KR20020057988A - Method and compositions for treating pulmonary diseases - Google Patents

Abstract

The present invention relates to the treatment of pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with an anti-inflammatory corticosteroid.

Description

METHOD AND COMPOSITIONS FOR TREATING PULMONARY DISEASES}

The identification of new therapeutic agents for treating lung disease is made difficult due to the fact that a number of mediators contribute to the development of the disease. Thus, it is not believed that elimination of the effects of a single agent can have a substantial effect on all three factors of chronic asthma. One alternative to the "mediator approach" is to modulate the activity of the cells that are responsible for the pathophysiology of the disease.

One such method is to raise the level of cAMP (adenosine cyclic 3 ', 5'-monophosphate). Cyclic AMPs are known as secondary messengers that mediate biological responses to a wide range of hormones, neurotransmitters and drugs (Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973). When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg ⁺² -ATP to cAMP at an accelerated rate. Cyclic AMPs regulate the activity of most cells, if not all, causing the pathogenesis of exogenous (allergic) asthma. As such, increases in cAMP include: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) inhibition of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. To produce a beneficial effect. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in inhibiting inappropriate activation of airway smooth muscle and various inflammatory cells. The major cellular mechanism for inactivation of cAMP is the hydrolysis of 3'-phosphodiester bonds by one or more groups of isoenzymes called cyclic nucleotide phosphodiesterases (PDEs).

PDE4, a unique cyclic nucleotide phosphodiesterase (PDE) isoenzyme, has been found to be responsible for cAMP degradation in airway smooth muscle and inflammatory cells. Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Studies have shown that inhibition of this enzyme results in inhibition of degranulation of mast cells, basophils and neutrophils as well as inhibition of airway smooth muscle relaxation, as well as activation of monocytes and neutrophils. In addition, as in vivo, the beneficial effect of PDE4 inhibitors is markedly enhanced when adenylate cyclase activity of target cells is increased by appropriate hormones or local hormones. Thus, PDE4 inhibitors will be effective in lungs with increased levels of prostaglandin E ₂ and prosaticycline (activators of adenylate cyclase). Such compounds provide a unique approach to pharmacotherapy of bronchial asthma and will have significant therapeutic benefits over currently available drugs.

In addition, it may be useful to combine therapies in view of the fact that the etiology of many lung diseases involves a large number of mediators. The present invention provides a combination therapy of PDE4 inhibitors and anti-inflammatory corticosteroids, in particular combination therapy delivered by inhalation, for the treatment of lung disease. This combination therapy is particularly useful for treating chronic obstructive pulmonary disease (COPD) or asthma.

Summary of the Invention

In a first aspect, the present invention provides a method of treating lung disease in a mammal by administering an effective amount of a PDE4 specificity inhibitor and an effective amount of a steroidal anti-inflammatory agent simultaneously or separately and sequentially to patients in need of treatment of lung disease, either sequentially or remotely. To a method of treatment.

In a second aspect, the present invention relates to a composition for treating lung disease in a mammal, comprising an effective amount of a PDE4 specificity inhibitor, an effective amount of a steroidal anti-inflammatory agent and a pharmaceutically acceptable excipient.

The present invention relates to compositions and methods for preventing or reducing the occurrence of symptoms of lung disease or for treating or alleviating severe lung disease. In particular it relates to compositions and methods for treating pulmonary diseases mediated by PDE4 by administering phosphodiesterase 4 (PDE4) inhibitors in combination with anti-inflammatory corticosteroids.

Combination therapies intended by the present invention include administering a PDE4 inhibitor in combination with steroidal anti-inflammatory agents to prevent the development of lung disease or to treat a condition that exists. The compounds may be administered together in a single form. Or in two different formulations, which may be the same or different. To illustrate, both drugs may be provided separately in oral dosage form, one may be an oral preparation, the other may be an inhalant, or both may be provided in an inhaled dosage form. They can be administered simultaneously. Or they may be administered as close in time or as far as if one drug is administered in the morning and the second drug is administered in the evening.

Combination therapy can be used prophylactically or after the onset of symptoms. In some cases, combination therapy may be used to prevent the progression of lung disease, or to stop the decline of function, such as lung function.

