CN1387404A - Method and compositions for treating pulmonary diseases - Google Patents
Method and compositions for treating pulmonary diseases Download PDFInfo
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- CN1387404A CN1387404A CN00815265A CN00815265A CN1387404A CN 1387404 A CN1387404 A CN 1387404A CN 00815265 A CN00815265 A CN 00815265A CN 00815265 A CN00815265 A CN 00815265A CN 1387404 A CN1387404 A CN 1387404A
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- pde4
- rolipram
- administration
- asthma
- inhibitor
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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
Invention field
The present invention relates to prevent or reduce the composition and the method for tuberculosis paresthesia epilepsy or the treatment or the serious state of an illness of minimizing tuberculosis.Specifically, the present invention relates to the composition and the method for tuberculosis that the treatment of phosphodiesterase 4 (PDE4) inhibitor and anti-inflammatory corticosteroid administering drug combinations is regulated by PDE4.
Background of invention
The formation of tuberculosis is this fact that is caused by multiple transmission matter, makes to find that new pneumotherapy agent is very difficult.As if can not substantial effect all be arranged to three factors of chronic asthma so eliminate the influence of single transmission matter.Another " transmits the matter approach " is to regulate determining the physiopathologic cytoactive of tuberculosis.
One of these class methods are to improve the level of cAMP (ring-type 3 ', 5 '-single adenosine phosphate).It is the second kind of courier who regulates multiple hormone, neurotransmitter and medicine biological respinse that ring-type AMP has been proved it; [Krebs Endocrinology Proceedinys of the 4th International Congress ExcerptaMedica, 17-29,1973].When suitable antagonist combined with the cell surface specific receptor, adenyl cyclase just was activated, with Mg
+ 2-ATP quickens to be converted into cAMP.Ring-type AMP can regulate great majority, but is not whole cytoactives that can work to the pathologic, physiologic of exogenous (hypersensitivity) asthma.Therefore, the beneficial effect that the rising of cAMP can produce comprises: 1) relaxing to airway smooth muscle, 2) papilla cell is transmitted the inhibition that matter discharges, 3) to the containment of neutrophil leucocyte threshing, 4) to the inhibition of basophil degranulation, and 5) to the inhibition of monocyte and macrophage activation.So, but the compound of activated adenyl cyclase or inhibition phosphodiesterase should effectively suppress airway smooth muscle and the unfavorable activation of various inflammatory cell.The main celelular mechanism of cAMP inactivation be be referred to as in ring-type nucleotide phosphodiesterase (PDEs) the isoenzymes family one or more hydrolysis 3 '-phosphodiester bond.
Shown that now unique ring-type nucleotide phosphodiesterase (PDE) isoenzymes PDE4 is determining the degraded of the cAMP in airway smooth muscle and the inflammatory cell.[Torphy, " phosphodiesterase isoenzyme: the potential target of anti-asthma new medicament ",
The asthma new drug, Barnes edits, IBC Technology Service Co., Ltd, 1989].Studies show that the inhibition to this kind of enzyme has not only produced the lax of airway smooth muscle, and suppressed the threshing of papilla cell, basophilic granulocyte and neutrophil leucocyte, simultaneously with inhibition monocyte and neutrophil activation.And when suitable hormone or endocrine improved the adenylate cyclase activity of target cell, the beneficial effect of PDE4 inhibitor was just strengthened significantly, and the situation in the body may come to this.So work as PGE
2And the level of prostacyclin (activator of adenyl cyclase) is when raising, and the PDE4 inhibitor will be effective to lung.This compounds provides a kind of method of uniqueness and them than present commercially available medicament significant treatment advantage to be arranged to the medicinal treatment of bronchial astehma.
In addition, comprise that according to the cause of disease of many tuberculosis the fact of multiple transmission matter can use in conjunction with therapy.In the present invention, proposed the combined therapy tuberculosis of PDE4 inhibitor and anti-inflammatory corticosteroid, particularly, delivered a kind of medicine with inhalation.This combination is particularly useful for treating chronic obstructive pulmonary disease (COPD) or asthma.
