SK7592002A3 - Method and compositions for treating pulmonary diseases - Google Patents

Abstract

This invention relates to treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with anti-inflammatory corticosteroid.

Description

Technical field

The present invention relates to the use of phosphodiesterase 4 (PDE4) inhibitors for the manufacture of a medicament for preventing or reducing the onset of lung disease symptoms or for treating or decreasing the severity of lung diseases. In particular, it relates to the use of phosphodiesterase 4 (PDE4) inhibitors together with an anti-inflammatory corticosteroid.

BACKGROUND OF THE INVENTION

It is difficult to identify new therapeutic agents for the treatment of lung diseases due to the fact that a number of mediators are responsible for the development of the disease. Therefore, it seems unlikely that eliminating the effects of one mediator could have a significant effect on all three components of chronic asthma. An alternative to this "mediator approach" is to regulate the activity of the cells responsible for the pathophysiology of the disease.

One approach is to increase cAMP (cyclic adenosine 3 ', 5'-monophosphate) levels. Cyclic AMP has been shown to be the second information mediator of biological response to a wide range of hormones, neurotransmitters and drugs; (Krebs Endocrinology Proceedings of the 4th International Congress of Excerpt Medic, 17, 29, 1973). When a suitable agonist binds to specific surface receptors, adenylate cyclase is activated, which converts Mg ²⁺ into cAMP at an increased rate. Cyclic AMP modulates the activity of most, if not all, of the cells involved in the pathophysiology of asthma caused by external (allergic) influences. An increase in cAMP as such could have useful effects, including: 1) relaxation of airway smooth muscle, 2) inhibition of mast cell mediator release, 3) neutrophil degranulation suppression, 4) inhibition of basophils degranulation, and 5) inhibition of monocyte and macrophage activation. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase could be effective in suppressing inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.

The basic cellular mechanism of cAMP inactivation is the hydrolysis of the 3-phosphodiester linkage by one or more of the isoenzyme family of cyclic nucleotide phosphodiesterases (PDEs).

The different cyclic nucleotide phosphodiesterase isoenzyme, PDE4, has been shown to be responsible for the breakdown of cAMP in airway muscles and inflammatory cells. (Torphy, "Phosphodiesterase Isozymes: Possible Targets for New Antiasthmatics," New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989). Research suggests that inhibition of this enzyme not only causes relaxation of airway smooth muscle, but suppresses degranulation of mast cells, basophils and neutrophils along with inhibition of monocyte and neutrophil activation. In addition, the beneficial effects of PDE4 inhibitors are greatly potentiated if the adenylate cyclase activity of the target cells is increased by appropriate hormones or autocoids, as would be the case in vivo. Therefore, PDE4 inhibitors could be effective in the lung where levels of prostaglandin E ₂ and prostacyclin (adenylate cyclase activators) are elevated. Such compounds would provide a unique approach to the pharmacotherapy of bronchial asthma and would provide significant therapeutic advantages over substances currently on the market.

In addition, it may be appropriate to combine treatment in accordance with the fact that many mediators are involved in the etiology of a number of lung diseases. The present invention provides a combination of a PDE4 inhibitor and an anti-inflammatory corticosteroid, particularly administered by inhalation, for the treatment of lung diseases. This combination is particularly suitable for the treatment of chronic obstructive pulmonary disease (COPD) and asthma.

SUMMARY OF THE INVENTION

The present invention provides the use of a PDE4 inhibitor and an anti-inflammatory corticosteroid for the manufacture of a medicament for the treatment of pulmonary disease for joint, separate or separate and sequential administration, wherein subsequent administration is carried out immediately after or over a prolonged period.

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

Combination therapy related to the present invention includes the administration of a PDE4 inhibitor and a steroidal anti-inflammatory drug to prevent or treat an existing lung disease. The compounds may be administered together in a single dosage form. They may also be administered in two medicaments which may be the same or different in terms of administration. By way of illustration, both drugs may be provided separately as oral drugs or one may be in the form of an oral drug and the other as an inhalation drug, or both may be administered in an inhalation form. They can be given at the same time. Alternatively, the administration may be carried out immediately after or after a prolonged period of time, e.g. one drug is administered in the morning and the other is administered in the evening.