PDE4 specificity inhibitors useful in the present invention are any compounds known to inhibit PDE4 enzymes or found to act as PDE4 inhibitors, and any compounds that are only PDE4 inhibitors, not compounds that inhibit not only PDE4 but also other enzymes of the PDE family. Can be. In general, rolls are preferably leaf alarm IC ₅₀ ratio obtained by dividing the IC ₅₀ for the form which combines low affinity for IC ₅₀ in roll leaf person for PDE4 catalytic form which combines a high affinity for the use of about 0.1 or more PDE4 antagonists .

As PDE inhibitors and bronchodilators used to treat inflammation, drugs such as theophylline and pentoxifylline indiscriminately inhibit PDE isoenzymes in all tissues. These compounds appear to have side effects because they nonselectively inhibit all five PDE isoenzymes in all tissues. The desired disease state can be effectively treated by such compounds, but if an unwanted secondary effect can be exhibited and can be avoided or minimized, the overall therapeutic effect of this approach to the treatment of certain disease states will be increased. For example, in clinical studies using the selective PDE4 inhibitor, Rolipram, which has been developed as an antidepressant, it is known that rolipram may have psychotropic effects and may exhibit gastrointestinal effects such as heartburn, nausea and vomiting. appear.

For the purposes of this disclosure, cAMP catalytic moieties that bind with low affinity to R and S roliprams are named "low affinity" binding sites (LPDE4) and other The form is named "high affinity" binding site (HPDE4). The term "HPDE4" should not be confused with the term "hPDE4", which is used to refer to human PDE4.

Initial experiments were performed to establish and establish the [ ³ H] -rollipram binding assay. This operation is described in detail in Example 1 below.

In order to determine whether both high affinity binding activity and low affinity binding activity are present in the same gene product, the yeast was transformed by a known method and then recombinant PDE4 was expressed during the fermentation period of 6 hours. Western blot analysis using an antibody against PDE4 showed that the amount of PDE4 expressed increased over time, peaking after 3 hours of proliferation. In addition, more than 90% of the immunoreactive product was in the high speed (100,000 × g) supernatant of yeast digestion. [ ³ H] R-(-)-rollipram binding and PDE activity were measured with protein expression. PDE4 activity was co-expressed with rolipram binding activity, indicating that both functions are on the same gene product. Similar to the results using Western blot analysis, it was found that greater than 85% of the rolipram-inhibiting PDE activity and the [ ³ H] -rollifram binding activity are present in the yeast supernatant fractions.

Overall, most recombinant PDE4 expressed in this system is present as LPDE4 and only a small part is present as HPDE4. As a result, inhibition of recombinant PDE4 catalytic activity mainly reflects the action of the compound in LPDE4. Thus, inhibition of PDE4 catalytic activity can be used as an indicator of the efficacy of a compound in LPDE4. The efficacy of compounds in HPDE4 can be assessed by examining their ability to compete with [ ³ H] R-rollipram. In order to develop SAR for the low and high affinity rolipram binding sites, the efficacy of the selected compounds was measured in two assay systems. The results of experiments with standard compounds were tabulated. As expected, certain compounds were certainly more effective at competing with [ ³ H] -rollipram at the sites where they showed high affinity binding than other sites where they were linked with low affinity. The SAR correlation between high affinity binding and low affinity binding was poor, and SAR for inhibition of high affinity [ ³ H] -rollifram binding was compared with SAR for binding to the low affinity rolipram binding site. Was concluded to be different.

Human monocyte recombinant PDE4 (hPDE4) with which the inhibitor interacts is currently known to have two or more binding forms. One explanation for this observation is that hPDE4 exists in two distinct forms. One binds high affinity to compounds such as rolipram and denbuphylline and the other binds low affinity to such compounds. Preferred PDE4 inhibitors for use in the present invention bind to high affinity to rolipram by better inhibiting cAMP catalytic activity when the compound has a beneficial therapeutic ratio, ie, the enzyme is in the form of low affinity binding to rolipram. It will be a compound that reduces the side effects that appear to be involved in suppressing the form. Another way of explaining this is that the preferred compound has an IC ₅₀ ratio of at least about 0.1, which means that the IC ₅₀ has a low affinity for the form of the PDE4 catalyst that binds to the high affinity for the liprifram. Divided by IC ₅₀ .