Summary of the invention
First aspect, the present invention relates to a kind of method for the treatment of mammal tuberculosis, comprise to the patient of this treatment of needs the steroidal anti-inflammatory agent of the PDE4-specific inhibitor of effective dose and effective dose is common or separately and administration continuously, wherein the time of successive administration is changeable.
Second aspect the present invention relates to a kind of composition for the treatment of mammal tuberculosis, and it contains the PDE4-specific inhibitor of effective dose, the steroidal anti-inflammatory agent of effective dose and pharmaceutically acceptable excipients.
Detailed description of the present invention
Combination treatment involved in the present invention comprises PDE4 inhibitor and steroidal anti-inflammatory agent administration is together prevented the outbreak of tuberculosis or treat existing symptom.These compounds can the administration together of single formulation.Perhaps they are with two kinds of identical or different preparation administrations.In more detail, can provide two kinds of medicines with oral formulations respectively, perhaps one is oral formulations and another is an inhalant, and perhaps two kinds of medicines all provide with inhalant dosage form.Their administrations simultaneously.Perhaps they are at close time or time administration far away, for example a kind of medicine of administration in morning and second kind of medicine of administration in evening.
This combination can be used for after prevention or the paresthesia epilepsy.Sometimes, this combination can be used to prevent the development of tuberculosis or the decline of prevention function such as PFT.
Be used for PDE4-specific inhibitor of the present invention and can be known inhibition PDE4 enzyme or has found the effect of PDE4 inhibitor with any compound that is the PDE4 inhibitor, be not the compound that not only can suppress other members of PDE family but also can suppress PDE4.IC about PDE4 catalysis form
50, general preferred use IC
50Than being about 0.1 or bigger PDE4 antagonist, IC wherein
50Be the IC of the PDE4 catalysis form that combines with the Rolipram high-affinity
50Divided by hanging down the IC of compatibility combining form with Rolipram
50
The PDE inhibitor that is used for the treatment of inflammation and resembles theophylline and Pentoxifylline (pentoxyfyllin) medicine as bronchodilator can both indistinguishably suppress the PDE isoenzymes in institute in a organized way.But because these compounds obviously can non-selectively suppress the whole 5 kinds of PDE isoenzymes groups in a organized way, so they have side effect.This compounds is the therapeutic purpose disease effectively, but has undesirable side effect, if these side effects can be avoided or reduce to minimum, will increase total result of treatment that this method is treated some disease.For example, show that with the clinical research that has been developed to the PDE4 selective depressant Rolipram of antidepressant it has neurotropic activity and intestines and stomach are exerted an influence as heartburn, nausea and vomiting.
For purposes of this disclosure, the cAMP catalytic site that can combine with the low compatibility of the Rolipram of R and S is referred to as " low compatibility " binding site (LPDE4) and the catalytic site of the another kind of form that can combine with the Rolipram high-affinity is referred to as " high-affinity " binding site (HPDE4).Term " HPDE4 " should not obscured mutually with the term that is used to represent people PDE4 " hPDE4 ".
Foundation and confirmation [3H]-Rolipram carry out initial trial in conjunction with mensuration.Following examples 1 will provide the details of this test.
Whether all be present on the homologous genes product expression of using the known method transformed yeast and following the trail of recombinant PDE4 at 6 hours yeast phase in conjunction with activity in conjunction with active and low compatibility in order to measure high-affinity.Western blot analysis with the antibody of direct anti-PDE4 shows that the expression of PDE4 increased along with the time, grows to reach maximum after 3 hours.In addition, greater than 90% immune reaction product in the high speed of yeast lysate (in 100,00 * g) supernatants.Also monitor in the time of with protein expression [
3H] R-(-)-Rolipram combination and PDE activity.PDE4 active with Rolipram to combine activity be co expression, this shows that two kinds of functions are present on the homologous genes product.Similar to the result of western blot analysis, find Rolipram-quenchable PDE 85% or more active with [
3H]-Rolipram all is present in the part of yeast supernatant in conjunction with activity.