The combination may be used prophylactically or after the onset of symptoms. In some cases, the combination (s) can be used to prevent the progression of a pulmonary disease or to maintain reduced function, e.g. pulmonary function.

A specific PDE-4 inhibitor useful in the present invention may be any compound known to inhibit the PDE-4 enzyme or which is described as having PDE4 inhibiting activity and compounds that are only PDE4 inhibitors, not compounds that inhibit other members of the group PDE as well as PDE4. In general, it is preferred to use PDE4 antagonists having an IC ₅₀ ratio of about 0.1 or greater in terms of the IC ₅₀ proportion for the PDE4 catalytic form that binds high affinity rolipram and the IC 50 for the form that binds rolipram with low affinity.

PDE inhibitors used to treat inflammation and as bronchodilators, drugs such as theophylline and pentoxyfylline, inhibit PDE isoenzymes without distinction in all tissues. These compounds have side effects, apparently because they non-selectively inhibit all 5 classes of PDE isoenzymes in all tissues. The target disease state can be effectively treated with these compounds, but unwanted secondary effects can occur, which, if preventable or minimized, would increase the overall therapeutic effect in this approach to the treatment of certain disease states. For example, clinical studies with the selective PDE4 inhibitor rolipram, which was developed as an antidepressant, suggest that it has psychotropic activity and has

- concomitant effects on the gastrointestinal tract, e.g. pyrosis, nausea and vomiting.

For the purposes of the present invention, a cAMP catalytic site that binds R and S rolipram with low affinity is designated as a "low affinity" binding site (LPDE4), and another type of this catalytic site that binds rolipram with high affinity is designated "binding site" with high affinity ”(HPDE4). This term "HPDE4" should not be confused with the term "hPDE4", which is used to refer to human PDE4.

Initial experiments were performed to determine and validate the [3 H] -rolipram binding assay. Details of this work are given in Example 1 below.

To determine whether high binding activity and low binding activity originated from the same gene product, yeast were transformed by known methods and expression of recombinant PDE4 followed after 6 h of fermentation. Western blot analysis using an antibody directed against PDE4 indicated that the expressed amount of PDE4 increased with time, reaching a maximum after 3 h of growth. In addition, more than 90% of the immunoreactive product was in the supernantant of yeast lysates at high speed (100,000x g). [ ³ H] - (-) - rolipram binding and PDE activity were monitored along with protein expression. PDE4 activity was co-expressed with rolipram binding activity, suggesting that both functions exist on the same gene product. Similar to the Western blot results, more than 85% rolipram inhibitory PDE activity and [ ³ H] -rolipram binding activity were found in the yeast supernatant fraction.

Overall, the majority of recombinant PDE4 expressed in this system is in the form of LPDE4 and only a small fraction such as HPDE4. Consequently, inhibition of recombinant PDE4 catalytic activity primarily reflects the effects of the compounds on LPDE4. Therefore, inhibition of PDE4 catalytic activity can be used as an indicator of the efficacy of compounds on LPDE4.

The potency of the compounds on HPDE4 can be determined by assessing their ability to compete with [ ³ H] -R-rolipram. The efficacy of selected compounds was determined in two assays for the development of SARs for rolipram binding sites with both low and high activity. The results of the experiments were inserted into a table. As expected, certain compounds were clearly more effective in competing with [ ³ H] - (-) - rolipram at the site where

-5 -rolipram showed high binding activity compared to the site where rolipram is bound by low affinity. The SAR correlation between high activity binding and low affinity binding was weak, and it was concluded that the SAR for inhibiting the binding of [ ³ H] - (-) rolipram with high affinity was distant from the SAR for the low affinity rolipram binding site.

It is now known that there are at least two binding forms to monocyte recombinant PDE4 (hPDE4) in humans with which inhibitors are interacting. One explanation for these findings is that hPDE4 exists in two different forms. One binds similarly to rolipram and denbufylline with high affinity and the other binds these compounds with low affinity. Preferred PDE4 inhibitors for use in the present invention will be those having a good therapeutic ratio, ie, compounds that preferentially inhibit cAMP catalytic activity, wherein the enzyme is in a form that binds rolipram with low affinity, thereby reducing the side effects that are bound to inhibition of the high affinity rolipram binding form. Another way to determine this is that preferred compounds will have an IC ₅₀ ratio of about 0.1 or greater in terms of the IC 50 for the PDE4 catalytic form that binds high affinity rolipram and the IC 50 for the form that binds rolipram with low affinity.

