Research (1989) Vol. 9 at p420. Useful metered dose inhalers as well as drug delivery systems that help deliver oral aerosolized medications from metered dose inhalers to the lungs include INHAL-AID and INSPIREASE -8drug delivery systems available from Schering-Plough Corporation, Kenilworth, New Jersey for as well as those disclosed in the Physicians Desk Reference, 1990 Edition, for use with bronchodilators. The output of the nebulizer or metered dose inhaler for treating and/or preventing asthma in accordance with this invention should consistently and reliably produce particles and/or droplets having a mass median aerodynamic diameter (M.M.A.D.) above about 2.0 microns, preferably having a M.M.A.D. above about 2.0 and less than about 8 microns and more preferably having a M.M.A.D. above about 2.0 to about 5.0 microns. Orally administered particles and/or droplets containing rhIFN-a having a M.M.A.D. in the range of above about 2.0 to less than about 8 microns are suitable for deposition on the peripheral airways and lungs and thus maximize the beneficial effects of inhaled rhIFN-a. Droplets and particles having a M.M.A.D. greater than 8 microns become impacted in the upper airways; and those having a M.M.A.D. less than about 0.5 microns tend to behave like a gas and are exhaled. The output of the nebulizer or metered dose inhaler for treating and/or preventing non-malignant pulmonary diseases in accordance with this invention should consistently and reliably produce particles and/or droplets having a mass median aerodynamic diameter (M.M.A.D.) above about 0.5 microns, preferably having a M.M.A.D. above about 0.5 and less than about 8 microns and more preferably having a M.M.A.D. above about 1.0 to about 3.0 microns. Orally administered particles and/or droplets containing rhIFN-a having a M.M.A.D. in the range of above about 0.5 to less than about 8 microns are suitable fcr deposition on the peripheral airways and lungs and thus maximize the beneficial effects of inhaled rhIFN-a. Droplets and particles having a M.M.A.D. greater than 8 microns become impacted in the upper airways; and those having a M.M.A.D. less than about 0.5 microns tend to behave like a gas and are exhaled. -9However, droplets and/or particles of rhIFN-a having the preferred M.M.A.D. have a high surface energy and tend to agglomerate. The addition of a surfactant preferably a non-volatile liquid soluble in the propellant used in nebulizers or metered dose inhalers is desirable to lessen such agglomeration.
The effective amount of rhIFN-α for treating and/or preventing asthma in accordance with this invention is a daily dosage range of rhIFN-α of about 0.25 χ 106 international units (IU) to about 2 χ 106 IU per day, preferably about 1 χ 106 IU to about 2 χ 106 IU per day, and more preferably about 1 χ 106 IU. The rhINF-α may be administered daily in single or divided doses. To prevent exercise-induced bronchospasm, the rhIFN-α may be administered 15 minutes prior to exercise.
The effective amount of rhIFN-α for treating and/or preventing a non-malignant proliferative pulmonary disease in accordance with this invention is a dosage range of rhIFN-α of about 0.5 χ 106 international units (IU) to about 8 χ 106 IU of rhIFN-α per day, preferably about 0.5 χ 106 IU to about 5 χ 106 IU of rhIFN-a per day, most preferably about 1.0 χ 106 IU to about 3.0 x 106 IU of rhIFN-α per day. The rhINF-α maybe administered daily in single or divided doses.
Based on the judgment of the attending clinician, the amount of rhIFN-a administered and the treatment regimen used will, of course, be dependent on the age, sex and medical history of the patent being treated, the severity of the specific asthma or asthmatic or non-malignant pulmonary disease condition and the tolerance of patient to the treatment regimen as evidenced by local toxicity (e.g. nasal irritation and/or bleeding) and by systemic side effects (e.g. fever, malaise, pancytopenia, CNS depression, gastrointestinal irritation and elevated liver enzymes). -10The following is a description of the clinical protocol to be utilized for treating and preventing asthma or asthmatic conditions especially reversible obstructive airway passage diseases and exercise-induced bronchospasm.
Study Design Prior to enrollment, all patients are throughly examined and their disease clinically staged using chest x-rays, and an electrocardiogram, hematologic and blood chemistries are measured. Pulmonary function including peak expiratory flow (PEF), forced expiratory volume in one second (FEVp, and forced vital capacity (FVC) are measured. Subjective and objective symptoms including the number and severity of coughing bouts, shortness of breath as well as body temperature, blood pressure, and heart rate are measured.