In a word, expressed most of recombinant PDE4 exist with LPDE4 and have only small part to exist with HPDE4 in system.So, the inhibition of recombinant PDE4 catalytic activity has mainly been reflected the effect of compound to LPDE4.Like this can be as the index of compound to the LPDE4 effect to the inhibition of PDE4 catalytic activity.Compound to the effect of HPDE4 can by detect they with [
3H] competitive ability of R-Rolipram estimates.In order to develop the SARs of low compatibility and high-affinity Rolipram binding site, measure the effect of selected compounds with two kinds of evaluation systems.Use the result of the test of n-compound to represent with form.As desired, be that the position that confirms the high-affinity combination at Rolipram is compared at the position of low compatibility bond with other positions such as a kind of Rolipram, some compound with [
3H]-Rolipram is obviously more effective in competing.High-affinity in conjunction with and low compatibility between SAR get in touch relatively poor, reach a conclusion be suppress high-affinity [
3H]-SAR of Rolipram combination is different from the SAR of low compatibility Rolipram binding site combination.
Now known can with the interactional person monocytic cell's recombinant of inhibitor PDE4 (hPDE4) on have two kinds of combining forms at least.A kind of explanation to these observations is that hPDE4 exists two kinds of different forms.A kind of high-affinity ground in conjunction with Rolipram and Denbufytline (denbufylline) and another low compatibility ground in conjunction with these compounds.Being used for preferred PDE4 inhibitor of the present invention is that those have the compound that is of value to restorative treatment ratio, promptly when enzyme be the compound that can preferably suppress the cAMP catalytic activity in the time of can hanging down compatibility in conjunction with the form of Rolipram, reduce thus obviously and the relevant side effect of inhibition form of Rolipram high-affinity ground combination.About another describing method of PDE4 catalysis form is to have 0.1 or bigger IC
50The preferred compound of ratio, IC wherein
50Than the IC that is the PDE4 catalysis form that combines with the Rolipram high-affinity
50Divided by hanging down the IC of compatibility combining form with Rolipram
50
The further improvement of this standard is that the PDE4 inhibitor has 0.1 or bigger IC
50The ratio those; This ratio is to use 1mM[
3H]-cAMP do substrate and 1nM [
3H] the R-Rolipram forms the IC of the PDE4 that can combine with the Rolipram high-affinity in conjunction with competition
50Value suppresses the IC of PDE4 catalytic activity to the form that can combine with the low compatibility of Rolipram
50The ratio of value.The further review of this test is explained and can be found with the content quotation of the document to this paper as a reference, the degree of institute's substance quoted is enough to make the present invention to be implemented in the U.S. Patent application 08/456274 of the common pending trial of application on May 31 nineteen ninety-five.
The example of available PDE4 inhibitor is:
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-the 4-methoxyphenyl]-2-Pyrrolidone;
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-the 4-methoxyphenyl]-2-Pyrrolidone;
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N '-[N2-cyano group-S-methyl-isothiourea group] benzyl)-2-pyrrole compares pyrrolidone;
Cis-4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid;
Cis-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane-1-alcohol;
(R)-(+) ethyl acetate-[4-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidines-2-subunit];
(S)-(+) ethyl acetate-[4-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidines-2-subunit].
IC most preferably
50Compare those PDE4 inhibitor, particularly IC greater than 0.5
50Compare those compounds greater than 1.0.Preferred compound is cis-4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-methoxycarbonyl base-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane-1-ketone and cis-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane-1-alcohol; These all be can preferentially combine with low compatibility binding site and have 0.1 or bigger IC
50The example of the compound of ratio.
Some compounds have been listed at the United States Patent (USP) 5,552,438 that on September 3rd, 1996 announced.This patent and its disclosed compound all are cited as list of references at this paper.Be disclosed in United States Patent (USP) 5,552, useful especially compound is cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl in 438) cyclohexane-1-carboxylic acid and salt, ester, pro-drug or physical form.
From the AWD-12-281 of Astra (Hofgen, N. etc., 15th EFMC Int Symp MedChem (Sept 6-10, Edinbergh) 1998, Abst is P.98; Name is called the 9-benzyladenine derivative (INSERM) of NCS-613; The D-4418 of Chiroscience and Schering-Plough; Be accredited as the benzodiazepine PDE4 inhibitor (PD-168787 of CI-1018; Parke-Davis/Warner-Lambert); Disclosed benzo benzodioxole derivatives in the WO9916766 of Kyowa Hakko; From the V-11294A of Napp (Landells, L.J. etc., Eur RespJ[Annu Cong Eur Resp Soc (19-23 day in September, Geneva) 1998] 1998,12 (annexes 28): summary P2393); The roflumilast of Byk-Gulden (CAS reference number 162401-32-3) and pthalazinone (WO9947505); Perhaps be accredited as compound (the Tanabe Seiyaku of T-440; Fuji, K. etc.,
J Pharmacol Exp Ther,1998,284 (1): 162).Any in these compounds or can maybe can be of value to method as herein described all.