Another improvement of this standard is that, when a PDE4 inhibitor ₅ of the IC ratio of about 0.1 or greater; this ratio is the ratio of the IC 50 value for competition with 1nM [ ³ H] -R-rolipram binding to form PDE4 that binds high affinity rolipram to the IC 50 value to inhibit the PDE4 catalytic activity of the low affinity rolipram binding form using 1µΜ [ ³ H 1 -cAMP as substrate. Further clear explanation of this test can be found in U.S. patent application Ser. No. 08/456274, filed May 31, 1995, the text of which is replaced herein by a reference indicating that the text is necessary to practice the invention.

Examples of suitable PDE4 inhibitors are: (R) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone; (/?) - (+) - 1- (4-bromobenzyl) -4 - [(3-cyclopentyloxy) -4-methoxyphenyl] -2-pyrrolidone; 3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N '- [N2-cyano-S-methylisothioureido] benzyl) -2pyrolidón;

cis -4-Cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid; c / s- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) cyclohexan-1-ol];

-6 (R) - (+) - Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidon-2-ylidene] acetate;

(S) - (-) - Ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidon-2-ylidene] acetate.

Most preferred are those PDE4 inhibitors whose IC ₅₀ ratio is greater than 0.5, and particularly those whose ratio is 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) cyclohexane- 1-one and cis - [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]; these are examples of compounds which bind in particular in cold binding activity and having a ratio of the IC ₅ by 0.1 or more.

The compounds are disclosed in U.S. Patent 5,552,438, issued September 3, 1996. This patent and the compounds it discloses are incorporated herein by reference. The compound of particular interest described in U.S. Patent 5,552,438 is cis -4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid and its salts, esters, precursors or physical forms.

AWD-12-281 by Astra (Hofgen, N.A. et al.: 15. EFMC Int Symp Med Chem (Sept. 6-10, Edinburgh) 1998, Abst. P. 98); A 9-benzyladenine derivative called NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plow; a benzodiazepine PDE4 inhibitor designated CI-1018 (PD-168787; Parke-Davis / Warner-Lambert); the benzodioxole derivative of Kyowa Hakko described in WO 9916766; V-11294A by Napp (Landells, L.J. et al. Eur Resp J [Annu Cong Eur Resp Soc (Sept. 19-23, Geneva) 1998], 12 (Suppl. 28); Abst P2393); roflumilast (CAS ref. 162401-32-3) and phthalazinone (WO 9947505) from Byk-Gulden; or a compound designated as T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1): 162). Any or all of these compounds could benefit from the method described herein.

Several of the specific compounds mentioned above, which do not have a generic or trade name, can be made by the method described in the patent applications also in the process of US Patent Application USSN 862 083 filed October 30, 1992; USSN 862,111 filed October 30, 1992; USSN 862 030 filed October 30, 1992 and USSN 862 114 on October 30, 1992, or in their predecessors, or in US patents claiming priority to one or more of these

-7prihlášok. Each of these applications or related patents is herein incorporated by reference in its entirety as it appears in this specification.

The steroid agents useful in the present invention are oral or inhaled corticosteroids and their precursors having anti-inflammatory activity. Examples of these steroids are methylprednisolone, prednisone, dexamethasone, fluticasone, beclomethasone, budesonide, flunizolide, mometasone furoate and triamcinolone acetonide. Methylprednisolone and prednisone are in the form of oral and injectable corticosteroids; are available from many manufacturers of original and generic medicines. Beclometasone dipropionate is marketed in the form of an aerosol for inhalation use under the names Beconase® and Beconase AQ® from Glaxo Wellcome.

