EP1320361A4 - Methode zur verminderung von verschlimmerungen in verbindung mit copd - Google Patents
Methode zur verminderung von verschlimmerungen in verbindung mit copdInfo
- Publication number
- EP1320361A4 EP1320361A4 EP01957262A EP01957262A EP1320361A4 EP 1320361 A4 EP1320361 A4 EP 1320361A4 EP 01957262 A EP01957262 A EP 01957262A EP 01957262 A EP01957262 A EP 01957262A EP 1320361 A4 EP1320361 A4 EP 1320361A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- copd
- exacerbations
- patients
- pde
- inhibitors
- 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- Withdrawn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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- 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
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to a method for reducing the incidences and/or the severity of exacerbations of COPD by administering a phosphodiesterase 4 (PDE4) inhibitor.
- PDE4 phosphodiesterase 4
- COPD Chronic obstructive pulmonary disease
- the disease is primarily caused by smoking, has a high incidence of mortality and morbidity and is poorly served by existing therapies.
- COPD accounts for approximately 6% of deaths in men and 4% of deaths in women and is the third most common cause of death (2).
- the World Health Organization Global Burden of Disease study showed COPD to be the sixth leading cause of death worldwide in 1990 and is predicted to rise to third position by 2020.
- COPD is associated with major healthcare costs, largely due to expensive treatments such as long-term oxygen therapy and hospital admissions, as well as indirect costs including loss of working capacity.
- Cyclic nucleotide phosphodiesterases represent a family of enzymes that hydrolyze the ubiquitous intracellular second messengers, adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5 -monophosphate (cGMP) to their corresponding inactive 5 - monophosphate metabolites.
- PDEs Cyclic nucleotide phosphodiesterases
- cAMP adenosine 3',5'-monophosphate
- cGMP guanosine 3',5 -monophosphate
- the target enzyme for use of the formulations of this invention is the PDE 4 isozyme in all its various forms and in the full domain of its distributions in all cells.
- inflammatory cells may contain a relatively high proportion of the form that binds rolipram with a low affinity while brain and parietal cells may contain a relatively high proportion of the form that binds rolipram with a high affinity.
- the targeted disease state may be effectively treated by such compounds, but unwanted secondary effects may be exhibited which, if they could be avoided or minimized, would increase the overall therapeutic effect of this approach to treating certain disease states.
- isozyme-selective PDE inhibitors should represent an improvement over non-selective inhibitors
- the selective inhibitors tested to date are not devoid of side effects produced as an extension of inhibiting the isozyme of interest in an inappropriate or untargeted tissue.
- clinical studies with the selective PDE 4 inhibitor rolipram which was being developed as an antidepressant, indicate it has psychotropic activity and produces gastrointestinal effects, e.g., pyrosis, nausea and emesis.
- side effects of denbufylline, another PDE 4 inhibitor targeted for the treatment of multi-inf arct dementia may include pyrosis, nausea and emesis as well.
- this invention relates to a method for reducing the incidences and/or severity of exacerbations of COPD in a mammal suffering from COPD, the method comprising administering an effective amount of a PDE4 inhibitor to a patient whom is suffering from COPD.
- this invention relates to the use of a PDE4 inhibitor in the manufacture of a medicament for reducing the incidences and or severity of exacerbations of COPD.
- Fig 2 Kaplan-Meier Estimates of Percentage of Patients Exacerbation-free - ITT in Clinical Study B
- Fig 4 Relative Risk (95% Cl) of a COPD Exacerbation in Principal Studies.
- Acute COPD exacerbations defined as worsening of COPD symptoms that required changes in treatment including antimicrobial therapy, a short course of oral corticosteroids or other bronchodilator therapy. Exacerbations were categorized to three levels:
- Level 1 self-managed by the patient at home by increasing usual medication for COPD.
- Level 2 requiring additional treatment prescribed by a family or primary care physician or as a result of a hospital outpatient visit including a visit to the Emergency Room.