The United States Patent (USP) of pending trial was stretched and is asked USSN 862 when the above-mentioned good several special compounds of listing that do not have popular name or trade name can be applied for according on October 30th, 1992,083, USSN 862,111, USSN 862,030 and USSN 862,114 or its subsequent application or these applications in one or morely require the methods preparation described in the United States Patent (USP) of priority.This paper all is cited as reference with these applications or relevant patent, lists in being listed in this document.
Being used for steroid medicament of the present invention is mouthful a corticosteroid with anti-inflammatory activity and the pro-drug thereof using and suck.The example of these steroids is that dragon, prednisone, dexamethasone, Fluticasone, Beclomethasone, budesonide, 9-remove fluorine fluocinolone acetonide, Mometasone Furoate and adcortyl A to first by force.Strong dragon of first and prednisone are the antiphlogistic corticoids of mouthful usefulness and injectable forms; They can obtain from the common drug company of many registrations.The dipropionic acid Beclomethasone is to be called Beconase as inhalation aerosol with name by GlaxoWellcome
With Beconase AQ
Sell.GlaxoWellcome also sells name and is called Flonase
Fluticasone Propionate.Rhone-Poulenc Roher sells name and is called Nasacort
Nasal spray and the adcortyl A of aerosol form.RocheLaboratories sells name and is called Masalide
And Nasarel
TMThe 9-of nose solution form remove the fluorine fluocinolone acetonide.Medeva drugmaker sells name and is called phosphoric acid Dexacort
TMThe dexamethasone of sodium ascorbyl phosphate form.Schering company sells name and is called Nasonex
The Mometasone Furoate of nasal formulations of monohydrate form.Budesonide still is the suction corticosteroid that another is used for the treatment of tuberculosis.It is by Astra Pharmaceuticals, and L.P. is with Pulmicort Turbohaler
Title turbohaler device in powder form on market, sell.Physicians ' the Desk reference of the versions in 1999 that all these medicines and nasal formulations or mouthful usefulness or injectable preparation can both be published in the medication economics cooperative venture of N.J.
(PDR) finding in also can be in the internet
Http:// www. tomescps.com/fraMain.asp? Mnu=0With the link webpage on buy.Table 1 listed now developing and can be used for other corticosteroids of the present invention.
Table 1
The corticosteroid that can suck
| Medicine | Company | Symptom |
| Mometasone Furoate | ?Schering-Plough | Asthma SAR |
| Rofleponide | ?AstraZeneca | Asthma |
| Ciclesonide | ?Byk-Gulden/Recordati | Asthma |
| Butixocort?propionate | ?Warner-Lambert/3M | Asthma/rhinitis |
| RPR-106541 | ?Rhone-Poulenc?Rorer | Asthma |
| ST-126 | ?SSP/Torii | Asthma |
Preferably be and cis 4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, cilomalast (Ariflo in conjunction with therapy
) one or more dexamethasone of administration, Fluticasone, Beclomethasone, budesonide, the therapy of removing fluorine fluocinolone acetonide, Mometasone Furoate and adcortyl A together.Preferred therapy be with steroid with inhalant with the together administration of acid with peroral dosage form, wherein every kind of medicine was administered once or twice in one day.With regard to acid, most preferably be the sustained release oral tablet.
Can expect two kinds of active agents whiles or very near time administration.Another method, the administration in morning of a kind of medicine, another kind of administration after a while in this day.Perhaps another scheme, a kind of medicine one day administered twice, and another kind of medicine with carry out one day medicine in twice administration simultaneously or separate administration, once a day.Preferred two kinds of medicine administrations together.