A further detail of this criterion is that the PDE4 inhibitor has an IC ₅₀ ratio of at least about 0.1, which ratio is a PDE4 catalyst in the form of binding a low affinity to rolipram using 1 μM [ ³ H] -cAMP as a substrate. of 1nM to the IC ₅₀ value for inhibiting the activity ^[3 H] R- roll leaves the person and the ratio of the IC ₅₀ value for competing to combining in the form of PDE4 which binds to affinity roll leaf person. Further review of the use of this test can be found in co-pending US patent application Ser. No. 08/456274, filed May 31, 1995, the text of which is hereby incorporated by reference to the extent necessary to practice the invention. Inserted.

Examples of useful PDE4 inhibitors are:

(R)-(+)-1- (4-bromobenzyl) -4-[(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone;

(R)-(+)-1- (4-bromobenzyl) -4-[(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone,

3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '-[N2-cyano-S-methyl-isothioureido] benzyl) -2-pyrrolidone,

Cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid;

Cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol];

(R)-(+)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate;

(S)-(-)-ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine-2-ylidene] acetate.

Most preferred are PDE4 inhibitors having an IC ₅₀ ratio greater than 0.5, in particular compounds having a ratio greater than 1.0. Preferred compounds are cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3- Cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane-1 -Ol] and these are examples of compounds that bind better to low affinity binding sites and have an IC ₅₀ ratio greater than 0.1.

The compounds are described in US Pat. No. 5,552,438, filed September 3, 1996. This patent and compound disclosed herein are incorporated by reference in their entirety herein. Particularly interesting compounds disclosed in US Pat. No. 5,552,438 are cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid and salts, esters thereof, In prodrug or physical form.

Astra's AWD-12-281 (Hofgen, N. et al . 15th EFMC Int Symp Med Chem (Sept 6-10, Edinburgh) 1998, Abst P. 98); 9-benzyladenin derivative (INSERM) named NCS-613; D-4418 from Chiroscience and Schering-Plough; Benzodiazepine PDE4 inhibitors identified as CI-1018 (PD-168787; Parke-Davis / Warner-Lambert); Benzodioxol derivatives disclosed by Kyowa Hakko in WO 9916766; Napp's V-11294A (Landells, LJ et al . Eur Resp J [Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998) 1998, 12 (Suppl. 28): Abst P2393); Roflumilast (CAS reference No 162401-32-3) and phthalhalinone (WO 9947505) from Byk-Gulden; Or compounds identified as T-440 (Tanabe Seiyaku; Fuji, K. et al . J Pharmacol Exp Ther, 1998, 284 (1): 162). Any one or all of these compounds may utilize the methods described herein.

Some of the specific compounds described above, without generic names or trade names, are disclosed in US patent application US Ser. No. 862,083, filed Oct. 30, 1992; USSN 862,111, filed October 30, 1992; USSN 862,030, filed October 30, 1992; And US Ser. No. 862,114, filed Oct. 30, 1992, or a progeny thereof, or a method described in US patents claiming priority from one or more of these applications. Each of these applications or related patents is incorporated herein by reference in their entirety as described in this document.

Steroid preparations useful in the present invention are oral and inhaled corticosteroids and pro-drugs thereof having anti-inflammatory activity. Examples of this steroid are methyl prednisolone, prednisone, dexamethasone, fluticasone, beclomethasone, budesonide, pullunisolide, mometasone furoate and triamcinolone acetonide. Methyl prednisolone and prednisone are anti-inflammatory corticosteroids in oral and injectable form and are available from many brands and generic pharmaceutical companies. Dipropionate beclomethasone is sold by Glaxo Wellcome as the inhalation aerosol under the names Beconase® and Beconase® AQ®. Propionic acid fluticasone is also sold by Glaxo Welcome under the name Flonase®. Triamcinolone acetonide is sold as a nasal spray and aerosol under the name Nasacort® by Rhone-Poulenc Roher. Flunisolid is sold as a nasal solution under the names Nasalide® and Nazarel ^™ by Roche Laboratories. Dexamethasone is sold by the company Medeva Pharmaceuticals, Inc. as the sodium phosphate salt under the name Dexacort ^™ phosphate. Mometasone furoate is marketed as a monosaccharide by monohydrate under the name Nasonex® by Schering Corp. Budesonide is another inhaled corticosteroid used to treat lung disease. It is sold by the company Astra Pharmaceuticals (LP) under the name Pulmicort Turbohaler® as a powder in a turbohaler device. All of these drugs and nasal or oral or injectable formulations can be found in the 1999 edition of the Physicians' Desk Reference (PDR) published by Medical Economics Corporation, Inc. of New Jersey, USA. It is available at http://www.tomescps.com/fraMain.asp?Mnu=0 site and linked page on the Internet. Additional corticosteroids currently under development for use in the present invention are listed in Table 1.