Serum rhIFN-α Concentrations Serum rhIFN-α concentrations are determined by use of commercially available immunoradiometric assays (Abbott Diagnotics and Centocor, respectively) or by vesicular stomatitis virus (VSV) plaque reduction in HEp2 cultures. Measurements are performed before inhalation and -½ hr, lhr, 1½ hr, 4hr, 6hr, 12hr and 24 hr after inhalation.
Toxicity Evaluation and Response Criteria For Asthma Each patient is vigorously monitored for early signs of toxicity as well as evidence of clinical effectiveness throughout the treatment course and on a regular basis thereafter. Methods of evaluation include frequent physician examination, a regular schedule for performance of laboratory procedures including hematologic and serum chemistries and pulmonary function -11studies. Toxicity is graded in accordance with the Work Health Organization's recommendations for grading of acute and subacute toxicity.
Other response criteria include relief of subjective and objective symptoms especially a significant (1) reduction in (a) the number and severity of coughing bouts and/or (b) the shortness of breath, and (2) an increase in (a) pulmonary capacity, and/or (b) exercise capacity and (3) a reduction in adjunctive or comcomitant therapies.
Symptoms and objective side effects of rhIFN-a therapy including changes in body temperature, airflow obstruction and flu-like symptom are also measured.
An improvement in pulmonary function by orally administering rhIFN-α to patients in need of such treating is expected.
The following is a description of the clinical protocol to be utilized for treating and preventing lung malignancies.
Study Design Prior to enrollment, all patients are throughly examined and their disease clinically staged using chest x-rays, computerized tomography, EKG, hematologic and blood chemistries. Clotting studies including total fibrinogen determination, PTT, PT, TT, and fibrin degradation products are conducted. Karnofsky performance status, pulmonary function including peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) are measured. Subjective and objective symptoms including the number and severity of coughing bouts, shortness of -12breath, pain and coughing-up of blood as well as body temperature, blood pressure, and heart rate are measured.
Serum rhIFN-α Concentrations Serum rhIFN-α concentrations are determined by use of commercially available immunoradiometric assays (Abbott Diagnotics and Centocor, respectively) or by vesicular stomatitis virus (VSV) plaque reduction in HEp2 cultures. Measurement are performed before inhalation and 2hr, 5hr, lOhr, 15hr and 24 hr after inhalation.
Toxicity Evaluation and Response Criteria For Non-Malignant Proliferative Pulmonary Disease Each patient is vigorously monitored for early signs of toxicity as well as radiographic evidence of clinical effectiveness throughout the treatment course and on a regular basis thereafter. Methods of evaluation include frequent physician examination, a regular schedule for performance of laboratory procedures including hematologic, serum chemical, pulmonary function and clotting studies. Radiographic studies include chest x-rays and CT scans as appropriate. Toxicity is graded in accordance with the Work Health Organization's recommendations for grading of acute and subacute toxicity. Performance status is graded from zero to four with complete disability being defined as four. Primary clinical response will differ on the specific disease state, and will include, but not be limited to, appearance of the chest X-ray, improvements in pulmonary function, improvements in the amount of oxygen saturation in the blood and in the alveolar-arterial gradient.
These improvements may be accompanied by increases in exercise tolerance, reductions in the systemic disease activity as measured by a comprehensive physical examination of the patient and laboratory test results -13(e.g., erythrocyte sedimentation rate) and reductions in concommitant therapy, e.g. corticosteroids or immunosuppressive agents.
Symptoms and objective side effects of rhIFN-a therapy including changes in body temperature, airflow obstructure and flu-like symptom are also measured.
An improvement in pulmonary function by orally administering rhIFN-α to patients in need of such treating is expected.
Claims (14)
1. A pharmaceutical composition for treating or preventing asthma or a non-malignant proliferative pulmonary disease in a mammal afflicted with asthma or such a pulmonary disease which composition comprises an amount of recombinant DNA human alpha interferon effective for such purpose.
2. A use of recombinant DNA human alpha interferon for the manufacture of a medicament for treating or preventing asthma or a non-malignant proliferative pulmonary disease in a mammal.
3. A method of preventing asthma in a mammal afflicted with airway passage disease or exercise-induced bronchospasm reversible obstructive which comprises orally administering by inhalation to such a mammal an amount of recombinant DNA human alpha interferon effective for such preventing.
4. A nethod of treating asthma in a mammal afflicted with asthma which comprises orally administering by inhalation to such a mammal an amount of recombinant DNA human alpha interferon effective for such treating.