Activated The compounds of this invention and pharmaceutically acceptable salt can be prepared to syrup, tablet, capsule, sustained release preparation or lozenge during oral administration.Syrup generally by this compound or its salt liquid-carrier for example ethanol, peanut oil, olive oil, glycerine contain flavouring or the water of colouring agent in suspension or solution composition.When composition is tablet, can use preparation solid dosage forms any pharmaceutical carrier commonly used.The example of this class carrier comprises dolomol, land plaster, talcum powder, gelatin, gum Arabic, stearic acid, starch, lactose and sucrose.When composition was capsule, the technology of any conventional preparation capsule all was suitable for, and for example uses aforementioned bearer in hard capsule case.When composition is soft capsule, can consider for example moisture natural gum of any pharmaceutical carrier, cellulose, silicate or oils that supending or dispersion liquid are commonly used, it is mixed in the Perle shell.
The composition of general parenteral comprises that by aseptic moisture or anhydrous carrier is optional the outer acceptable oil of stomach and intestine for example form by the solution or the suspension of the compound or its salt in polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or the sesame oil.
General inhalant composition be can the dry powder form administration solution, suspension or emulsion form or with propellant commonly used as fluoridizing the aerosol form of hydro carbons such as Arcton 11.
The PDE4 inhibitor combination is unit dosage forms such as tablet or capsule preferably.The preferably Foradil Aerolizer formoterol fumarate of metered aerosol, metering or nasal spray concerning steroid.
This active component can administration in a day 1 to 6 time, enough has desired activity.The administration of active component preferably once a day or twice, more preferably one day twice.
The present composition can be used for treating exercise induced asthma (EIA), pollute two kinds of the chronic and batch-type of the asthma (CIA) that the asthma (PIA) bring out and cold brings out, also to consider to have the participation of stimulus.The compounds of this invention is preferred for extended regimen.
With regard to dosage, think to every per day for adults of PDE4 inhibitor with the amount administration between 1 to 200 milligram.To the label administration of steroid according to authorization.
The mensuration that embodiment 1-phosphodiesterase combines with Rolipram
Embodiment 1A
Measure isolated person monocytic cell PDE4 and the hPDE4 (people's recombinant PDE4) that mainly exists with low compatibility form.So, with 1mM [
3H] cAMP makes the activity (torphy etc., journal of biological chemistry, 1992 the 267th volumes, the 3rd phase 1798-1804 page or leaf) that substrate uses the low compatibility form of the anti-PDE4 of standard test method assessment test compound of PDE4 catalytic activity.
With the supernatant of the high-speed separation of rat brain do protein sources and will [
3H]-two kinds of enantiomters of Rolipram are prepared into the proportion of 25.6Ci/mmol.The standard test condition that improves in the disclosed method is consistent with the PDE condition determination, except the cAMP: 50mM Tris HCl (pH7.5), 5mM MgCl
2, 5 '-AMP of 50mM and 1nM [
3H]-Rolipram (Torphy etc., journal of biological chemistry, 1992 the 267th volumes, the 3rd phase 1798-1804 page or leaf).This is determined at 30 ℃ and carried out 1 hour.Cessation reaction is also separated binding partner with the Brandel cell harvester from free ligand.Except do not contain [
3H]-cAMP outside, with the competition of measuring under the condition of measuring the active term harmonization that uses of low compatibility PDE the high-affinity binding site.
Embodiment 1B
The mensuration of phosphodiesterase activity
With supplier (Amersham Life Sciences) described [
3H] cAMP SPA or [
3H] cGMPSPA enzymatic determination PDE activity.At room temperature react in the reaction buffer of 0.1ml on 96 cave plates, this reaction buffer contains the Tris-HCl of (ultimate density): 50mM, the MgCl of pH7.5,8.3mM
2, 1.7mM EGTA, [
3H] cAMP or [
3H] inhibitor of cGMP (approximately 2000dpm/pmol), enzyme and various concentration.The SPA yttrium silicate pearl cessation reaction of 50 μ l was carried out 1 hour and passed through to add to mensuration in the presence of zinc sulphate.The vibration plate also left standstill 20 minutes in room temperature.Measuring radiolabeled product with scintillation spectrometry forms.
