MXPA02004350A - 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

METHOD AND COMPOSITIONS TO TREAT PULMONARY DISEASES FIELD OF THE INVENTION This invention relates to compositions and methods for preventing or reducing the onset of pulmonary disease symptoms, or treating or reducing the severity of lung diseases. In particular, it relates to compositions and methods for treating pulmonary diseases mediated by phosphodiesterase 4 (PDE4) by the administration of a PDE4 inhibitor with an anti-inflammatory corticosteroid.

BACKGROUND OF THE INVENTION The identification of novel therapeutic agents to treat lung diseases is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a particular mediator can have a substantial effect on the three components. of chronic asthma. An alternative to the "mediator method" is to regulate the activity of the cells responsible for the pathophysiology of the disease. One of these ways is by raising cAMP levels (3 'cyclic adenosine, 5'-monophosphate). The cyclic AMP has been shown to be «.... - ^ ^. ^« I. *. ~ * * 1, t mtfftÉfiMi iÉ ilÉi iÉi the second messenger that mediates the biological responses for 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. The cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP could produce beneficial effects including: 1) smooth muscle relaxation of the airways, 2) inhibition of release of mediators from mast cells, 3) suppression of neutrophil degranulation, 4) inhibition of the degranulation of the basophil; and 5) inhibition of monocyte and macrophage activation. Therefore, compounds that activate adenylate cyclase or that inhibit phosphodiesterase may be effective in suppressing inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The main cellular mechanism for the inactivation of cAMP is the hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDE). It has been shown that a distinct isozyme cyclic nucleotide phosphodiesterase (PDE), PDE4, is responsible for the breakdown of cAMP in the smooth muscle of the airways and in inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only results in smooth muscle relaxation of airways, but also suppresses the degranulation of mast cells, basophils and neutrophils together with the inhibition of activation of monocytes and neutrophils. In addition, the beneficial effects of PDE 4 inhibitors are markedly enhanced when the adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as might be the case in vivo. Therefore PDE 4 inhibitors could be effective in the lung, where the levels of prostaglandin E2 and prostacyclin (adenylate cyclase activators) are elevated. These compounds could offer a unique method towards the pharmacotherapy of bronchial asthma and have significant therapeutic advantages over agents currently on the market. In addition, it may be useful to combine therapies in light of the fact that the etiology of many lung diseases involves multiple mediators. In this invention the combination of a PDE 4 inhibitor and an anti-inflammatory corticosteroid, particularly one administered by inhalation, is present to treat pulmonary diseases. This combination is particularly useful for treating chronic obstructive pulmonary diseases (COPD) or asthma.