- Level 3 requiring the patient to be admitted to the hospital for treatment.
- Ariflo® cis-4- cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]cyclohexane-l-carboxylic acid
- 15mg immediate release tablet, BID had a lower incidence of all categories of exacerbations as well as the more severe exacerbations (Levels 2 and 3) requiring treatment by a physician or hospitalization than patients who received placebo.
- Exacerbation-free survival rate is estimated using Kaplan-Meier estimates of time-to-first exacerbation. P-values based on log-rank test.
- a preferred group of inhibitors are those that have an IC50 ratio (high/low binding) of about 0J or greater, as that IC50 ratio determination is described in U.S. patent 5,998,428. It is incorporated herein in full by reference as if fully set forth herein.
- a preferred standard for PDE 4-s ⁇ ecific inhibitors which can be used in this invention is one where the compound has an IC50 ratio of about 0.1 or greater; said ratio being the ratio of the IC50 value for competing with the binding of InM of pH]R-rolipram to a form of PDE 4 which binds rolipram with a high affinity over the IC50 value for inhibiting the PDE 4 catalytic activity of a form which binds rolipram with a low affinity using 1 uM[ ⁇ H]-cAMP as the substrate.
- PDE 4 inhibitors that may be included in these formulations include those set out in U.S. patent 5,552,438 issued 03 September 1996. This patent and the compounds it discloses are incorporated herein in full by reference.
- the compound of particular interest which is disclosed in U.S. patent 5,552,438, is c ⁇ -4-cyano-4-[3- (cyclopentyloxy)- 4-methoxyphenyl]cyclohexane-l-carboxylic acid and its salts, esters, pro-drugs or physical forms.
- This compound is identified here by its IUPAC name, by its registered trademark Ariflo, by its generic name cilomilast, and by an alphanumeric SB207499.
- PDE 4 inhibitors which may be of interest include: AWD-12-281 from Astra (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P.98); a 9- benzyladenine derivative nominated NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4 inhibitor identified as CI-1018 (PD-168787; Parke-Davis/Warner-Lambert); a benzodioxole derivative Kyowa Hakko disclosed in WO 9916766; V- 11294A from Napp (Landells, LJ. et al.
- Preferred compounds of this invention are those which have an IC50 ratio of greater than 0.5, and particularly those compounds having a ratio of greater than 1.0.
- the most preferred compounds are roflumilast and cw-4-cyano-4-[3- (cyclopentyloxy)-4- methoxyphenyl]cyclohexane- 1-carboxylic acid.
- drugs useful in treating PDE4-related diseases can be incorporated into this therapy as well.
- examples of other therapeutics by category are drugs which treat: inflammatory respiratory diseases such as bronchodilators, leukotriene receptor antagonists and leukotriene biosynthesis inhibitors; non-respiratory inflammatory diseases such as irritable bowel disease (IBD); immunomodulating drugs, cognition enhancers; drugs for treating rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis; septic shock; endotoxic shock; gram negative sepsis; toxic shock syndrome; adult respiratory distress syndrome; cerebral malaria; silicosis; pulmonary sarcoidosis; drugs for treating bone resorption diseases; reperfusion injury; graft vs.
- AIDS cachexia secondary to infection or malignancy
- cachexia secondary to human acquired immune deficiency syndrome AIDS
- AIDS AIDS
- ARC AIDS related complex
- keloid formation scar tissue formation; Crohn's disease; ulcerative colitis; pyresis; autoimmune diseases such as multiple sclerosis, autoimmune diabetes and systemic lupus erythematosis
- drugs for treating viral infections such as cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus, and drugs for treating yeast and fungal infections.