[
3
H] the R-Rolipram is in conjunction with mensuration
Improvement method with Schneider and colleague carry out [
3H] the R-Rolipram in conjunction with measuring.Referring to Nicholson etc., Trends Pharmacol.Sci., Vol.12,19-27 page or leaf (1991) and McHale etc., Mol.Pharmacol., Vol.39,109-113 (1991).The R-Rolipram combines with the catalytic site of PDE4 referring to Torphy etc., Mol.Pharmacol., and Vol 39, pp.376-384 (1991).So, [
3H] competition of r-Rolipram combination provides the independent proof to the PDE4 inhibitor effect of unlabelled competitor.This mensuration is to carry out in 30 ℃ of buffer solutions at 0.5ul, and buffer solution wherein contains the Tris-HCl of (ultimate density): 50mM, the MgCl of pH7.5,5mM
2, 0.05% fetal bovine serum albumin, 2[
3H] R-Rolipram (5.7 * 104dpm/pmol) and the nonradioactive labeling's of various concentration inhibitor.The ice-cold reaction buffer of adding 2.5ml (do not contain [
3H]-the R-Rolipram) cessation reaction and WhatmanGF/B filter paper fast vacuum filtration (Brandel Cell Harvester) by having soaked at 0.3% polymine.With the ice-cold buffer flushing filter paper of other 7.5ml, the dry liquid crystal scintillation spectrometry counting of also using.
Embodiment 2
The Cilomalast/ low dosage sucks corticosteroid (CIS) dosage-distribution test
Experimental scheme:
This is the dosage-distribution test of a slight/moderate asthma patient's IIB phase placebo at random, carries out the blind placebo test of list a week, 6 all double-blind treatment phases and all follow-up period.
The test crowd: suck at low dosage that corticosteroid (being no more than 500mcg dipropionic acid Beclomethasone/sky or a great deal of) is not enough to control, the age 18 and 70 years old between the sex patient who suffers from light to moderate asthma be standard compliant.Require that the patient has that pair height, age, sex and race predicted 〉=50% and≤FRV of 80% generaI investigation
1With behind administration β-2 antagonist, have 12% or bigger invertibity.Go to a doctor on the basis of selecting at random and to carry out 4 days patients in 7 days and just have 6 or higher symptom total points.Number of subjects is 300 appreciable patients.
With cilomalast with 5mg, 10mg and one day 6 week of twice administration of 15mg.
Although the mean dose of ICS is 652mcg, the experimenter still uses the mean value 500mcg of Beclomethasone equivalent.
First terminal point: kind was interior from the clinical expired volume (FEV of the tank of origin-to-destination in 1 second
1) change, weekly with the administration for the first time of double blinding medicine after clinical FEV in 4 hours
1Variation.
Second terminal point: use the salvage drug and the symptom of spending the night.
The 3rd terminal point: forced vital capacity (FVC), peak expiratory velocity (PEFR)/at 25-75% (FRF clinically clinically
25-75) and 75% (FEF
75) forced expiration speed, the PEFR of family variable, the PEFR of family, symptom total points.
Evaluation criteria
The mensuration of first effect is defined as the 1 second interior expired volume of tank clinically (FEV from origin-to-destination of kind
1) variation.Also analyze clinical FEV during 4 hours weekly with after the administration for the first time of double blinding medicine in the double-blind treatment phase
1Variation.Second efficacy variable is the SOA that uses and spend the night of suction/spraying β-2 antagonist.The 3rd efficacy variable be firmly vital capacity (FVC), clinical peak expiratory velocity (PEFR), at 25-75% (FRF
25-75) and 75% (FEF
75) forced expiration speed, the PEFR of family variable, the PEFR of family (morning and night), symptom total points (night, morning and whole daytime asthma composite score), morning asthma, the asthma on whole daytime, suck corticosteroid uses, cough, breathe, can't breath/chest tightly, asthma deterioration rate and doctor and patient's the overall evaluation.
Result of the test:
At the cilomalast BID of the analysis 15g of terminal point ITT tank FEV to placebo
1Improvement (the 0.16L that does not have statistical significance; P=0.062).
Analyze tank FEV at terminal point ITT
1Reaction with dosage be the order.
If get rid of ICS dosage＞500mcg Beclomethasone patient's tank FEV of cilomalast 15mg BID simultaneously
1Significant improvement (0.21L is arranged; P=0.033).