BRIEF DESCRIPTION OF THE INVENTION In a first aspect this invention relates to a method for treating a lung disease in a mammal by administering to a patient in need thereof an effective amount of a specific inhibitor of PDE 4 and an effective amount of an anti-inflammatory steroidal agent in where the drugs are administered concomitantly together or separately and sequentially where the sequential administration is close in time or remote in time. In a second aspect, this invention relates to a composition for treating a lung disease in a mammal comprising an effective amount of a specific inhibitor of PDE 4, an effective amount of an anti-inflammatory steroidal agent and a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION The combination therapy contemplated by this invention comprises administering a PDE 4 inhibitor with an anti-inflammatory steroidal agent to prevent the onset of a pulmonary disease event or to treat an existing condition. The compounds can be administered together in a single dose form. Or they can be administered as two different formulations which may be the same or different. For illustrate, both drugs may be provided separately as oral formulations, or one may be an oral preparation and the other an inhalant, or both may be provided in an inhaled dosage form. These can be administered at the same time. Or these may be administered either close in time or remotely in time, such as when a drug is administered in the morning and the second drug is administered in the afternoon. The combination can be used prophylactically or after the onset of symptoms. In some cases the combination (s) may be used to prevent the progression of a lung disease or to arrest the decline of a function, such as lung function. The specific PDE 4 inhibitor useful in this invention may be any compound that is known to inhibit the PDE 4 enzyme or which is found to act as a PDE 4 inhibitor and which are only PDE 4 inhibitors, not compounds that inhibit other PDE 4 inhibitors. members of the PDE family as well as PDE4. It is generally preferred to use PDE 4 antagonists which have an IC50 ratio of approximately 0.1 or greater with respect to IC50 for the catalytic form of PDE 4 which binds to rolipram with a high affinity divided by IC50 for the form that binds to rolipram with a low affinity. PDE inhibitors used to treat inflammation and used as bronchodilators, drugs similar to theophylline and pentoxifylline, inhibit PDE isozymes indiscriminately in all tissues. These compounds exhibit side effects, apparently due to that these inhibit non-selectively all 5 classes of PDE isozymes in all tissues. The targeted disease state can be effectively treated by said compounds, but unwanted side effects can be exhibited which, if these could be avoided or minimized, could increase the overall therapeutic effect of this method to treat certain disease states. For example, clinical studies with the selective PDE4 inhibitor rolipram, which has been developed as an antidepressant, indicate that it has a psychotropic activity and produces gastrointestinal effects, ie, heartburn, nausea and emesis. For the purpose of this description, the catalytic site of cAMP that binds rolipram R and S with a low affinity is called the "low affinity" binding site (LPDE 4) and the other form of this catalytic site which binds a rolipram with a high affinity is called the "high affinity" binding site (HPDE 4). This term "HPDE4" should not be confused with the term "hPDE4" which is used to denote human PDE 4. Initial experiments were carried out to establish and validate a [3 H] -rolipram binding assay. The details of this work are given in example 1 below. To determine whether both the high affinity binding activity and the low affinity binding activity reside in the same gene product, the yeasts were transformed by known methods and the expression of recombinant PDE 4 was followed during a fermentation period of 6 hours .

Western blot analysis using an antibody directed against PDE 4 indicates that the amount of PDE 4 expressed increased with time, reaching a maximum after 3 hours of growth. In addition, more than 90% of the immunoreactive product was in the high-speed supernatant (100,000 x g) of the used yeast. Binding to [3 H] R - (-) - Rolipram and PDE activity were monitored together with the expression of the protein. The PDE 4 activity was co-expressed with the binding activity to rolipram, indicating that both functions exist on the same gene product. Similar to the results with the Western blot analysis, more than 85% of the PDE activity that is inhibited by rolipram and the binding activity to [3H] -rolipram was found to be present in the fraction of the yeast supernatant. In general, most of the recombinant PDE 4 expressed in this system exist as LPDE 4 and only a small fraction as HPDE 4. Consequently, the inhibition of primarily active catalytic recombinant PDE 4 reflects the actions of the compounds in LPDE 4. Inhibition The active catalytic PDE 4 can then be used as an index of the potency of the compounds in LPDE 4. The potency of the compounds in HPDE 4 can be evaluated by examining their ability to compete for [3 H] R-rolipram. To develop SAR for both low affinity and high affinity rolipam binding sites, the potencies of selected compounds were determined in two assay systems. The results were tabulated from the experiments using compounds ^ • r ^. - ^ ii ^ J,. ^^^^^ standards. As expected, certain compounds are clearly more potent to compete with [3 H] R-rolipram at the site in which rolipram demonstrated a high affinity binding compared to the other site, that to which rolipram binds with low affinity. The SAR correlation between the high affinity binding and the low affinity binding was scarce and it was concluded that SAR for the inhibition of high affinity [3H] R-rolipram binding was different from SAR for binding to the site of union to rolipram of low affinity. At present it is known that there are at least two forms of binding in PDE 4 (hPDE 4) of recombinant human mocito with which the inhibitors interact. One explanation of these observations is that hPDE 4 exists in two different forms. One binds the similar elements of rolipram and denbuphylline with high affinity while the other binds these compounds with low affinity. Preferred PDE 4 inhibitors for use in this invention will be those compounds having a healthy therapeutic relationship, i.e., compounds that preferably inhibit the catalytic activity of cAMP wherein the enzyme is in the form that binds rolipram with a low affinity , therefore reducing the side effects which apparently are related to the inhibition of the form that binds rolipram with a high affinity. Another way of establishing this is that the preferred compounds will have an IC50 ratio of about 0.1 or greater with respect to IC50 for the catalytic form of PDE 4 which binds to rolipram with a high affinity divided by the IC50 of the bound form to rolipram with a low affinity.