Suction corticosteroids drug company Indication Mometasone furoate Schering-Plough Asthma SAR Loplefonide AstraZeneca asthma Ciclesonide Big-Gulden / Recordati asthma Propionic acid butyxocoat Warner Lambert / 3M Asthma / Rhinitis RPR-106541 Long franc Laura asthma ST-126 SSP / Tori asthma

Preferred combination therapies are with cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, cilomalast (Ariflo®) At least one dexamethasone, fluticasone, beclomethasone, budesonide, flunisolide, mometasone furoate and triamcinolone acetonide administered. Preferred therapies are simultaneous administration of the acid in the form of steroids and oral dosage as inhalants, with each drug being administered once or twice a day. With respect to acid, controlled release oral tablets are most preferred.

Both active agents are intended to be administered simultaneously or at very close time intervals. Alternatively, one drug may be administered in the morning and the other drug later in the day. Alternatively, one drug can be administered twice a day, the other once a day, so that one of two times a day is administered simultaneously or separately. Preferably both drugs will be administered together at the same time.

The compounds of the present invention and pharmaceutically acceptable salts which are active upon oral administration can be formulated as syrups, tablets, capsules, controlled release preparations or lozenges. Syrup formulations will generally consist of a suspension or solution of a compound or salt in a liquid carrier such as ethanol, peanut oil, olive oil, glycerin or water together with a flavoring or coloring agent. If the composition is in the form of a tablet, any pharmaceutical carrier commonly used to prepare solid dosage forms can be used. Examples of such carriers include magnesium stearate, clay, talc, gelatin, gum arabic, stearic acid, starch, lactose and sucrose. If the composition is in the form of a capsule, conventional encapsulation is suitable, for example using the carrier described above in the hard gelatin capsule shell. When the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier commonly used to prepare dispersions or suspensions, such as aqueous rubber, cellulose, silicates or oils, may be considered, which is a soft gelatin capsule shell. It is embedded in.

Conventional parenteral compositions are solutions of compounds or salts in sterile aqueous or non-aqueous carriers optionally containing parenterally acceptable oils such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Or in suspension.

Conventional inhalable compositions are formulations of solutions, suspensions or emulsions which can be administered as dry powder or formulations of aerosols using conventional propellants such as fluorinated hydrocarbons such as trichlorofluoromethane.

Preferably the composition for the PDE4 inhibitor is in unit dosage form such as a tablet or capsule. In the case of steroids, quantitative aerosol dosing, quantitative dry powder inhalants or nasal sprays are preferred.

The active ingredient may be administered 1 to 6 times per day, sufficient to exhibit the desired action. Preferably, the active ingredient is administered about once to twice a day, more preferably twice a day.

The compounds of the present invention are useful in the treatment of motor-induced asthma (EIA), pollution-induced asthma (PIA) and cold-induced asthma (CIA) in both intermittent and chronic conditions, in anticipation of problematic stimuli. Preferably, the compounds of the present invention are used for long term therapy.

Regarding the amount of drug administered, it is contemplated that the PDE4 inhibitor will be administered in an amount of 1 to 200 micrograms per day per adult. Steroids can be administered according to approved product labels.

Example 1 Phosphodiesterase and Rolipram Binding Assays

Example 1A

Isolated human monocytes PDE4 and hrPDE (human recombinant PDE4) were determined to exist mainly in low affinity form. Therefore, the activity of the low affinity forms of PDE4 of the test compound can be assessed using standard assays for PDE4 catalytic activity using 1 μM [ ³ H] cAMP as substrate (Torphy et al., J. of Biol). Chem. , Vol. 267, No. 3 pp1798-1804, 1992).

