Novel methods

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: the use of aclidinium for preparing a medicine for treating or preventing a respiratory disease or condition in a patient by inhalation, wherein said patients showed no systemic antimuscarinic actions, where the patient suffers a condition or is susceptible thereto, which may be exacerbated by systemic antimuscarinic activity (versions), and a related method of treating or preventing.

EFFECT: invention provides local therapeutic action of aclidinium in lungs and has no significant systemic antimuscarinic action as it quickly hydrolysed in blood plasma, and its main metabolites are completely deprived of affinity to muscarinic receptors.

13 cl, 3 ex

 

The scope of the invention

The present invention offers new ways anticholinergic treatment, especially the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), do not cause side effects typical of the class of compounds antimuskarinovoe act occurs.

The background to the present invention

Acridine (3(R)-(2-hydroxy-2,2-dition-2-RECETOX)-1-(3-phenoxypropan)-1-azoniabicyclo[2.2.2]octane) is an effective antagonist of muscarinic receptors and are described, for example, in applications WO 01/04118, WO 05/115467, WO 05/115466, WO 05/115462, the contents of which are incorporated in this description by reference. Acridine is a bronchodilator means prolonged action intended for inhalation in the treatment of respiratory diseases, especially asthma and COPD, the specified drug is currently undergoing clinical trials.

Antagonists of muscarinic receptors, which are available as commercial preparations include Tiotropium ((1α,2β,4β,7β)-7-[(2-hydroxy-2,2-dithienylethene]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3,3,1,02,4]nonan), ipratropium ([8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3,2,1]Oct-3-yl]-3-hydroxy-2-phenylpropanoate) and glycopyrrolate ((1,1-dimethyl-2,3,4,5-tetrahydropyrrolo-3-yl)-2-cyclopentyl-2-hydroxy-2-Hairdryer shall acetat).

Acetylcholine is a neurotransmitter that is associated with the parasympathetic innervation in the body, as well as with the transmission of impulses in the brain. Acetylcholine is involved in the control of the functioning of the heart, blood vessels, respiratory tract, urinary and digestive tracts. He also takes part in the processes of memory, learning and concentration. Antimuskarinovoe act occurs compounds inhibit the action of acetylcholine on muscarinic receptors, which are known, are the most common type of cholinergic receptors in the body. Compounds that inhibit the activity of acetylcholine at muscarinic M3 receptors in the respiratory tract, can be used for the treatment of respiratory diseases, as they inhibit mediated askarinam reduction of smooth muscles of the respiratory tract, which leads to bronchodilatation, and also reduces the secretion of mucus in the lungs.

However, one of the problems of applying antimuskarinovoe act occurs compounds in the treatment of respiratory diseases is the risk of side effects associated with systemic suppression of cholinergic activity. These side effects may include, for example, dry mouth, irritated throat, impaired sweating, increased pupil size, deterioration of visual acuity, increased CH is the heat pressure, increased heart rate, chest pain, decreased peristalsis of the stomach, constipation, difficulty initiating and continuing urination, loss of bladder control due to incontinence overflow. Anticholinergic activity may also affect the Central nervous system, such as impaired concentration, confusion, restlessness, anxiety, delirium, impaired attention, impaired memory, dizziness, drowsiness, respiratory depression. It was found that cholinesterase inhibitors, which inhibit the breakdown of acetylcholine, have a beneficial effect in the treatment of Alzheimer's disease and dementia, and thus the doctor possibly prefer not to use anticholinergics in the treatment of such patients. Acetylcholine plays a complex role in the development of Parkinson's disease patients. It is assumed that acetylcholine plays a role in accelerating the release of dopamine in action on muscarinic receptor M4 and M5 in the brain tissue, and in this regard, the cholinesterase inhibitors are sometimes prescribed to patients with a diagnosis of Parkinson's disease, first of all, before the advent of levodopa, anticholinergics used to treat symptoms of Parkinson's disease, which are apparently due under the effect of dopamine inhibitory activity of muscarinic M1 receptors.

The elderly to a greater extent feel unwanted antiholinergicescoe action because in their body there is reduced production of acetylcholine. Cells in many parts of the body (such as the digestive tract) in patients older can contain a reduced number of acetylcholine receptors. Thus, the effect produced by acetylcholine is reduced, and the effect of anticholinergics, respectively is increased. Moreover, in patients older reduced function of the kidneys and/or liver and also observed a tendency to increase in the concentration of many anticholinergics in serum. As indicated below, a number of standard medicines has anticholinergic activity, and, thus, patients who administered various drugs, manifesting anticholinergic side effects, are at increased risk. Older people are at greatest risk of side effects because of the difficulty of urination associated with anticholinergic activity may cause exacerbation due to an enlarged prostate gland or its obstruction. In General, anticholinergic side effects are most common associated with medicines from izuchennyh effects, experiencing the elderly.

Modern commercial antimuskarinovoe act occurs means can be considered unsuitable for administration to patients sensitive to conditions that can be exacerbated by systemic anticholinergic action. The levels of systemic anticholinergic activity, which is easy to carry young healthy people, are unacceptable for such patients. Conditions that can be exacerbated by systemic anticholinergic action, include schizophrenia, glaucoma, dry eye, enlarged prostate gland or its obstruction, narrowing or obstruction of the small intestine, increase colon, chronic constipation, enlargement of the lower esophagus, heart disease (primarily of the state, which are aggravated by tachycardia, such as restenosis or plaques in the coronary arteries, the predisposition to arrhythmia, damage caused by previous heart attacks and congestive heart failure), Parkinson's disease, Alzheimer's disease, dementia and severe psevdomatematicheskoe male. Antimuskarinovoe act occurs agents also pose a risk if they are administered in conjunction with drugs that exhibit anticholinergic action, such as atypical neuroleptics or tricyclic antidepressants. Antihistamines, is first of all the first generation, sedative antihistamines such as diphenylhydramine can contact muscarinic receptors and in addition to histamine receptor type I, and thus can exhibit anticholinergic action. In extreme cases, anticholinergic agents can induce anticholinergic delirium, i.e. a condition representing a danger to life and which is characterized by the following symptoms: fever, dry skin, dry mucous membranes, dilated pupils, lack of intestinal noises and tachycardia. Finally, the system active agents antimuskarinovoe act occurs can affect the action of other medications that are designed to enhance the action of acetylcholine, such as cholinesterase inhibitors and cholinergic agonists.