The overall evaluation mark that comprises 4 hours FEV1, the PEFR of family, FEF25-75 and doctor and patients that provides powerful support for to the 15mg BID of cilomalast.
Embodiment 3
The Cilomalast/ low dosage sucks corticosteroid (CIS) test
Experimental scheme:
The patient is slight/patient of moderate asthma R, DB, PC, the DR when the Beclomethasone of 〉=800mcg.
Cilomalast
Dosage is 5,10 and totally 4 weeks twice of 15mg every day.
The test of 2 weeks.
First terminal point: clinical tank FEV
1
Second terminal point: the PEFR in morning, symptom, PEFR variable, night PEFR, clinical PEFR, PEFR25-75, PEFR75, used salvage drug.
Result of the test:
Any dosage group does not all demonstrate clinical tank FEV in ITT analyzes
1Statistics on marked change.
Do not observe dose levels from first terminal point.
The tank FEV that uses the replication analysis when the cilomalast of 10mg BID, to improve on the statistics
1Be the patient (0.16L that gets rid of at＜800mcg ICS; P=0.009)
ICS (Beclomethasone) dosage range is from 100 to 4000mcg, average 1136mcg.
The cilomalast BID of 10g is also come from superior results on the numerical value of 4 hours clinical FEV1, clinical FVC, PEFR as providing powerful support for of effective dose.
Do not measure dose-response relationship, tank concentration is directly proportional with dosage and is similar to former test.
Table 1
Contrast in the selectivity test between compound
The test of anti-allergen
Correction data: the test of anti-allergen
| ??Ariflo ??15mg?bd | ??Singulaire | ????Ultair | ICS 800mcg budesonide | ????B2 | |
| The maximum decline LAR (therapeutic action) of % | ????1.3 | ????12.3 | ????10.7 | ????22.9 | ????+6.9 |
| The maximum decline LAR of % protection | Do not have | ????36.4 | ????30.8 | ????32 | Do not descend |
| The AUC of %LAR (therapeutic action) | ????3.5 | ????63.5 | ????42.4 | Do not do | |
| The AUC LAR of % protection | Do not have | ????56.9 | ????42.6 | Do not do |
The data of marginal data: cilomalast are that the protocal analysis from the asthmatic patient of the ICS of＜652mcg obtains.Montelukast (MT), budesonide (BDP) and the data of the two are to obtain from can measure the single test of Singulair with respect to the SingulairSBA of the effect that sucks corticosteroid.
There were significant differences in behavior in two kinds of tests between placebo (Pbo) group.Although conclusion is the fact that the Pbo group also has improvement in the cilomalast test, cilomalast is better than Singulair when joining the ICS of low dosage.
Above description and embodiment are of the present invention in order to illustrate, rather than it is limited.The content that the inventor protected is with reference to the claims below this paper.
Claims (2)
1. method for the treatment of tuberculosis comprises to the patient of this treatment of needs the PDE4 inhibitor of effective dose and anti-inflammatory cortex cholesterol with combining form, divided mode, or separately and the conitnuous forms administration, wherein the time of successive administration is changeable.