Flluticasone propionate is also traded under the name Flonase® by Glaxo Wellcome. Triamcinolone acetonide is marketed by Rhone-Poulenc Roher under the name Nasacort® as a nasal spray and aerosol. Flunizolide is traded as a nasal solution under the names Nasalide® and Nasarel ™ from Roche Laboratoires. Dexamethasone is traded as the sodium phosphate salt from Medeva Pharmaceuticals, Inc. under the name Dexacort ™ phosphate. Mometasone furoate is marketed as a monohydrate in the form of a nasal formulation under the name Nasonex®. Budesonide is another inhaled corticosteroid used to treat lung diseases. It is marketed by Astra Pharmaceuticals, L. P. as a powder in a turbohaler apparatus under the name Pulmicort Turbohaler®. All of these drugs and nasal formulations or oral or injectable formulations can be found in the 1999 Physicians' Desk Reference® (PDR) edition of Medical Economics Corporation, Inc. New Je.rsey, USA and is available on the Internet at http: www. tomescps.com/fraMain.asp?Mnu=0 and other sites. Other corticosteroids are under development and those that could be used in the present invention are listed in Table I.

Table I

Inhaled corticosteroids

The drug Company Indications mometasone furoate Schering-Plow asthma, SAR

rofleponide AstraYeneca asthma ciclesonide Byk-Gulden / Recordati asthma butixocort propionate Warner-Lambert / 3M asthma, rhinitis RPR-106541 Rhone-Poulenc Rorer asthma ST-126 SSP / Torii asthma

A preferred combination treatment is one wherein the one or more drugs selected from dexometasone, fluticasone, beclomethasone, budesonide, flunisolide, mometasone furoate and triamcinolone acetonide are administered with cis-4-cyano (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane acid. -1-carboxylic acid (Ariflo®). A preferred treatment is the simultaneous administration of the steroid as an inhaled drug and an acid in an oral dosage form wherein each drug is administered once or twice daily. As regards the acid, it is preferred that it is in the form of an extended release tablet.

Both active substances are expected to be administered at the same time or close to each other. Alternatively, one medicine could be given in the morning and the other later in the day. According to another scheme, one drug could be administered twice a day and the other once a day, either concurrently with one of the two administrations or separately. It is preferred that both drugs be administered concurrently.

The compounds mentioned herein and their pharmaceutically acceptable salts, which are effective for oral administration, can be formulated as syrups, tablets, capsules, sustained release preparations or lozenges. Syrup formulations generally comprise a suspension or solution of the compound or salt in a liquid carrier such as e.g. ethanol, peanut oil, olive oil, glycerin or water with a flavoring and coloring agent. When the composition is in the form of a tablet, any pharmaceutical carriers conventionally used in the manufacture of solid compositions may be used. Examples of such carriers are magnesium stearate, gypsum, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. If the compositions are in the form of a capsule, any conventional encapsulation, e.g. using the aforementioned carriers in a hard gelatin capsule. When the compositions are in the form of a soft capsule shell, any commonly used pharmaceutical carrier can be used to produce dispersions or suspensions, e.g. liquid mucilages, celluloses, silicates or oils and these are embedded in a soft gelatin shell.

Conventional parenteral formulations comprise a solution or suspension of a compound or salt in a sterile water-based carrier or a non-aqueous carrier optionally containing a parenterally acceptable oil, e.g. polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil.

Conventional formulations for inhalation use are in the form of a solution, suspension or emulsion, which can be administered as a dry powder or in the form of an aerodispersion using a conventional propellant such as fluorocarbons such as e.g. trichórfluórmetán.

The composition containing PDE4 inhibitors is preferably in unit dosage form, such as e.g. tablet or capsule. For metered dose steroids, metered dry powder inhalers are preferred.

The active ingredient may be administered 1 to 6 times a day, which is sufficient to produce the desired effect. Preferably, the active ingredient is administered 1 to 2 times daily, more preferably 2 times daily.

The present compounds are useful for the treatment of exercise-induced asthma (EIA), environmental pollution-induced asthma (PIA), and cold-induced asthma (CIA) in the case of chronic disease as well as intermittent treatment if an inducing stimulus is expected. The present compounds are preferably used in long-term treatment.

Regarding the amount of drug administered, it is contemplated that for PDE4 inhibitors an amount between 1 and 200 µg per day in an adult human will be administered. Steroids may be administered in accordance with the approved label.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Phosphodiesterase and rolipram binding assays

Example 1A

Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) were determined to be primarily in low affinity form. Therefore, the efficacy of PDE4 compounds with low affinity can be determined by standard assays for PDE4

-10PDE4 catalytic activity using 1 μΜ [ ³ H] cAMP as substrate (Torphy et al., J. Biol. Chem., Vol. 267, No. 3, pp. 1798-1804, 1992).