Accordingly, there is a need to develop ways antimuskarinovoe act occurs treatment, especially respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD), and when indicated, patients should not be subjected to adverse action, characteristic of the class system active compounds antimuskarinovoe act occurs.

Summary of the invention

Unexpectedly, it was found that acridine can be used in the treatment of respiratory diseases, without exposing patients to the risk of developing the adverse action, typical active system connections antimuskarinovoe act occurs. Although acridine contains ester residue, similar, for example, Tiotropium (2-hydroxy-2,2-dition-2-RECETOX), it has been unexpectedly found that acridine with the introduction of inhalation is degraded in the plasma to a greater extent with the formation of its inactive acid or alcohol metabolites. Therefore, the connection it has little systemic effect. Due to the rapid metabolism of acridine significantly reduces the likelihood of undesirable systemic anticholinergic action. Acridine, however, is characterized by a significant duration of action on the receptor and can provide long-lasting beneficial effects in antimuskarinovoe act occurs the treatment of lung and respiratory tract.

Accordingly, in the first embodiment, the present invention proposes the use of acridine for obtaining a medicinal product intended for the treatment or prophylaxis of respiratory diseases and conditions in patients by inhalation, with the specified patient there is no systemic action antimuskarinovoe act occurs.

Usually respiratory disease means a disease that is treatable, reduced the intensity of its symptoms, or such zabolevania.patienta at the effect of the antagonist of muscarinic receptors. It is more preferable that the respiratory disease or condition selected from acute or chronic bronchitis, emphysema, especially asthma and COPD, most preferably asthma and COPD.

In a typical case, the patient suffers from States (or sensitive to them), which can be exacerbated by the activity system activity antimuskarinovoe act occurs. More preferably, the patient suffers from one or more States (or sensitive to them), selected from the following States:

a) schizophrenia, impaired concentration, confusion, anxiety, delirium, impaired attention, memory impairment, respiratory depression,

b) glaucoma, dry eyes, increased the size of the pupil, blurred vision, increased eye pressure

c) an enlarged prostate or obstruction, difficulty urinating, urinary bladder overflow,

d) a narrowing or obstruction of the small intestine, enlarged colon, chronic constipation, enlargement of the lower esophagus, reduced peristalsis of the stomach, constipation,

e) dry mouth, irritated throat, impaired sweating,

f) cardiovascular disease (including any restenosis, arteriosclerosis, previous stroke or heart attack, congestive heart failure), arrhythmia, taxicard is I,

g) Parkinson's disease, Alzheimer's disease, dementia and/or

h) heavy pseudoparticle myasthenia gravis.

Usually patients are men. In addition, the age of the patients is usually more than sixty years.

In another embodiment, the drug is intended for administration to patients who drive a car or work with machinery during the course of treatment.

In yet another variant, patients receive a second drug, which is a system of active anticholinergic agent or agent that can cause or exacerbate the condition listed above. Usually the second drug is selected from neuroleptics, tricyclic antidepressants, and antihistamines.

In another embodiment, the patient is administered a drug that is intended to enhance acetylcholine function, for example, a cholinesterase inhibitor or a cholinergic agonist, for example, the agents listed below.

Usually, acridine presented in the form of a salt of the anion X, where X means a pharmaceutically acceptable anion of one or polonovski acid. More preferably, X denotes the anion of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid, or organic acids, such as methanesulfonanilide, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid and maleic acid. Preferably aclidinium presented in the form of the bromide acridine.

Usually acridine is a dry powder suitable for inhalation.

Typically the medicinal product contains a pharmaceutically acceptable carrier selected from mono-, di - or polysaccharides and alditol. A preferred carrier is lactose.

Typically, the system antimuskarinovoe act occurs the action that should be deleted, choose from a dry mouth, irritated throat, disorders of sweating, increased pupil size, deterioration of visual acuity, increased intraocular pressure, increased heart rate, chest pain, difficulty urinating, prostate enlargement or obstruction, decreased peristalsis of the stomach, constipation, difficulty in concentration, confusion, excited state, delirium, lack of attention, memory impairment and respiratory depression.

Usually the patient for the treatment of respiratory disease or condition is administered one or more additional drugs. More preferably additional drug for the treatment of respiratory disease or condition is chosen from beta-adrenal the practical agonists, corticosteroids or steroids, inhibitors of PDE IV, antihistamines, antibodies, anti-IgE, inhibitors of leukotriene D4, inhibitors of EGFR kinase, kinase inhibitors R and/or antagonists of NK1 receptors, for example, selected from the compounds listed below. Preferably the additional drug is selected from a corticosteroid and/or beta-adrenergic agonists.

In addition, the invention further features of acridine, as described above, or drug, as described above, for inhalation in the treatment or prophylaxis of respiratory diseases or conditions, as indicated above, patients, as indicated above, however, these patients do not develop systemic action antimuskarinovoe act occurs, as described above.

The invention also proposes a method of treatment or prevention of inhalation of respiratory diseases or conditions, as described above, in a patient in need of such treatment, as described above, with the specified patient does not develop systemic action antimuskarinovoe act occurs, as described above, and this method is the introduction to a specified patient an effective amount of acridine, as described above.