A further refinement for this standard is one in which the PDE 4 inhibitor has an IC 50 ratio of approximately 1 to 5%. 0.1 or greater, this ratio is the ratio of the IC50 value to compete with the binding of 1nM of [3H] R-rolipram to a form of PDE 4 which binds rolipram with a high affinity on the IC50 value to inhibit the activity catalytic PDE 4 in a way that binds rolipram with a low affinity using 1 microM [3H] R-AMPc as the substrate.An additional explanation of critical evaluation with this test can be found in the co-pending US application No. 08 / 456274 filed May 31, 1995, the text of which is incorporated herein by reference to the extent to which the text is necessary for the practice of this invention 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) cyclohexane-1-ol]; (R) - (+) - ethyl - (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidone-2-ylidine] acetate; (S) - (-) - ethyl [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidone-2-ylidine] acetate; More preferred are those PDE 4 inhibitors which have an IC 50 ratio greater than 0.5, and particularly those compounds that have a ratio greater than 1.0. Preferred compounds are cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexane-1-carboxylic acid, carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -cyclohexan-1-one, and is- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -cyclohexan-1-yl]; these are examples of compounds that are preferably attached to the low affinity binding site and which have an IC500.1 or greater ratio. The compounds are set forth in the U.S. Patent. No. 5,552,438 issued September 3, 1996. This patent and the disclosed compounds described herein are hereby incorporated by reference in their entirety. The compound of particular interest, which is described in the U.S. Patent. No. 5,552,438 is c / s-4-cyano-4- [3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid and its salts, esters, prodrugs or physical forms. 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-Plow; and benzodiazepine inhibitor PDE4 identified as Cl-1018 (PD-168787; Parke-Davis / Warner-Lambert); a benzodioxole derivative Kyowa Hakko described in WO 9916766; V-11294A from Napp (Landells, L.J. et al., Eur Resp J [Annu Cong Eur Resp Soc (Sep 19-23, Geneva) 1998] 1998, 12 (Suppl 28): Abst P2393); roflumilast (reference CAS No 162401-32-3) and phthalazinone (WO 9947505) from Byk-Gulden; or a compound identified as T-440 (Tanabe Seiyaku, Fuji, K. et al., J Pharmacol Exp Ther, 1998, 284 (1): 162). Any or all of these compounds can or could benefit from the process described herein. Various specific compounds set forth above that do not have a generic or brand name can be made by the process described in co-pending patent applications of E.U.A. USSN 862,083 filed October 30, 1992; USSN 862,111 filed October 30, 1992; USSN 862,030 filed October 30, 1992; filed on October 30, 1992; and USSN 862,114 filed October 30, 1992 or its progeny or Patent (s) of E.U.A. who claim priority from one or more of these requests. Each of these related applications or patents are hereby incorporated by reference in their entirety as if they were set forth herein. The steroidal agents useful in this invention are oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity. Examples of these steroids are methyl prednisolone, prednisone, dexamethasone, fluticasone, declometasone, budesonide, flunisolide, mometasone furoate, and triamcinolone acetonide. Methyl prednisolone and prednisone are oral and injectable forms of . toi M »^^ i ^? I ^ itÉt ^? Á? Jm ^ l ^ A ^^? .1 l * m - + *. ? I anti-inflammatory corticosteroids; These are available from numerous brands and generic pharmaceutical companies. Beclomethasone dipropionate is sold as an inhalation spray under the names of Beconase® and Beconase®AQ® by Glaxo Wellcome. Fluticasone propionate is also sold under the name Flonase® by Glaxo Wellcome. The triamcinolone acetonide is sold by Rhone-Poulenc Roher under the name Nasacort® as a nasal spray and aerosol. Flunisolide is sold as a nasal solution under the name Nasalide® and Nasarel ™ by Roche Laboratories. Dexamethasone is sold as the sodium phosphate salt by Medeva Pharmaceuticals, Inc. under the name Dexacort ™ phosphate. Mometasone furoate is sold as the monohydrate as a nasal preparation by Shering Corp under the name Nasonex®. Budesonide is also another inhaled corticosteroid used to treat lung diseases. This is marketed by Astra Pharmaceuticafs, L.P. as a powder in a turbo-inhaler device under the name Pulmicort Turbohaler®. All of these drugs and nasal preparations 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, E.U.A. and it is available on the Internet at http://www.tomescps.com/fraMain.asp?Mnu=0 and related pages. Additional corticosteroids that are currently under development and which can be used in this invention are set forth in Table 1.