Rabbit brain high-speed supernatant was used as a source of protein and both enantiomers of [ ³ H] -rollipram were prepared with an inactivation of 25.6 Ci / mmol. The conditions of the standard assay were changed from known procedures to be identical to the PDE assay conditions except for cAMP: 50 mM Tris HCl (pH 7.5), 5 mM MgCl ₂ , 50 μM 5′-AMP and 1 nM [ ³ H] -Rolipram (Torphy et al., J. of Biol. Chem. , Vol. 267, No. 3 pp1798-1804, 1992). The analysis was performed at 30 ° C. for 1 hour. The reaction was terminated and the bound ligand was separated from the free ligand using a Brandel cell harvester. Competition for the high affinity binding site was evaluated under the same conditions used for the determination of low affinity PDE activity except that no [ ³ H] -cAMP was present.

Example 1B

Determination of phosphodiesterase activity

PDE activity was analyzed using the [ ³ H] cAMP SPA or [ ³ H] cGMP SPA enzyme assay as described by the supplier (Amersham Life Sciences). The reaction contains 50 mM Tris-HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EGTA, [ ³ H] cAMP or [ ³ H] cGMP (approximately 2000 dpm / pmol), enzymes and inhibitors of various concentrations (final concentration) Was performed at room temperature on 96-well plates in 0.1 ml of reaction buffer. The assay was allowed to proceed for 1 hour and terminated by adding 50 μl of SPA yttrium silicate beads in the presence of zinc sulfate. The plate was shaken and left at room temperature for 20 minutes. Radiolabeled product formation was assessed by flash spectroscopy.

[ ³ H] -rollifram binding assay

[ ³ H] -rollifram binding assays were performed by Schneider and collaborators (Nicholson, et al., Trends Pharmacol. Sci., Vol. 12, pp. 19-27 (1991) and McHale et al., Mol. Pharmacol., Vol. 39, 109-113 (1991)). R-rollipram binds to the catalytic site of PDE4 (see Torphy et al., Mol. Pharmacol., Vol. 39, pp. 376-384 (1991)). As a result, competition for [ ³ H] R-rollipram binding allows independent identification of PDE4 inhibitor efficacy of unlabeled competitors. The assay was performed with 50 mM Tris-HCl, pH 7.5, 5 mM MgCl ₂ , 0.05% bovine serum albumin, 2 nM [ ³ H] R-rollipram (5.7 x 10 ⁴ dpm / pmol) and various concentrations of non-radiolabeled The reaction was carried out at 30 ° C. for 1 hour in 0.5 μl buffer containing inhibitor (final concentration). By adding 2.5 ml of ice-cold reaction buffer (without [ ³ H] -R-rollipram) and rapid vacuum filtration through Whatman GF / B filters soaked in 0.3% polyethyleneimine The reaction was stopped. The filter is washed with an additional 7.5 ml of cooling buffer, dried and counted through liquid scintillation spectroscopy.

Example 2

Silomalast / Low Dose Inhaled Corticosteroids (ICS), Dose-Range Study

Study design :

-This was a randomized, placebo-controlled, dose-range study on IIB including 1 week of single blind placebo preparations, 6 weeks of double blind treatment, and 1 week of follow-up for mild / moderate asthma patients.

Study population: 18-70 year old male or female patients with mild to moderate asthma, with moderate doses of low dose inhaled corticosteroids (500 mgg of dipropionate beclomethasone / day or equivalent). Patients who were not eligible were eligible. Patients were required to have at least 12% reversibility after administration of ≧ 50% and ≧ 80% of the selected FEV ₁ and beta-2 agonists predicted for height, age, gender and race. Patients had to have a summary symptom score of at least 6 on 4 of 7 days preceding the baseline visit to be randomized. Sample size was 300 evaluable patients.

Silomalast was administered at 5 mg, 10 mg, 15 mg twice daily for 6 weeks.

The average dose of ICS was 652 mcg, but subjects received a median 500 mcg of beclomethasone equivalent.

Primary endpoint: Change from baseline to endpoint of the lowest clinical expiratory volume (FEV ₁ ) for 1 second, change in clinical FEV ₁ over 4 hours after the first dose of weekly and double-blind medications.

Second endpoint: first aid and overnight

Tertiary endpoint: clinical effort spirometry (FVC), maximum clinical expiratory flow rate (PEFR), effort expiratory volume at 25-75% (FEF _25-75 ) and 75% (FEF ₇₅ ), PEFR variability in the residence, PEFR, summary symptom score.