Detailed description of the invention

Drugs, which can manifest anticholinergic action, or to increase sensitivity is alnost patients to anticholinergic action, include, for example,

a) medicines for nausea or dizziness, especially anticholinergic agents, for example, promethazine (phenergan), prochlorperazine (compazine), trimethobenzamide (tigan), meclizine (antivert), cyclizine (Martin), scopolamin,

b) drugs for treatment of Parkinson's disease, primarily anticholinergic agents, such as benztropine, biperiden, procyclidine, trihexyphenidyl, ethopropazine,

c) antidepressants, especially tricyclic compounds, such as amitriptyline (elavil), doxepin (sinequan), imipramine (Tofranil), trimipramine (surmontil), nortriptyline (pamelor) protriptyline (vivactil), amoxapine (Asendin), maprotiline (ludiomil), clomipramine (anafranil), desipramine (Norpramin),

d) antigistaminny agents, primarily sedative first generation antihistamines, such as diphenhydramine (Benadryl), chlorpheniramine (chlor-trimeton), hydroxyzine (atarax/vistaril), cyproheptadine at (periactin),

e) muscle relaxants, for example, metaxalon (skelaxin), cyclobenzaprine (flexeril), orphenadrine (norflex),

f) caused some medicines, such as belladonna alkaloids,

g) some antidiarrheal drugs such as Diphenoxylate/atropine (lomotil),

h) antispasmodics for urinary tract and gastrointestinal symptoms such the th path, for example, oxybutynin (ditropan), flavoxate (urispas), dicyclomine (bentyl), giostsiamin, belladonna alkaloids, tolterodine (detrol), tropi, kilindini, propantheline, pirenzepine, telenzepine,

i) antiarrhythmic drugs such as disopyramide (norpac), procainamide (pronestyl), quinidine, atropine,

j) antipsychotics, such as chlorpromazine (Chorazin), thioridazine (mellaril), clozapine (clozaril), fluphenazine (stelazine), thiothixene (Navan).

Drugs that increase cholinergic activity include

a) reversible cholinesterase inhibitors, for example, Adriani, taken, donepezil, physostigmine, pyridostigmine, rivastigmine, galantamine, neostigmine,

b) cholinergic agonists, for example, metafolin, bethanechol, pilocarpine.

Beta-adrenergic agonists that can be combined with aclidinium of the present invention, preferably include β2-adrenergic agonists suitable for the treatment of respiratory diseases or conditions, for example, selected from the group comprising arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, geksoprenalin, ibuterol, izoprenalin, mabuterol, meleagrin, nyamira, ortsiprenalin, pirbuterol, procaterol, reproterol, ritodrin, rimiterol, salbutamol, salmeterol, sibenadet, su is hantera, terbutaline, tulobuterol, GSK-597901, GSK-159797, KUL-1248, TA-2005 and QAB-1491 in free form or in the form of pharmaceutically acceptable salts. Preferred β2-adrenergic agonist is a β2-adrenergic agonist with a prolonged action, for example, selected from the group comprising formoterol, salmeterola and QAB-149 in free form or in the form of pharmaceutically acceptable salts.

Corticosteroids, which can be combined with aclidinium of the present invention, preferably include agents suitable for administration by inhalation, intended for the treatment of respiratory diseases and conditions, such as prednisolone, methylprednisolone, dexamethasone, Napocor, deflazacort, acetate of halopedia, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, acetonide fluoqinolona, fluocinonide, pialat of clocortolone, aceponate methylprednisolone, palmitat dexamethasone, tipredane, aceponate hydrocortisone, prednicarbate, dipropionate of alometasone, halometasone, sulatan methylprednisolone, mometasone furoate, rimexolone, frenzied prednisolone ciclesonide, propionate of depradine, fluticasone propionate, propionate halobetasol, etabonate loteprednol, propionate-butyrate betamethasone, flunisolide, prednisone, sodium phosphate, dexamethasone, triamcinolone, 17-valerate betamethasone betamethasone, dipr is peanut betamethasone the hydrocortisone acetate, sodium succinate hydrocortisone, sodium phosphate prednisolone and probuct hydrocortisone. Above all, preferred budesonide and mometazon.

Inhibitors PDE, which can be combined with aclidinium of the present invention, include denbufylline, rolipram, cipamfylline, arofylline, filaminast, piclamilast, mesopram, drotaverine hydrochloride, lyrikill, roflumilast, cilomilast, 6-[2-(3,4-dioxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine, N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-terbisil)-5-hydroxy-1H-indol-3-yl]-2-oxoacetate, 9-(2-terbisil)-N6-methyl-2-(trifluoromethyl)adenine, N-(3,5-dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide, N-[9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-yl][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide, hydrochloride 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purine, 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalene-1-yl]-1-(2-methoxyethyl)pyridine-2(1H)-he 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-deformational)cyclohexane-1-he, CIS-[4-cyano-4-(3-cyclopropylmethoxy-4-deformational)cyclohexane-1-ol, ONO-6126 (Eur Respir J, 22 (Suppl. 45): Abst 2557 (2003)) and compounds described in PCT applications WO 03/097613 and PCT/EP 03/14722 and in Spanish patent application P 200302613.