- CMV cytomegalovirus
- Exemplary types of compounds for treating respiratory diseases are leukotriene antagonists; mucolytics; antitussives and expectorants; antibiotics; oral or inhaled beta- agonists; phosphodiesterase inhibitors other that PDE4-specific inhibitors; nasal decongestants; elastase inhibitors; protein therapeutics such as IL4, IL5, IL8, and IL13 monoclonal antibodies, anti-IgE; or oral or inhaled corticosteriods.
- Particularly preferred combination therapies are the use of a therapeutic amount of a corticosteriod, a beta agonist, an anticholinergic, an inhaled cromone, a leukotriene antagonist, or an antibiotic to treat secondary infections.
- the amount of inhibitor that is effective in this treatment method falls between 100 micrograms and 100 mg per dose, administered as needed from one to four times per day.
- a preferred range is 1-60 mg per dose administered once or twice a day. More preferred is a 5-30 mg dose administered one or twice a day. Most preferred is a 10-20, or 10-15mg dose administered once or twice per day, e.g. a twice-a-day 15 mg dose, or once-a-day 30 or 60 mg dose.
- the dose for reducing exacerbations and/or the severity of them can be smaller than that which is used to treat COPD per se.
- the inhibitor will be administered by conventional means. For example, it will be administered orally or as an inhaled powder or aerosol. It may be possible to formulate some of these inhibitors in the form of a topical patch, a sustained release injectable or a suppository, it is believed that an oral preparation or one administered as an inhalant will be the superior route of delivery.
- the preferred formulation will be an immediate release or controlled release oral tablet containing between about lmg to 200 mg of Ariflo, more preferably 5 to lOOmg, and most preferably between 5, or 10 to 60mg of the active ingredient. Additional preferred dosage amounts within these ranges are 10, 15, 20, 30, 40, 50, 60, 70, 80 or 90mg per preparation. Specific Examples
- the clinical studies protocol were carried out generally as follows: Eligible patients had a clinical diagnosis of COPD (according to international treatment guidelines), a % predicted FEV j > 30% and ⁇ 70% post-bronchodilator, a FEVi/FNC of ⁇ 0.7, and fixed airway obstruction defined by ⁇ 15% reversibility following administration of a beta2-agonist.
- patients with COPD entered a 4-week placebo run-in period and were then randomized to receive Ariflo 15 mg twice daily or placebo in a ratio of 2 to 1. Patients were monitored following 1, 2 and 4 weeks of treatment and subsequently at 4- week intervals. Patients were permitted to receive concomitant salbutamol (prn) and/or short acting anticholinergic therapy at a stable dose during these studies.
- Study B included a 2-week, randomised, double-blind, run-out phase to examine the effects of discontinuation of treatment. Patients who received Ariflo during the initial 24 week period, were randomized (1:1 ratio) to Ariflo 15mg BID or placebo for the run-out phase; patients who received placebo during the initial 24 weeks, continued on placebo during the run-out phase.
- Pulmonary function measurements were performed at each visit (with the exception of Week 1).
- the St. George's Respiratory Questionnaire (SGRQ) was administered at Baseline, and Weeks 12 and 24 (or at the time of withdrawal).
- efficacy measures were analyzed for the intent-to-treat population (ITT), defined as all patients who received randomized study medication and had a baseline evaluation and at least one on-therapy efficacy evaluation during the double-blind period.