TABLE 1 Inhaled corticosteroids A preferred combination therapy is one or more of dexamethasone, fluticasone, declometasone, budesonide, flunisolide, mometasone furate, and tpamcinolone acetonide administered with c / S-4-cyano-4- (3-cyclopentyloxy-4-) acid. methoxyphenyl) cyclohexane-1-carboxylic acid, cilomalast (Ariflo®). A preferred therapy is the concomitant administration of the steroid as an inhaler and the acid in an oral dosage form, wherein each drug is administered once or twice a day. With respect to the acid, an oral controlled release tablet is more preferred. It is contemplated that both active agents could be administered at the same time, or very close in time. Alternatively, a drug it could be taken in the morni «! * ofro later in the day. Or in another scenario, a drug could be taken twice a day and the other once a day, either at the same time as one that occurs in dosing twice a day, or separately. Preferably both drugs could be taken together at the same time. The present compounds and pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules, controlled release preparations or tablets. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used to prepare solid formulations can be employed. Examples of such vehicles include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the formula of a capsule, any routine encapsulation is suitable, for example using the above-mentioned vehicles in hard gelatin capsule caps. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used to prepare dispersions or suspensions, for example aqueous gums, celluloses, silicates or oils, can be considered and incorporated into a gelatin capsule shell. soft.

Typical parental compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier which optionally contains a parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion which may be prepared as a dry powder or be in the form of an aerosol using a conventional propellant such as fluorinated hydrocarbons such as trichlorofluoromethane. Preferably the composition for PDE4 inhibitors is a unit dose form such as a tablet or capsule. For steroids, a metered dose of aerosol, measured inhaler of dry powder or nasal spray is preferred. The active ingredient may be administered 1 to 6 times a day, sufficiently to exhibit the desired activity. Preferably, the active ingredient is administered approximately once or twice a day, more preferably twice a day. The present compounds are useful for the treatment of exercise-induced asthma (EIA), pollution-induced asthma (PIA) and cold-induced asthma (CIA), both as chronic conditions and intermittently, in anticipation of the stimulus in question. Preferably, the present compounds are used for long-term therapy.

As well as for the amount of drug administered, it is believed that PDE4 inhibitors will be administered in an amount of between 1 and 200 micrograms per day per human adult. Steroids can be administered in accordance with approved labeling.

EXAMPLE 1 Phosphodiesterase-binding assays v Rolipram EXAMPLE 1A PDE 4 and hrPDE isolated from human monocytes (recombinant human PDE4) were determined to exist mainly in the low affinity form. Therefore, the activity of the compounds tested against the low affinity PDE 4 form can be evaluated using standard methods for the catalytic activity of PDE 4 using 1 microM [3 H] cAMP as a substrate (Torphy et al., J. Of Biol. Chem., Vol. 267, No. 3 pp1798-1804, 1992). High-speed rat brain supernatants were used as a protein source and both enantiomers of [3 H] -rolipram were prepared for a specific activity of 25.6 Ci / mmol. The standard assay conditions were modified from the published procedure to be identical to the conditions of the PDE assay, except for the latter of the cAMPs: 50 mM Tris HCl (pH 7.5), 5 mM MgCl 2, 5'-AMP 50 microM and 1 nM of [3 H] -rolipram (Torphy et al., J. Of Biol. Chem., Vol. 267, No. 3 pp 1798-1804). The runs were run for one hour at 30 ° C. The reaction was terminated and the bound ligand was separated from the free ligands using a Brandel cell harvester. Competition for high affinity binding sites was evaluated under conditions that were identical to those used to measure low affinity PDE activity, except that [3 H] -AMPc was not present.