LTD4 antagonists that can be combined with aclidinium the present invention, include timelocal, ibudilast, pobilukast, hydrate pranlukast, zafirlukast, retrocast, verlukast, soloist, sinologist, iralukast sodium, montelukast sodium, 4-[4-[3-(4-acetyl-3-hydroxy-2-propylenoxide)propylsulfonyl]phenyl]-4-oxomethane acid, [[5-[[3-(4-acetyl-3-hydroxy-2-propylenoxide)propyl]thio]-1,3,4-thiadiazole-2-yl]thio]acetic acid, 9-[(4-acetyl-3-hydroxy-2-n-propylenoxide)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidine-4-one, sodium salt of 5-[3-[2-(7-chlorhydrin-2-yl)vinyl]phenyl]-8-(N,N-dimethylcarbamoyl)-4,6-diciottenni acid, sodium salt 3-[1-[3-[2-(7-chlorhydrin-2-yl)vinyl]phenyl]-1-[3-(dimethylamino)-3-oxopropylidene]methylsulfanyl]propionic acid, 6-(2-cyclohexylethyl)[1,3,4]thiadiazolo[3,2-a]-1,2,3-triazole[4,5-d]pyrimidine-9(1H)-he, 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenyl)propoxy]-2-propylenoxide]butyric acid, (R)-3-methoxy-4-[1-methyl-5-[N-(2-methyl-4,4,4-trifloromethyl)carbarnoyl]indole-3-ylmethyl]-N-(2-methylphenylsulfonyl)benzamide, (R)-3-[2-methoxy-4-[N-(2-methylphenylsulfonyl)carbarnoyl]benzyl]-1-methyl-N-(4,4,4-Cryptor-2-methylbutyl)indole-5-carboxamide, (+)-4(S)-(4-carboxyphenyl)-7-[4-(4-phenoxyethoxy)phenyl]-5(Z)-heptanone acid and the compounds described in the application PCT/EP 03/12581.

The term "treatment" means the treatment and/or reduction in intensity of symptoms of the disease or condition, as well as addressing the causes of the disease or condition is of. The term "prevention" of a disease means the prevention and/or suppression of the disease.

Acridine designed for use in the method of the invention, it is possible to enter any suitable way to ensure local actions antimuskarinovoe act occurs. The preferred method includes inhalation, for example, in the form of a powder, spray or aerosol, preferably in the form of a dry powder. Pharmaceutical compositions containing acridine, obtained using standard solvent or excipient by known methods. For example, the dry powder composition may contain a powder mix for inhalation, comprising aclidinium and a suitable powder base (carrier), such as lactose and starch. The application preferably lactose. Suitable devices for inhalation is known in the art. Doses depend, for example, from an individual, the method and frequency of administration, nature and severity of the condition to be treated. The daily dose for an adult weighing 40 kg is usually changed, for example, in the range from approximately 100 to 1000 mg of active agent in the form of a dry powder for inhalation.

Example 1

Stability clonidine in vitro compared with Tiotropium and ipratropium and glycopyrrolate in plasma

In vitro experiments were carried out at 36°C and a concentration of 5 μg/ml (6 MK the solution of each compound in dimethyl sulfoxide (concentration 1 mg/ml) was added to a final volume of 1.2 ml). After pre-incubation for 3 min the reaction was initiated by adding the investigated compounds. After 0, 5, 15, 30 and 60 min were collected plasma samples of 100 μl, and the reaction was stopped by adding 1 ml of 20 mm sodium acetate buffer solution, pH of 4.0. In the control samples instead of the investigated compounds were added to the buffer solution. The human plasma was obtained from volunteers who had signed informed consent to testing. The blood was collected in tubes containing lithium salt of heparin as anticoagulant, immediately centrifuged at 4°C and stored the resulting plasma at -20°C until its use.

Contents acridine, Tiotropium, ipratropium and glycopyrrolate in plasma (100 ál) were determined by liquid chromatography high resolution (IHVR) using UV detector at a wavelength of 238 nm for acridine and Tiotropium and 203 nm for ipratropium, plasma samples were applied on the column after processing in an automatic system for solid-phase extraction using an autosampler. Suitable chromatographic system includes a high pressure pump (Kontron model 322 for acridine and Tiotropium and Waters model 515 for ipratropium), the system Prospekt (Spark Holland)equipped with an injector for sampling 233XL (Gilson Medical Electronics), adjustable detector wavelength (model 2487, Waters Ass.) and to the pewter Digital Alpha Server 1000 4/266 software access*Chrom (Perkin Elmer Nelson Systems, Inc.). Contents acridine and Tiotropium were determined on a column of Spherisorb ODS2, 5 μm, 150×4.6 mm (Waters Ass.), connected with precolonial Guardapack ábondapak CN (Waters Ass.), the mobile phase acetonitrile (50:50 vol.% for acridine and 22:78% for Tiotropium): 20 mm Na-phosphate buffer solution, pH 3.0, containing 0.2% triethylamine, flow rate 1 ml/min Approximate retention time of acridine and Tiotropium is 9.8 and 9.5 min, respectively. The content of ipratropium was determined on column Symmetry C18, 5 μm, 150×4.6 mm (Waters Ass.), the mobile phase acetonitrile (12:88 vol.%): 20 mm Na-phosphate buffer solution, pH 3.0, containing 0.2% triethylamine, flow rate 1 ml/min Approximate retention time Tiotropium is 9.5 minutes of Acridine, Tiotropium and ipatory were extracted from plasma cartridges C2 (Baker), which are activated by 1.5 ml of acetonitrile and washed with 1.5 ml of water. Plasma samples pre-dilute 1 ml of 20 mm Na-phosphate buffer solution, pH of 4.0, was applied to the cartridge C2. After washing the cartridge with 1 ml water and 1 ml of a mixture acetonitrile/water (40:60 vol.%) for acridine or 3 ml of water for Tiotropium, or 1 ml water and 1 ml of a mixture acetonitrile/water (90:10 vol.%) for ipratropium, the remaining components were suirable mobile phase for 1 min In the chromatograms were observed endogenous peaks with retention times corresponding to the analyzed compounds, i.e. to analyze the samples were absent impurities, which affect the accuracy of quantitative determination. Output acridine from human plasma was approximately 95%. The output of Tiotropium and ipratropium from plasma ranged from 80 to 100%. The stability of glycopyrrolate in plasma was determined as described above for the other three drugs. The lower limit of sensitivity of the assay was 5 ng/ml for all the investigated compounds.