- Efficacy analyses for the per protocol population (PP) were limited to trough FEVp and the total score of the SGRQ, the co-primary measures of efficacy, and the secondary parameters, exercise tolerance test, post-exercise breathlessness, summary symptom score, and trough FNC.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22127500P | 2000-07-27 | 2000-07-27 | |
US221275P | 2000-07-27 | ||
PCT/US2001/023542 WO2002009689A1 (en) | 2000-07-27 | 2001-07-26 | Method for reducing exacerbations associated with copd |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1320361A1 EP1320361A1 (de) | 2003-06-25 |
EP1320361A4 true EP1320361A4 (de) | 2006-04-05 |
Family
ID=22827112
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01957262A Withdrawn EP1320361A4 (de) | 2000-07-27 | 2001-07-26 | Methode zur verminderung von verschlimmerungen in verbindung mit copd |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1320361A4 (de) |
JP (1) | JP2004505039A (de) |
KR (1) | KR20030019620A (de) |
CN (1) | CN1444476A (de) |
AR (1) | AR029984A1 (de) |
AU (2) | AU7902301A (de) |
BR (1) | BR0112682A (de) |
CA (1) | CA2417336A1 (de) |
CZ (1) | CZ2003141A3 (de) |
HU (1) | HUP0300685A3 (de) |
IL (1) | IL153919A0 (de) |
MX (1) | MXPA03000714A (de) |
NO (1) | NO20030332D0 (de) |
PL (1) | PL365612A1 (de) |
WO (1) | WO2002009689A1 (de) |
ZA (1) | ZA200300476B (de) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
US7776315B2 (en) | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
DE10110772A1 (de) * | 2001-03-07 | 2002-09-12 | Boehringer Ingelheim Pharma | Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und PDE-IV-Inhibitoren |
GB0118373D0 (en) * | 2001-07-27 | 2001-09-19 | Glaxo Group Ltd | Novel therapeutic method |
MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
DE10230769A1 (de) * | 2002-07-09 | 2004-01-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkompositionen auf der Basis neuer Anticholinergika und PDE-IV-Inhibitoren |
ME00524B (me) | 2003-03-10 | 2011-10-10 | Astrazeneca Ab | Novi postupak za dobijanje roflumilasta |
EP2100599A1 (de) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalationszusammensetzung enthaltend Aclidinium zur Behandlung von Asthma sowie chronisch-obstruktiver Lungenerkrankung |
EP2100598A1 (de) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalationszusammensetzung enthaltend Aclidinium zur Behandlung von Asthma sowie chronisch-obstruktiver Lungenerkrankung |
EP2510928A1 (de) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium zur Verbesserung der Schlafqualität bei atemwegserkrankten Patienten |
KR102087661B1 (ko) * | 2018-07-27 | 2020-03-11 | 강원대학교산학협력단 | Gebr―7b 화합물을 유효성분으로 포함하는 만성폐쇄성 폐질환의 예방 또는 치료용 조성물 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000051598A1 (en) * | 1999-03-01 | 2000-09-08 | Smithkline Beecham Corporation | Method for treating copd |
WO2001011933A2 (en) * | 1999-08-18 | 2001-02-22 | Astrazeneca Uk Limited | Pharmaceutical compositions comprising a 7-(2-aminoethyl)-benzothiazolone and a pde4 inhibitor |
WO2001032165A1 (en) * | 1999-10-29 | 2001-05-10 | Smithkline Beecham Corporation | Method for administering a phosphodiesterase 4 inhibitor |
-
2001
- 2001-07-25 AR ARP010103546A patent/AR029984A1/es not_active Application Discontinuation
- 2001-07-26 EP EP01957262A patent/EP1320361A4/de not_active Withdrawn
- 2001-07-26 CN CN01813330A patent/CN1444476A/zh active Pending