Evaluation standard

Primary efficacy measures were defined as the change from baseline to endpoint of the lowest clinical effort exhalation volume (FEV ₁ ) for 1 second. Clinical FEV ₁ was also analyzed over 4 hours immediately after each week of the double blind treatment period and the first dose of the double blind medication. Secondary efficacy variables were the use of inhalation / spray beta-2-agonists and asthma symptoms overnight. Tertiary efficacy variables included effort spirometry (FVC), maximum clinical expiratory flow rate (PEFR), effort exhalation volume at 25-75% (FEF _25-75 ), and 75% (FEF ₇₅ ), residential PEFR variability, and residential PEFR (Morning and evening), summary symptom score (mixed score of overnight, morning and total daytime asthma), morning asthma, total daytime asthma, use of inhaled corticosteroids, cough, wheezing, dyspnea / chest tightness, rate of asthma exacerbation And global assessment by physicians and patients.

Results

There was no statistical improvement in the lowest FEV ₁ at the end of the 15 mg siolomalast BID ITT assay compared to placebo (0.16 L; p = 0.062).

At the end of the ITT analysis, the response to the lowest FEV ₁ was dose dependent.

There was a significant improvement in the lowest FEV ₁ (0.21 L; p = 0.033), except for those who received ICS doses> 500 mcg of beclomethasone with silomalast 15 mg BID.

The conclusive evidence for xylomalast 15 mg BID included a 4-hour FEV ₁ , residential PEFR, FEF _25-75 and physician and patient overall scores.

Example 3

Silomalast / High Dose Inhaled Corticosteroid (ICS) Study

Study design

R, DB, PC, DR in mild / moderate asthma patients receiving ≧ 800 mcg of beclomethasone

Silomalast® doses were 5, 10 and 15 mg twice daily for 4 weeks.

-2 week preparation period.

1st endpoint: Lowest clinical FEV ₁ .

Secondary endpoints: morning PEFR, symptoms, PEFR variability, evening PEFR, clinical PEFR, FEF _25-75 , FEF ₇₅ , first aid medication used.

Findings :

There was no statistically significant change in the lowest clinical FEV ₁ in all dose groups in the ITT analysis.

No dose dependence was observed for the primary endpoint.

-The statistically improved lowest FEV ₁ at 10 mg of siolomalast BID using repeated measures analysis excludes patients receiving <800 mcg of ICS (0.16 L; p = 0.009).

ICS (beclomethasone) doses ranged from 100 to 4000 mcg with an average of 1136 mcg.

The numerically good results of the 4-hour clinical FEV1, clinical FVC, PEFR also provided convincing evidence for 10 mg of silomalast BID as an effective dose.

The dose-response relationship was not determined and the trough concentration was proportional to dose and similar to previous studies.

Comparison between Compounds in Selected Studies Allergen-induced research comparison data: allergen-induced research Ariflo 15 mg bid Singulaire Ultire ICS800 mcg budesonide B2 % Max drop LAR (treatment effect) 1.3 12.3 10.7 22.9 +6.9 % Protection Max Drop LAR radish 36.4 30.8 32 No drop LAR% AUC (Therapeutic Effect) 3.5 63.5 42.4 Do not measure % Protection AUCLAR radish 56.9 42.6 Do not measure

Legend: Data for cilomalast were obtained from protocol analysis in asthmatic patients receiving <625 mcg of ICS. Data for montelukast (MT), budesonide (BDP) and both were obtained from a single study at Singulare SBA, which validates the effect of Cingulare over inhaled corticosteroids.

In both studies, there was a significant difference between the behavior of the placebo (Pbo) group. Despite the fact that the placebo group was also improved in the siolomalast study, the conclusion was that when xylomalast is added to the low dose ICS. It is more effective than singular.

The above description and examples are intended to illustrate the invention, but not to limit the invention. For what is reserved for the inventors, see the claims.

Claims (2)

Treating pulmonary disease by administering to a patient in need thereof a sequential and individual method of administering an effective amount of a PDE4 inhibitor and an anti-inflammatory corticosteroid in combined form, either individually, or sequentially or in close proximity to time. Way. The method of claim 1, wherein the PDE4 inhibitor is cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid and the steroid is dexamethasone, fluticasone, beclo Metason, budesonide, flunisolid, mometasone furoate and triamcinolone acetonide.