Acridine rapidly hydrolyzed in human plasma with the formation of its alcohol and acid metabolites. For both metabolites acridine was determined by binding to muscarinic receptors in human M1, M2, M3 and M4, the obtained results show no significant affinity for these receptors. The half-life of acridine in plasma is less than 5 minutes moreover, acridine stable in acidic aqueous solution (pH≤4), and the hydrolysis of ester bonds occurs at neutral or alkaline pH values.

In contrast, the other three antimuskarinovoe act occurs of ester sufficiently resistant to degradation under the action of esterases in the plasma. Degradation in plasma Tiotropium (16%), ipratropium (0%) and glycopyrrolate (9%) not important from the biological point of view during the time of the study (60 min).

Example 2

Clinical trials phase I

Bromide acridine experienced double blind is m, partly cross, placebo-controlled method. When testing determined the activity, pharmacokinetic parameters and tolerability of acridine.

Methods

12 healthy men randomized in groups of different treatment courses (4 courses), including a single dose of acridine (50, 300, and 600 mg) or placebo, which were introduced in the form of a dry powder inhalation. Time to wash between injections was at least 6 days. The final performance parameters included specific bronchial conductance (sGaw), respiratory resistance (Raw) and bronchial hypersensitivity (sGAW, metafolin RS).

Results

Aclidinium significantly increases the magnitude of the sGaw in all periods of time (1-24 h, p<0,001 compared with placebo). Accordingly, the Raw value is significantly reduced with the introduction of acridine at all time points except for 1 h and 24 h (p<0,001 compared with placebo): With the introduction of acridine at a dose of 300 and 600 mcg also significantly reduces the value of sGaw (metafolin RS) at all time periods after administration (p<0,001 compared with placebo): dose methacholine necessary to decrease the amount of sGaw 235% after 24 h, was 142,7 and 181,7 compared with the dose 27,1 mg/ml (for acridine in the dose of 300 and 600 mcg compared to placebo, respectively) and after 24 h 207,1 and 256,0 compared to 35.5 mg/ml, respectively. In x is de test plasma is not detected acridine or its metabolites, and was not observed related to the study drug negative side effects.

Conclusions

With the introduction of acridine there is a significant and long-lasting protection against methacholine induced bronchostenosis in healthy male volunteers, it was found that acridine you can enter once a day, and its content in the plasma was not found.

Example 3

Clinical trials, phase II

The tests were carried out double-blind, randomized, partially cross-method control placebo, evaluated the activity, pharmacokinetic parameters, the portability of acridine and its impact on patients diagnosed with COPD.

Methods

Men with a diagnosis of COPD (predicted forced expiratory volume in 1 s (FEV1)<65%), which reversed the respiratory tract after administration of ipratropium, randomized in groups with different treatments (4 courses), including a single dose of acridine (100, 300 and 900 mg) and placebo, which was introduced in the form of a dry powder inhalation, the period of washing between doses was 1 week. Lung function was determined by the following parameters: predicted forced expiratory volume in 1 s (FEV1) and the fixed vital capacity (FVC).

Results

The test was attended by 17 m is gcin (mean age 63.5 years, the average FEV1was 1,63 l). With the introduction of acridine (100, 300 and 900 μg) significantly increased the mean value of FVC AUC(0-24)/24 compared with placebo (1,800 l (p=0.002), 1,798 l (p<0,0001) and 1,827 l (p<0,0001) compared with 1,597 l for placebo, respectively). The increase in FVC values statistically significantly within 24 h at all doses acridine. With the introduction of acridine at doses of 300 and 900 µg observed higher maximum effect FEV1that appears much earlier than the introduction of a dose of 100 µg. With the introduction of 300 and 900 μg of acridine observed a similar effect on the value of FVC. During the tests after the introduction of the 900 mcg acridine plasma is not detected neither acridine nor its alcohol metabolite found a negligible content of its acid metabolite. Acridine characterized by high portability: there were only 6 cases of minor or moderate headache (compared with 2 cases with the introduction of placebo) and 1 case of a slight increase in sweating, possibly connected with the course of treatment.

Conclusions

With the introduction of single doses acridine (100, 300 and 900 mcg) is a rapid and long-lasting bronchodilatory effect in patients with COPD, with his plasma level is not defined.

1. Application acridine to obtain Lakers the governmental funds, intended for the treatment or prevention of a respiratory disease or condition in a patient by inhalation, these patients are not observed systemic actions antimuskarinovoe act occurs where the patient suffers from a condition or sensitive to it, which can be exacerbated by the activity system activity antimuskarinovoe act occurs.

2. The use according to claim 1, where the respiratory disease or condition selected from acute or chronic bronchitis, emphysema, asthma and chronic obstructive lung diseases, especially asthma and chronic obstructive pulmonary disease.

3. The use according to any one of the preceding paragraphs, where a patient suffering from, or susceptible to one or more conditions selected from the following States:
1) schizophrenia, impaired concentration, confusion, restlessness, delirium, impaired attention, memory impairment, respiratory depression,
2) glaucoma, dry eye, increased the size of the pupil, blurred vision, increased eye pressure,
3) due to an enlarged prostate or obstruction, difficulty urinating,
4) narrowing or obstruction of the small intestine, increase colon, chronic constipation, enlargement of the lower esophagus, reduced peristalsis of the stomach, constipation,
6) cardiovascular disease (including any restenosis, arteriosclerosis, previous stroke or heart attack, congestive heart failure), arrhythmia, tachycardia,
7) Parkinson's disease, Alzheimer's disease, dementia and/or
8) heavy psevdomatematicheskoe myasthenia gravis.

4. The use according to any one of the preceding paragraphs, where
the patient is male; and/or
the patient's age is more than sixty years; and/or
the patient drives a car or work with machinery during the course of treatment; and/or
the patient is given a second drug, which is a system of active anticholinergic agent that can cause any condition according to claim 3 or exacerbate these conditions, where the second drug selected from the atypical neuroleptics, tricyclic antidepressants, and antihistamines.