High centrifuged supernatants from rat brain were used as a protein source and both [ ³ H] -rolipram enantiomers were produced for a specific activity of 25.6 Ci / mmol. Standard assay conditions were modified according to published procedure to be identical in PDE assay conditions except for the last cAMP: 50 mM Tris HCl (pH 7.5), 5 mM MgCl 2, 50 μΜ 5'-AMP and 1 nM [ ³ H] ] -rolipram (Torphy et al., J. Biol. Chem., Vol. 267, No. 3, pp. 1798-1804, 1992). The test was allowed to run at 30 ° C for 1 h. The reaction was terminated and bound ligand was separated from the free ligand using a Brandel cell collector. Competition to the high affinity binding site was determined under conditions that were the same as those for measuring PDE activity with low affinity except that [ ³ H] cAMP was not present.

Example 1B

Measurement of phosphodiesterase activity

PDE activity was determined using the [ ³ H] cAMP SPA or [ ³ H] cGMP SPA enzyme assay as reported by the supplier (Amersham Life Sciences). Reactions were performed in 96-well plates at room temperature, in 0.1 ml reaction buffer containing (final concentrations): 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), enzyme and various inhibitor concentrations. The reaction was allowed to proceed for 1 h and was quenched by the addition of 50 mL SPA yttrium silicate drops in the presence of zinc sulfate. Plates were shaken and allowed to stand at room temperature for 20 min. Radiolabeled product was determined by scintillation spectrometry.

[ ³ H] -rolipram binding assay

[ ³ H] -rolipram binding assay was performed by modifying the method of Schneider et al. See Nicholson et al., Trends Pharmacol Sci., Vol. 12, p. 19-27 (1991) and McHale et al. Mol. Pharmacol., Vol. 39, 109-113 (1991). Rrolipram binds to the catalytic site of PDE4. See Torphy et al., Mol. Pharmacol., Vol. 39, p. 376-384 (1991). Subsequently, competition for [ ³ H] -rolipram

-11 binding provides independent confirmation of PDE4 inhibitory properties of unlabeled competitors. The assay was performed at 30 ° C for 1 h in 0.5 ml buffer containing (final concentrations): 50 mM Tris HCl, pH 7.5, 5 mM MgCl 2, 0.05% bovine serum albumin, 2 nM [ ³ H] -rolipram (5.7 x 10 4 dpm / pmol) and various concentrations of unlabeled inhibitors. The reaction was stopped by the addition of 2.5 ml ice-cold buffer (without [ ³ H] -rolipram) and rapid vacuum filtration (Brandel cell collector) through Whatman GF / B filters soaked with 0.3% polyethyleneimine. The filters were washed with an additional 7.5 ml of cold buffer, dried and evaluated by liquid scintillation spectrometry.

Example 2

Cilomalast / low dose inhaled corticosteroid (ICS), dose range study

Study design • This was phase IIB, randomized, placebo-controlled, dose-range study, single-week blinded placebo, with a 6-week double-blind treatment phase, and one-week follow-up of patients with mild to moderate asthma.

• Study population. Men and women aged between 18 and 70 years, with mild to mild asthma, were not selected to be adequately controlled with low doses of corticosteroids (not more than 500 μg beclomethasone dipropionate / day or equivalent). The screening FEVi was required to have 50% and 80% predicted by height, age, race sex, and 12% or greater reversibility upon administration of beta-2 agonists. Patients should have had an overall symptom score of 6 or more for 4 out of 7 days, prior to randomization during the initial visit. The sample consisted of 300 evaluable patients.

Cilomast was dosed at doses of 5 mg, 10 mg and 15 mg twice daily for 6 weeks.

Subjects were adjusted to a mean dose of 500 µg beclomethasone equivalent, although the mean dose of ICS was 652 µς.

• Primary endpoint: change from baseline to reaching clinical expiratory volume in 1 s (FEVj), changes in clinical FEVi every week and more than 4 hours after the first dose of double-blind medication.

• Secondary endpoints: use of rescue treatment and overnight symptoms.

• Tertiary endpoints: clinically induced vital capacity (FVC), clinically highest exhalation rate (PEFR), induced exhalation flow at 25 to 75% (FEF25-75) 3 75% (FEV75) PEFR variability at home, PEFR at home, overall symptom score .