2. the method for claim 1, wherein the PDE4 inhibitor is cis 4-cyano group-4 (3-cyclopentyloxy-4-anisyl) cyclohexane-1-carboxylic acid, and steroid is selected from dexamethasone, Fluticasone, Beclomethasone, budesonide, 9-and removes fluorine fluocinolone acetonide, Mometasone Furoate and adcortyl A.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16315899P | 1999-11-02 | 1999-11-02 | |
| US60/163,158 | 1999-11-02 |
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| CN1387404A true CN1387404A (en) | 2002-12-25 |
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| CN00815265A Pending CN1387404A (en) | 1999-11-02 | 2000-11-01 | Method and compositions for treating pulmonary diseases |
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| JP (1) | JP2003513028A (en) |
| KR (1) | KR20020057988A (en) |
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| BG (1) | BG106748A (en) |
| BR (1) | BR0015270A (en) |
| CA (1) | CA2388333A1 (en) |
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| WO2003024489A2 (en) | 2001-09-19 | 2003-03-27 | Altana Pharma Ag | Combination of a nsaid and a pde-4 inhibitor |
| US20040259863A1 (en) * | 2001-10-31 | 2004-12-23 | Hans-Michael Eggenweiler | Type 4 phosphodiesterase inhibitors and uses thereof |
| UA82323C2 (en) * | 2002-08-09 | 2008-04-10 | Меда Фарма Гмбх & Ко. Кг | Novel combination of a glucocorticoid and pde-inhibitor for the treatment of respiratory diseases, allergic diseases, asthma and chronic obstructive pulmonary diseases |
| TW200410923A (en) * | 2002-10-17 | 2004-07-01 | Ono Pharmaceutical Co | Therapeutic agent for chronic obstructive pulmonary disease |
| EP1616569A1 (en) * | 2003-03-31 | 2006-01-18 | Kyowa Hakko Kogyo Co., Ltd. | Medicinal composition |
| US20050026883A1 (en) * | 2003-07-31 | 2005-02-03 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease |
| US20070287689A1 (en) * | 2004-10-13 | 2007-12-13 | Kyowa Hakko Kogyo Co., Ltd. | Therapeutic And/Or Preventive Agents For Chronic Skin Diseases |
| EP1948167A1 (en) * | 2005-10-19 | 2008-07-30 | Ranbaxy Laboratories, Ltd. | Compositions of phosphodiesterase type iv inhibitors |
| JP6017961B2 (en) | 2010-01-05 | 2016-11-02 | マイクロドース セラピューテクス，インコーポレイテッド | Inhalation device and method |
| WO2015063669A1 (en) | 2013-10-30 | 2015-05-07 | Wockhardt Limited | Pharmaceutical compositions comprising combination of roflumilast and acebrophylline or pharmaceutically acceptable salts thereof |
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| AU7174794A (en) * | 1993-06-18 | 1995-01-17 | Smithkline Beecham Corporation | Compounds |
| DE4332041C2 (en) * | 1993-09-21 | 1997-12-11 | Rentschler Arzneimittel | Use of pentoxifylline in certain lung diseases |
| PE44995A1 (en) * | 1994-01-27 | 1995-12-18 | Schering Corp | MOMETASONE FUROATE FOR THE TREATMENT OF LUNG DISEASES AND RESPIRATORY TRACT |
| SE9801368D0 (en) * | 1998-04-20 | 1998-04-20 | Astra Ab | New use |
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| PL355261A1 (en) | 2004-04-05 |
| NO20022057L (en) | 2002-06-27 |
| TR200201211T2 (en) | 2002-08-21 |
| NO20022057D0 (en) | 2002-04-30 |
| AP2002002496A0 (en) | 2002-06-30 |
| EP1225866A2 (en) | 2002-07-31 |
| HUP0203152A2 (en) | 2003-01-28 |
| BG106748A (en) | 2003-02-28 |
| EA200200518A1 (en) | 2002-10-31 |
| BR0015270A (en) | 2002-06-18 |
| CA2388333A1 (en) | 2001-05-10 |
| ECSP003747A (en) | 2002-05-23 |
| TWI242431B (en) | 2005-11-01 |
| IL149367A0 (en) | 2002-11-10 |
| MXPA02004350A (en) | 2002-11-07 |
| AR029189A1 (en) | 2003-06-18 |
| JP2003513028A (en) | 2003-04-08 |
| CZ20021512A3 (en) | 2003-04-16 |
| DZ3225A1 (en) | 2001-05-10 |
| SK7592002A3 (en) | 2002-11-06 |
| HK1049107A1 (en) | 2003-05-02 |
| WO2001032127A3 (en) | 2001-12-06 |
| PE20011005A1 (en) | 2001-09-28 |
| EP1225866A4 (en) | 2004-04-21 |
| AU1357501A (en) | 2001-05-14 |
| CO5261512A1 (en) | 2003-03-31 |
| KR20020057988A (en) | 2002-07-12 |
| WO2001032127A2 (en) | 2001-05-10 |
| OA12076A (en) | 2006-05-04 |
| HUP0203152A3 (en) | 2004-06-28 |
| ZA200203435B (en) | 2003-06-25 |
| MA26841A1 (en) | 2004-12-20 |
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