5. The use according to claim 4, where the patient is given a drug that may enhance the function of acetylcholine.

6. The use according to any one of the preceding paragraphs, where acridine presented in the form of the bromide acridine.

7. The use according to any one of the preceding paragraphs, where acridine presented in the form of a dry powder suitable for inhalation.

8. The use according to any one of predictious the point where the patient is administered one or more additional drugs for the treatment of respiratory disease or condition.

9. The use of claim 8, where the additional drug for the treatment of respiratory disease or condition selected from beta-adrenergic agonists, corticosteroids, or steroids, inhibitors of PDE IV, antihistamines, antibodies against IgE, inhibitors of leukotriene D4, inhibitors of EGFR kinase, kinase inhibitors R and/or antagonists of the NK1 receptor.

10. The use according to claim 9, where the additional drug is selected from corticosteroids and beta-adrenergic agonists.

11. The use of pharmaceutical compositions for obtaining a medicinal product intended for the treatment or prevention through inhalation of respiratory disease or condition according to any one of claims 1 or 2 in a patient according to any one of claims 1, 3-5 and 8-10, and the said pharmaceutical composition comprises a pharmaceutically acceptable carrier and, as active agent, acridine according to any one of claims 1, 6 and 7.

12. The application of claim 11, where the pharmaceutically acceptable carrier is a carrier selected from mono-, di-, and polysaccharides and alditol, preferably lactose.

13. The method of treatment or prevention through inhalation of respiratory disease or condition on any the mu one of claims 1 or 2 in a patient according to any one of claims 1, 3-5 and 8-10, and this method is the introduction of acridine according to any one of claims 1, 6 and 7.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel isoquinolinone derivatives of formula (I) , wherein R1 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (CH2)a-X-Ar and (CR101R102)a-X-Ar, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkoxy, -halogen, -OH, -heterocycloalkyl, (C3-C7)cycloalkyl and -NR8R9; R2 is selected from H and (C1-C6)alkyl; R is selected from H, (C1-C6)alkyl and (CH2)d-Y; provided that when R3 is (CH2)d-Y, R2 is selected from H; R4 and R5 are independently selected from H, (C1-C6)alkyl and halogen; R is (C3-C7)cycloalkyl; R7 is H; Ar is phenyl or heteroaryl, optionally substituted with 1, 2 or 3 groups independently selected from -(C1-C6)alkyl, -(CH2)e-O-(C1-C6)alkyl, -(CH2)e-S(O)f(C1-C6)alkyl, -(CH2)e-N(R10)-(C1-C6)alkyl, -(CH2)e-Z-(C1-C6)alkyl, -halogen, heterocycloalkyl, -C(O)NR8R9, -NR8R9 and -C(O)OH, where (C1-C6)alkyl in each case is independently optionally substituted with 1, 2 or 3 groups, independently selected from -NRI2R13; X is selected from a single bond; Y is NR16R17, where R16 and R17 together with a nitrogen atom with which they are bonded form a 5-7-member ring, optionally containing an additional heteroatom NR27, where said ring is optionally substituted on the carbon atom with 1 or 2 substitutes independently selected from -(C1-C6)alkyl, where said -(C1-C6)alkyl is optionally substituted with -OH; and where R27 is selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -OH; Z is selected from C(O)N(R18); R8 and R9 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups, independently selected from NR19R20; or R8 and R9 together with the nitrogen atom with which they are bonded form a 5-6-member ring, optionally containing an additional heteroatom, selected from NR21; R12 and R13 are independently selected from H and (C1-C6)alkyl, where said (C1-C6)alkyl is optionally substituted with -(C1-C6)alkoxy, -OH; or R12 and R13 together with the nitrogen atom with which they are bonded form a 5-6-member ring optionally containing an additional heteroatom selected from NR24; R10, R18, R19, R20, R21, R22, R23 and R24 are independently selected from H and (C1-C6)alkyl; a is selected from 1, 2, 3, 4, 5 and 6; d equals 0 or 1; e equals 0; f is independently selected from 1 and 2; where the heterocycloalkyl is a 5-6-member non-aromatic cyclic ring bonded at a C atom, having 1-2 NR28 atoms; optionally having one double bond; the heteroaryl is a 6-member aromatic ring containing 1 N atom; R is selected from H, (C1-C6)alkyl and -C(O)O-(C1-C6)alkyl; R101 is (C1-C6)alkyl; R102 is H; or pharmaceutically acceptable salts thereof or N-oxides. The invention also relates to methods of producing said compounds and use thereof as a p38 kinase inhibitor.

EFFECT: improved method.

13 cl, 4 dwg, 1 tbl, 128 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: composition, which contains β2-agonist, except formoterol and salmoterol, and antagonist of muscarinic receptors M3, which represents 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxy-propyl)-1-azoniumbicyclo[2.2.2]octane in form of salt with anion X, which represents pharmaceutically acceptable anion of mono- or polyvalent acid (aclinidium) and its application for obtaining medication for simultaneous, joined, separate or successive introduction for treatment of respiratory disease, reacting to M3 antagonism (versions), product, set, package, including said combination and respective treatment method.

EFFECT: claimed composition does not give traditional for combination of β2-agonist and antagonist of muscarinic receptors M3 side effects (tachycardia, palpitation, complaints of pains in angina pectoris, arrhythmias) and can be used for treating patient with earlier acquired heart disease or state, which can be aggravated by tachycardia).

19 cl, 4 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: there are offered: a pharmaceutical product for treating a respiratory disease containing a combination of a first active ingredient specified in a muscarine antagonist and a second active ingredient, a β2-adrenoreceptor agonist wherein each active ingredient is prepared in the form of a preparation for inhalations, a respective kit, a pharmaceutical composition. What is shown is intensifying inhibition of the declared combination of metacholine induced tracheal ring tonus in vitro vs. separate introduction of the active ingredients, including enhancing bronchoprotection (bronchostenosis inhibition) in vivo.