EXAMPLE 1B Measurement of phosphodiesterase activity The PDE activity was assayed using an enzyme assay [3H] AMPc SPA or [3H] GMPc SPA as described by the supplier (Amersham Life Sciences). The reactions were carried out in 96-well plates at room temperature, in 0.1 ml of reaction buffer containing (final concentrations): 50 mM Tris-HCl, pH 7.5, 28.3 mM MgCI, 7 mM EGTA, [3H] CAMP or [3H] cGMP (approximately 2000 dpm / pmol), enzyme and various concentrations of the inhibitors. The assay was allowed to proceed for one hour and was terminated by adding 50 μl of yttrium silicate globules SPA in the presence of zinc sulfate. The plates were shaken and allowed to stand at room temperature for 20 minutes. The formation of the radiolabelled product was evaluated by scintillation spectrometry.

F3H1R-rolipram binding assay The [3H] R-rolipram binding assay was carried out by modifying the method of Schneider et al. See Nicholson, et al., Trends Pharmacol. Sci., Vol. 12, pp. 19-27 (1991) and McHaie et al., Mol. Pharmacol., Vol. 39, 109-113 (1991). R-Rolipram binds to the catalytic site of PDE4 see Torphy et al., Mol. Pharmacol., Vol. 39, pp. 376-384 (1991). Consequently, competition for the [3H] R-rolipram binding site provides independent confirmation of the PDE4 inhibitor potencies of unlabeled competitors. The assay was carried out at 30 ° C for one hour in 0.5 μl of buffer containing (final concentrations): 50 mM Tris-HCl, pH 7.5, 5 mM MgCl 2, 0.05% bovine serum albumin, [3 H] R -rolipram 2 nM (5.7x104 dpm / pmol) and several concentrations of non-radiolabelled inhibitors. The reaction was stopped by the addition of 2.5 ml of ice-cooled reaction buffer (without [3H] -R-rslipram) and rapid vacuum filtration (Brandel cell harvester) through Whatman GF / B filters that have been soaked in 0.3% polyethyleneimide. the filters were washed with an additional 7.5-ml of cold buffer, dried, and counted by liquid scintillation spectrometry.

EXAMPLE 2 Dosage interval study of Cylomalast / inhaled corticosteroid at low dose ICICS) Study design: • This was a phase IIB, randomized, placebo-controlled, phase-range study, with a one-week blind blind placebo, a 6-week double blind treatment phase and a follow-up phase of one week in patients with mild / moderate asthma. • Study population: The patients were men or women between 18 and 70 years old, with mild to moderate asthma, those who were not adequately controlled with two inhaled corticosteroid lows (no greater than 500 mcg of decomegrason / decleptone) were eligible. day or equivalent). The patients were required to have a selection of FEVi from >; 50% and < 80% predicted for height, age, sex and race and 12% or greater reversibility after administration of beta-2 agonist. The patients had to have an evaluation of total symptoms of 6 or more at 4 or 7 days that preceded the baseline of the visit to be randomized. The sample size was 300 evaluable patients. • Cilomalast was dosed at 5 mg, 10 mg, 15 mg twice a day for 6 weeks.

• The subjects were on an average of 500 mcg of beclomethasone equivalent, although the average dose of ICS was 652 mcg. • Main terminal point: The change from baseline to terminal point is through the expiratory clinical volume in one second (FEVi), changes in clinical FEVi each week and during a period of 4 hours after the first dose of double medication blindness. • Secondary endpoints: Use of rescue medicines and nighttime symptoms. • Tertiary terminal points: forced clinical vital capacity (FVC), clinical peak expiratory flow rate (PEFR), forced expiratory flow at 25-75% (FEF25-75) and 75% (FEF75), home PEFR variability, home PEFR, evaluation of total symptoms.