- 2001-07-26 AU AU7902301A patent/AU7902301A/xx active Pending
- 2001-07-26 BR BR0112682-2A patent/BR0112682A/pt not_active IP Right Cessation
- 2001-07-26 JP JP2002515242A patent/JP2004505039A/ja not_active Withdrawn
- 2001-07-26 KR KR10-2003-7001144A patent/KR20030019620A/ko not_active Application Discontinuation
- 2001-07-26 CA CA002417336A patent/CA2417336A1/en not_active Abandoned
- 2001-07-26 PL PL01365612A patent/PL365612A1/xx not_active Application Discontinuation
- 2001-07-26 WO PCT/US2001/023542 patent/WO2002009689A1/en not_active Application Discontinuation
- 2001-07-26 AU AU2001279023A patent/AU2001279023B2/en not_active Ceased
- 2001-07-26 CZ CZ2003141A patent/CZ2003141A3/cs unknown
- 2001-07-26 MX MXPA03000714A patent/MXPA03000714A/es unknown
- 2001-07-26 IL IL15391901A patent/IL153919A0/xx unknown
- 2001-07-26 HU HU0300685A patent/HUP0300685A3/hu unknown
-
2003
- 2003-01-17 ZA ZA200300476A patent/ZA200300476B/en unknown
- 2003-01-22 NO NO20030332A patent/NO20030332D0/no not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000051598A1 (en) * | 1999-03-01 | 2000-09-08 | Smithkline Beecham Corporation | Method for treating copd |
WO2001011933A2 (en) * | 1999-08-18 | 2001-02-22 | Astrazeneca Uk Limited | Pharmaceutical compositions comprising a 7-(2-aminoethyl)-benzothiazolone and a pde4 inhibitor |
WO2001032165A1 (en) * | 1999-10-29 | 2001-05-10 | Smithkline Beecham Corporation | Method for administering a phosphodiesterase 4 inhibitor |
Non-Patent Citations (5)
Title |
---|
CHRISTENSEN S B ET AL: "THE EVOLUTION OF ARIFLO(TM) (SB207499), A SECOND GENERATION PDE4 INHIBITOR FOR THE TREATMENT OF ASTHMA AND COPD", AMERICAN CHEMICAL SOCIETY. ABSTRACTS OF PAPER. AT THE NATIONAL MEETING, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 217, no. 1/2, 1999, pages MEDI269, XP001029595, ISSN: 0065-7727 * |
NORMAN P: "PDE4 INHIBITORS 1999", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 9, no. 8, 1999, pages 1101 - 1118, XP001058161, ISSN: 1354-3776 * |
See also references of WO0209689A1 * |
SILVESTRE J. GRAUL A. CASTANER J.: "SB-207499: Antiasthmatic/antiinflammatory phosphodiesterase IV inhibitor", DRUGS OF THE FUTURE, vol. 23, no. 6, 1998, pages 607 - 615, XP002365569 * |
UNDERWOOD D C ET AL: "THE SECOND GENERATION PHOSPHODIESTERASE (PDE)4 INHIBITOR, SB 207499, INHIBITS ANTIGEN-INDUCED BRONCHOCONSTRICTION AND EOSINOPHILIA AND LPS-INDUCED AIRWAY NEUTROPHILIA AND EDEMA IN THE GUINEA PIG", EUROPEAN RESPIRATORY JOURNAL, MUNKSGAARD INTERNATIONAL PUBLISHERS, COPENHAGEN, DK, vol. 12, no. SUPPL 29, December 1998 (1998-12-01), pages 86S, XP001096459, ISSN: 0903-1936 * |
Also Published As
Publication number | Publication date |
---|---|
KR20030019620A (ko) | 2003-03-06 |
AR029984A1 (es) | 2003-07-23 |
CZ2003141A3 (cs) | 2004-07-14 |
IL153919A0 (en) | 2003-07-31 |
EP1320361A1 (de) | 2003-06-25 |
AU7902301A (en) | 2002-02-13 |
HUP0300685A3 (en) | 2004-10-28 |
NO20030332L (no) | 2003-01-22 |
AU2001279023B2 (en) | 2005-11-10 |
HUP0300685A2 (hu) | 2003-12-29 |
BR0112682A (pt) | 2003-06-24 |
CA2417336A1 (en) | 2002-02-07 |
NO20030332D0 (no) | 2003-01-22 |
JP2004505039A (ja) | 2004-02-19 |
MXPA03000714A (es) | 2003-06-04 |
ZA200300476B (en) | 2004-04-23 |
WO2002009689A1 (en) | 2002-02-07 |
CN1444476A (zh) | 2003-09-24 |
PL365612A1 (en) | 2005-01-10 |
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