EFFECT: said product is applicable for preparing a drug for treating respiratory diseases, such as chronic obstructive pulmonary disease.

12 cl, 9 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and aims at treating chronic obstructive pulmonary disease (COPD). It involves the combined nebuliser therapy by means of introducing 25% magnesium sulphate 3.0 ml and one of the preparations: the M-cholinolytic 0.025% atrovent 0.25 ml or the β2-adrenoceptor agonist 0.1% berotec 0.25 ml, or the combination of the M-cholinolytic and the β2-adrenoceptor agonist berodual 0.25 ml for 5 minutes twice a day.

EFFECT: method allows achieving reduced dosages, frequency rate, duration of the use of drugs, and also reaching the more manifested improvement of bronchial passability in comparison with the bronchial spasmolytic monotherapy due to total bronchodilatatory effects of magnesium sulphate and M-cholinolytic and/or β2- adrenoceptor agonist.

4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to aerosol composition, suitable for application for treatment of bronchospasms and associated with them disorders, which contains therapeutically efficient amount of troventol, microground together with propellant and one or more pharmaceutically acceptable carrier. Composition preferably contains 40-640 mcg of troventol and carrier can be selected from surface-active substance, co-solvent, antioxidant and/or filling agent.

EFFECT: invention also relates to dosing inhalator which contains aerosol composition for treatment of bronchospasms and associated with them disorders.

22 cl, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride of formula I showing antispasmodic and bronchial spasmolytic activity.

EFFECT: invention extends the range of antispasmodic and bronchial spasmolytic low-toxic agents.

3 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and deals with combination of R,R-glycopyrrolate with glucocorticoids, applied for inhalation, and its application in symptomatic and preventive treatment of upper respiratory tract diseases, especially with obstructive component or inflammation-based, such as asthma and chronic obstructive pulmonary disease.

EFFECT: combination possesses high efficiency.

19 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neonatology, and can be used for prevention of development of severe forms of bronchopulmonary dysplasia (BPD) in preterm newborn babies. For this purpose, in child of 3-4 days old presence of at least two of five criteria is detected: 1) gestation age <32 weeks, 2) performing artificial lung ventilation (ALV) for not less than 3 days or application of respiratory support with positive pressure in respiratory ways through nasal catheters, 3) dependence on oxygen in concentration more than 21% for not less than 3 days, 4) presence of symptoms of respiratory failure (RF) for more than 3 days, 5) X-ray changes in form of interstitial edema, nodose-reticular network, increased pneumatisation, homogenous shadows without hyperinflation. In case if at least two of said criteria are present, nebuliser treatment with budesonide is administered; if child had symptoms of moderate severe or severe RF, simultaneously inhalations with berodual or atrovent are carried out; in case of impossibility to disconnect child from ALV apparatus, aminofylline is added. On the 14-th day of life repeated examination is performed. From 14 to 28 day of life inhalations with budesonide are continued, in case of RF is absent; in case of RF of I-III degree - inhalations with budesonide with addition of berodual or atrovent, in case of impossibility to disconnect child from ALV apparatus, dexamethasone is applied.

EFFECT: invention contributes to efficient prevention of development of severe BPD in children of risk group due to differentiated administration of drug therapy.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to treating male patients suffering bronchial asthma early acquired androgen deficiency. That is ensured by a singular therapy 10 mg once a day combined with andriol 40 mg twice a day in the morning and in the evening. The therapeutic course makes 2 months.

EFFECT: potentiation of a bronchodilating effect of singular with no side effects.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with combination of R,R-glycopyrrolate or its physiologically acceptable salts and montelukast in effective amount for treatment of respiratory diseases, selected from group, which includes allergic rhinitis, bronchial asthma, chronic obstructive lung diseases and common cold. Also described are pharmaceutical composition for treatment of respiratory diseases, which contains R,R-glycopyrrolate or its physiologically acceptable salts and montelukast in effective amount, and application of R,R-glycopyrrolate or its physiologically acceptable salts and montelukast or its physiologically acceptable salts in effective amount for preparation of pharmaceutical composition.

EFFECT: claimed combination inhibits release of IL-2 synergically.

15 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of silibinin component of general formula (I) for obtaining medication for parenteral introduction for trweatment of viral hepatitis, with medication optionally containing cyclodextrin and/or phospholipid, and set of similar purpose, which includes said silibinin component and other medication, representing one or several pharmaceutical agents from: arginine, glutamate, silymarin, citiolone, epodemiol, ornithine oxoglurate, tidiacic arginine, myoinosite, methionine and N-acetyl methionine, choline, ornithine aspartate, cyanidanol, thiopronin, betaine, cyanocobalamin, leucine, levolose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudin, interferon. Medication preferably does not contain silidianin, and/or silicristin, and/or isosilibinin.

EFFECT: reduction of viral strain and reactivation of patients after parenteral introduction of claimed silibinin component.

21 cl, 12 dwg, 5 ex

Organic compounds // 2482838

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of reducing tendency of glycopyrronium salt to aggregate and/or form agglomerates during storage. Claimed method includes crushing glycopyrronium salt with obtaining particles with the average size of 10 mcm and processing of crushed glycopyrroneum salt with dry medium at temperature from 40°C to 120°C for from 6 to 96 hours. Invention also relates to inhaled composition of dry powder, which contains glycopyrroneum salt, proceeds by said method.