Evaluation criteria The primary effective measurement was defined as the change from the terminal point of the baseline through which the forced clinical expiratory volume is one second (FEVi). Changes in clinical FEV1 were also analyzed every week during the double-blind treatment phase and during a 4-hour period immediately after the first dose of double-blind medication. Secondary effi- ciency variables were used for inhaled / nebulized beta-2 agonists and nocturnal asthma symptoms. The tertiary efficiency variables were forced vital capacity (FVC), clinical expiratory peak flow velocity (PEFR), flow forced expiratory at 25-75% (FEF25-75) and 75% (FEF75), home PEFR variability, home PEFR (morning and afternoon), evaluation of total symptoms (a composite assessment of nocturnal asthma, in the morning and generally during day), morning asthma, general asthma during the day, use of inhaled corticosteroids, cough, wheezing, shortness of breath / tightness in the chest, speed of asthma exacerbation and overall evaluation by the doctor and the patient.

Results of the study: • There is no statistical improvement in FEV1 at the terminal point of the ITT analysis at 15 mg of cilomalast BID against placebo (0 16 L; p = 0.062) • The response was ordered by the dose for FEV1 in the analysis of ITT endpoint • Significant improvement in FEV1 (0.21 L; p = 0.033) was excluded in patients with ICS dose > 500 mcg of beclomethasone while on cilomalast 15 mg BID. • It was corroborated that the maintenance for cilomalast 15 mg BID included 4 hours of FEV1, PEFR, FEF25-75 domiciliary and global evaluations by the doctor and the patient.

'* J, LL, Ji ^ "" > * - ^ - ^ ~ - ^ - ^ t-l - ^^ - ****? **** ~ * - + ^ ¿EXAMPLE 3 Study of inhaled corticosteroid cortomateroid at high dose (ICS Study design • R, DB, PC, DR in patients with mild / moderate asthma > 800 mcg of beclomethasone • The doses of cilomalast ® were 5, 10 and 15 mg twice daily for 4 weeks. • 2 week run • Main terminal point- through the clinical FEVi. • Secondary endpoints: morning PEFR, symptoms, PEFR variability, evening PEFR, PEFR, FEF25-75, clinical FEF75, use of rescue medication.

Results of the study: • There were no statistically significant changes in the clinical FEVi in any dose group that was evidenced in the ITT analysis. • No ordering of the dose was observed from the main terminal point. • Through FEVÍ statistically improved to 10 mg of cilomalast BID using repeated measurement analysis in patients excluded on < 800 mcg of ICS (0.16 L; p = 0.009).

• The dose of ICS (beclo etasone) had a range of 100 to 4000 mcg and averaged 1136 mcg • The maintenance of 10 mg of cilomalast BID was corroborated as the effective dose that also obtained numerically superior results in the clinical FEVi of 4 hours, Clinical FVC, PEFR. • No dose-response relationship could be determined, through the concentrations where proportional doses were used and similar to the previous studies.

TABLE 1 Comparison between the compounds in selected studies Allergic test studiesComparative data: allergic test studies Ariflo Singulair Ultair ICS B2 15 mg bd and 800 mcg of budesonide% Maximum fall of 1.3 12.3 10.7 22.9 +6.9 LAR (treatment effect)% protection None 36.4 30.8 32 No fall drop maximum LAR% AUC of LAR (effect 3.5 63.5 42.4 Not performed of the treatment)% AUC protection None 56.9 42.6 Not performed LAR Legend: the data with cilomalast were taken from the protocol analysis in patients with asthma in < 652 mcg of ICS. The data in montelukast (MT), budesonide (BDP) and both were taken from a particular study in the Singulair SBA that examined the effect of Singulair in relation to inhaled corticosteroids. There are significant differences between the behavior of the placebo groups (Pbo). ) in both studies. The conclusion is that cilomalast improved the performance of Singulair when it was added in low ICS doses, despite the fact that the Pbo group was also improved in the study with cilomalast. It is intended that the above-mentioned evaluations and the examples illustrate the invention, not limit it. The claims are referred to for what is reserved to the inventors below.

Claims (1)

NOVELTY PE tA TVENTION CLAIMS

1. - The use of a PDE 4 inhibitor and an anti-inflammatory corticosteroid to prepare a medicament for treating a lung disease wherein the drug components are administered in a combined form, separately, or separately and sequentially where the sequential administration is close in the time or remote in time. 2 - The use as claimed in 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 group consisting of dexamethasone, fluticasone, declometasone, budesonide, flunisolide, mometasone furoate, and triamcinolone acetonide.