5. A method of treating a non-malignant proliferative pulmonary disease in a mammal afflicted with a proliferative disease which comprises orally administering by inhalation to such a mammal an amount of recombinant DNA human alpha interferon effective for such treating. -156. A pharmaceutical composition or use or method of any preceding claim wherein the recombinant DNA human alpha interferon is administered by a nebulizer or by a metered dose inhaler.
6. 7. A pharmaceutical composition or use or method of any preceding claim wherein the recombinant human DNA alpha interferon is interferon alpha-2a or interferon alpha-2b.
7. 8. A pharmaceutical composition or use or method of any preceding claim where the amount of recombinant human DNA alpha interferon is in the range of about 0.25 x 10 6 IU to about 2 x 10 IU/day.
8. 9. A pharmaceutical composition or use or method of any preceding claim wherein the output of the nebulizer is in the form of particles of an aqueous solution of recombinant human alpha interferon having a mass median aerodynamic diameter of above about 2.0 to about 5.0 microns.
9. 10. A pharmaceutical composition or use or method of any preceding claim wherein the output of the metered dose inhaler is in the form of particles of an aqueous solution of recombinant human alpha interferon having a mass median aerodynamic diameter of above about 2 to about 5.0 microns. - 16
10. 11. A pharmaceutical composition as defined in Claim 1, substantially as described herein by way of Example.
11. 12. Use of recombinant DNA human alpha interferon for the manufacture of a medicament, substantially as described herein by way of Example.
12.
13. A method of preventing asthma in a mammal, substantially as described herein by way of Example.
14. A method of treating asthma in a mammal, substantially as described herein by way of Example.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63156590A | 1990-12-21 | 1990-12-21 | |
| US63155290A | 1990-12-21 | 1990-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE914444A1 true IE914444A1 (en) | 1992-07-01 |
Family
ID=27091422
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE444491A IE914444A1 (en) | 1990-12-21 | 1991-12-19 | Administering alpha interferon by oral inhalation to treat¹asthma and non-malignant proliferative pulmonary diseases |
Country Status (6)
| Country | Link |
|---|---|
| AU (1) | AU9132091A (en) |
| IE (1) | IE914444A1 (en) |
| IL (1) | IL100415A0 (en) |
| MX (1) | MX9102702A (en) |
| PT (1) | PT99837A (en) |
| WO (1) | WO1992011025A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU738838B2 (en) | 1996-09-12 | 2001-09-27 | Valentis, Inc. | Compositions and methods for pulmonary gene delivery |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5028422A (en) * | 1986-05-27 | 1991-07-02 | Schering Corporation | Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon |
| ZA873743B (en) * | 1986-05-27 | 1987-11-25 | Schering Corporation | Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon |
| OA08768A (en) * | 1986-10-22 | 1989-03-31 | Schering Corp | Treatment of AIDS virus with recombinant human alpha interferon. |
| WO1988009673A1 (en) * | 1987-06-02 | 1988-12-15 | Schering Corporation | Treatment of chronic type b hepatitis with a combination of recombinant human alpha and gamma interferons |
| EP0423191A1 (en) * | 1988-07-05 | 1991-04-24 | Schering Corporation | Treatment of genital warts with a combination of podophyllin and recombinant dna human alpha interferon |
| US4959210A (en) * | 1988-11-01 | 1990-09-25 | Schering Corporation | Treatment of genital warts with a combination of liquid nitrogen and recombinant DNA human alpha interferon |
| AU634511B2 (en) * | 1988-12-01 | 1993-02-25 | Schering Corporation | Treatment of squamous cell carcinoma intralesionally with recombinant human alpha interferon |
-
1991
- 1991-12-18 PT PT99837A patent/PT99837A/en not_active Application Discontinuation
- 1991-12-18 IL IL100415A patent/IL100415A0/en unknown
- 1991-12-18 WO PCT/US1991/009177 patent/WO1992011025A2/en active Application Filing
- 1991-12-18 AU AU91320/91A patent/AU9132091A/en not_active Abandoned
- 1991-12-19 MX MX9102702A patent/MX9102702A/en unknown
- 1991-12-19 IE IE444491A patent/IE914444A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PT99837A (en) | 1992-12-31 |
| WO1992011025A2 (en) | 1992-07-09 |
| AU9132091A (en) | 1992-07-22 |
| WO1992011025A3 (en) | 1992-09-17 |
| MX9102702A (en) | 1992-06-01 |
| IL100415A0 (en) | 1992-09-06 |
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