EFFECT: invention makes it possible to reduce tendency of crushed glycopyrroneum salt to aggregate and/or form agglomerates without application of solvents for provision of medication stability.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology, and concerns creating a drug preparation of an active substance of rifabutin by parenteral administration for treating human and animal infectious when administered parenterally. The parenteral drug preparation of rifabutin for therapy for the human and animal infectious diseases containing the active substance of rifabutin, excipients and water for injections, with the excipients presented by sodium metabisulphite and disodium edetate in the following ratio, g per 1 litre of water for injections: rifabutin 20-40, sodium metabisulphite, 0.7-0.9; 0.1-0.3 disodium edetate, water for injections - 1 litre.

EFFECT: invention provides a high therapeutic effect and high stability of the drug preparation, reduces the gastrointestinal toxicity of rifabutin, well tolerated, does not cause allergies and other side effects.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using a powder containing 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (TMC278) or its stereoisomer form, dispersed in water-soluble polyvinyl pyrrolidone/vinyl acetate to be mixed with water for preparing a drug preparation for treating a HIV patient. Polyvinyl pyrrolidone/vinyl acetate is related to TMC278 as 50:1 to 1:1. The invention refers to a supersaturated solution of TMC278 or its stereoisomer form and water-soluble polyvinyl pyrrolidone/vinyl acetate in an aqueous medium for preparing the drug preparation for treating a HIV patient The invention also concerns a method for preparing said supersaturated solution.

EFFECT: invention aims at providing effective concentrations and improved absorption of the poorly water-soluble active substance TMC278.

15 cl, 5 tbl, 1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, particularly to the compositions of biocompatible microparticles of alginic acid for regulated release of the active ingredients in intravenous introduction, to a method for preparing and using it. The composition contains microparticles of alginic acid of 5 mcm or less with negative Z-potential; the active ingredient represents blood coagulation factor.

EFFECT: group of inventions provides a combination of size adequate for prolongation of blood half-life or survival of the active ingredient, with lower hepatic absorption and fast cell clearance in intravenous introduction.

23 cl, 5 ex, 8 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry and represents a composition with anti-infectious activity presented in the solid dosage form for oral administration in the form of a powder, representing a balanced complex containing a probiotic agent, an adsorbent and an excipient; the probiotic agent is sterilised cultural fluid containing metabolites of the strain Bacillus subtilis VKPM (Russian National Collection of Industrial Microorganisms) No. B-2335; the adsorbent is zeolite; the excipient is calcium stearate or aerosil; the composition is characterised by the fact that it additionally contains a high-active immunomodulatory agent representing a complex of polysaccharides - products of polymer enzymatic hydrolysis of internal and external layers of brewers' yeast cell coating in the form of β-glucane and mannan with the ingredients of the composition taken in specific proportions, wt %.

EFFECT: invention provides high effectiveness and versatility with respect to dangerous bacterial and viral infections; it is storage safe and stable.

11 ex, 10 tbl, 10 dwg

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, particularly a method of treating hyperglycemia and/or diabetes, reduction of glucose levels, as well as kits for treating. A method involves the meal-time rapid introduction of the GLP-1 dosage form into pulmonary circulation, e.g. by inhalation immediately into pulmonary alveolar capillaries with the use of a drug delivery system in the form of a dry powder wherein said therapeutically effective amount leads to the blood GLP-1 concentration which is 100 pmole/l or more.

EFFECT: method causes at least none side effects, such as excessive sweating, nausea and vomiting which are usually associated with the subcutaneous and intravenous introduction of glucagon-like peptide GLP-1.

25 cl, 8 ex, 6 tbl, 20 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention includes compositions and methods for obtaining activated polymer nanoparticles for targeted delivery of medication. Nanoparticle includes biocompatible polymer and amphiphilic stabilising agent, non-covalently bound with linker, which includes, at least, one elecrophile, selectively reacting with any nucleophile on targeting substance, and places targeting substance on external surface of biodegradable nanoenvelope, active substance being loaded into nanoenvelope. Biocompatible po;ymer includes one or several polyesters, selected from group, containing polylactic acid, polyglycolic acid, copolymer of lactic and glycolic acids and their combinations. Amphiphilic stabilising agent includes polyol. Active substance represents anti-cancer medication, preferably, curcumin.

EFFECT: invention ensures delivery of therapeutic substance to the place of its action.

27 cl, 11 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine and represents a contrast agent for T1 and/or T2 magnetic resonant scanning consisting of a nano-sized superparamagnetic powder of cubic cobalt ferrite spinel CoxFe3-xO4, wherein 0.1 ≤ x ≤ 0.99 of particle size 3÷20 nm.

EFFECT: invention provides preparing the contrast agent having a simultaneous effect on relative positive T1 and negative T2 contrasts in magnetic resonant scanning.

4 cl, 3 tbl, 7 dwg

FIELD: medicine.

SUBSTANCE: pharmaceutical oral dosage form contains a mixture treated in a melt and consisting of one active ingredient which represents a solid dispersion, at least one pharmaceutically acceptable polymer and a solubilising composition containing at least one tocopheryl-containing compound and at least one propylene glycol monofatty acid ester or a mixture of propylene glycol mono- and difatty acid esters. The active ingredient (ingredients) may be presented by a HIV protease inhibitor. The invention also refers to a method for preparing said pharmaceutical form which consists in preparing a homogenous melt of said active ingredient, said pharmaceutically acceptable polymer, and said solubilising composition, and making the melt to harden to form a solid disperse product.

EFFECT: solubilising composition provides higher biological availability of the active ingredient after the oral introduction.

Novel composition // 2483716

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and deals with pharmaceutical composition, which includes dipeptidyl peptidase IV (DPPIV) inhibitor, preferably vildagliptin in amount from 1.5 to 20% and metformin in amount from 80 to 98.5%. Active ingredients constitute from 60 to 98% of composition. Cellulose or its derivatives in amount from 1 to 20% is used as binding agent. Also described is method of obtaining said composition.

EFFECT: novel composition is claimed.

47 cl, 7 ex, 8 tbl

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