Evaluation criteria

The primary efficacy rate was defined as the change from baseline to end-of-study status in the induced expiratory volume in 1 s (FEV1) before the next dose. Changes in clinical FEV-γ were also analyzed weekly in the double-blind treatment phase and 4 hours immediately after the first dose of the double-blind treatment. Secondary efficacy parameters were the use of inhaled / nebulized beta 2-agonist and symptoms overnight. Tertiary efficacy parameters were clinically induced vital capacity (FVC), clinically highest expiratory rate (PEFR), induced expiratory flow at 25-75% (FEF25-75) and 75% (FEV75) PEFR variability at home, PEFR at home (morning and evening) total symptom score (total night, morning asthma and daytime asthma scores), morning asthma, persistent daytime asthma, use of inhaled corticosteroid, cough, grunting, wheezing / breast tightness, degree of asthma exacerbation, and overall doctor and patient scores.

Study results:

• no statistically significant improvement in FEV1 before administration of the next dose in ITT analysis of 15 mg cilomast BID versus placebo (0.16 I; p = 0.062) • response was dose-dependent for FEV1 before administration of the next dose in ITT analysis • significant improvement in FEV-γ before administration of the next dose (0.21 I; p = 0.033) after patient exclusion at ICS doses> 500 μ9 beclomethasone during administration of cilomast 15 mg BID • Confirmation of support for cilomast 15 mg BID included 4 h FEV-ι, PFER, FEF25-75 at home and overall physician and patient assessment.

Example 3

Cilomalast / high dose inhaled corticosteroid (ICS)

Study design • R, DB, PC, DR in patients with mild to mild asthma per 800 µg beclomethasone • Cilomast® doses were 5.10 and 15 mg twice daily for 4 weeks • 2-week series • primary endpoint at end of treatment : clinical BIT before the next dose • secondary end-of-treatment parameters: morning PEFR, symptoms, PFER variability, evening PFER, clinical PFER, FEF25-75, use of rescue treatment

Study results:

• no statistically significant change in FEVi before the next dose in any dose group in the ITT analysis • no dose effect has a primary endpoint at the end of the study • FEVi before the next dose was significantly improved when 10 mg cilomast BID was excluded after excluding patients receiving <800 pg ICS (0.16 l; p = 0.009) • ICS (beclometasone) dose ranged from 100 to 4000 pg and the average dose was 1136 pg • confirmation of support for cilomast 10 mg BID as effective dose also resulted ₍ many improved results at 4 h FEV-γ, clinical FVC, PFER • no response / dose dependence could be established, pre-dose concentrations were dose proportional and similar to previous studies

Table 1

Comparison of compounds in selected studies

Studies with allergen induction

Comparative data: Studies with allergen induction

Ariflo 15 mg bid Singulair ULTIAIR ICS 800 μg of budesonide B2 % max reduction LAR (effect of treatment) 1.3 12.3 10.7 22.9 +6.9 % protection max reduction LAR no 36.4 30.8 32 no reduction % AUCoELAR (treatment effect) 3.5 63.5 42.4 nerobené % protection of AUC LAR no 56.9 42.6 nerobené

Legend: Cilomaste data is selected from protocol analysis in asthmatics at <652 μ9 ICS. The data for montelukaste (MT), budesonide (BD), and both are selected from a study of Singulair SBA that assessed the effect of Singulair in relation to inhaled corticosteroids.

In both studies, there were no differences in the behavior of the placebo (Pbo) groups. The conclusion is that cilomast outperformed Singulair when added to a low dose of ICS, but the Pbo group also improved in the cilomast study.

The foregoing statements and examples serve to illustrate the invention, not to limit it. Below are claims that indicate what is reserved for the inventors.

Claims (2)

PATENT CLAIMS Use of a PDE4 inhibitor and an anti-inflammatory corticosteroid for the manufacture of a medicament for the treatment of a pulmonary disease for joint, separate or separate and sequential administration, the sequential administration being carried out closely or after a prolonged period. The use according to claim 1, wherein the PDE4 inhibitor is cis -4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid and the steroid is selected from dexamethasone, fluticasone, beclomethasone, budesonide, flunisolide, mometasone furoate, and triamcinolone acetonide.