Methods of treating pulmonary bacterial infection with application of fluoroquinolones

FIELD: medicine.

SUBSTANCE: group of inventions relates to therapy, namely to pulmonology, and can be used for suppressing bacteria Pseudomonas aeruginosa, growing in anaerobic conditions, as well as for the treatment of the pulmonary bacterial infection, caused by them. For this purpose an effective quantity of an aerosol of a fluoroquinolone antibiotic, selected from the group, consisting of levofloxacin and ofloxacin, in a concentration of 0.125-0.128 mg/l is introduced.

EFFECT: application of the claimed inventions makes it possible to influence the said bacteria with the quantity of the fluoroquinolone antibiotic, effective of their growth suppression.

22 cl, 3 dwg

 

The scope of the invention

This invention relates to the fields of pharmaceutical chemistry and medicine. In particular, it relates to methods for treating bacterial infections of the lungs.

Description of the prior art

Pathogen associated with most chronic infections affecting patients with cystic fibrosis (CF) is Pseudomonas aeruginosa. According to the cystic fibrosis Foundation (CFF), approximately 55% of patients with cystic fibrosis colonized by P. aeruginosa. Acute pulmonary exacerbations are a common manifestation of chronic infections caused by P. aeruginosa.

P. aeruginosa can grow anaerobically using nitrate or nitrite for anaerobic respiration or by fermentation of arginine. Sputum of patients with CF contains medium levels of nitrates 250-350 microns, and can contain levels up to 1000 μm. Therefore, the sputum in CF can provide the cells of P. aeruginosa environment that encourages colonization in anaerobic conditions and supports it.

It was shown that in dense pulmonary secretion in the lungs of patients with CF, there are areas with low oxygen pressure. Although P. aeruginosa is a common aerobe, it can colonize and proliferate in these microaerophilic environments in the sputum in CF.

A BRIEF DESCRIPTION of the INVENTION

Some embodiments disclosed here relate to methods for treating bacterial infections easy is x, involving the introduction of a therapeutically effective amount of an aerosol fluoroquinolone antibiotic where bacterial infection of the lungs includes bacteria, able to grow under anaerobic conditions.

Some embodiments include a method of treating a bacterial infection of the lungs, including the introduction of a therapeutically effective amount of an aerosol fluoroquinolone antibiotic selected from the group consisting of levofloxacin and ofloxacin, where bacterial infection of the lungs includes bacteria growing under anaerobic conditions.

In some embodiments the method comprises analysis of a bacterial infection of the lungs for the presence of bacteria growing under anaerobic conditions. In some embodiments, the bacteria grow anaerobically using nitrate or nitrite.

Some embodiments further include the analysis of a bacterial infection of the lungs for the presence of bacteria growing under anaerobic conditions using nitrate or nitrite. In some embodiments bacteria include Pseudomonas aeruginosa. In some embodiments the method comprises analysis of a bacterial infection of the lungs for the presence of Pseudomonas aeruginosa.

In some embodiments ftorhinolonovy antibiotic represents levofloxacin. In some embodiments ftorhinolonovy antibiotic represents ofloxacin.

In some embodiments is about at least a portion of bacteria, cause bacterial infection of the lungs, grows in anaerobic conditions. In some embodiments, the bacterial infection of the lung is defined as having at least some of these bacteria growing under anaerobic conditions.

In some embodiments, the bacterial infection of the lungs of the subject with cystic fibrosis. In some embodiments, the lung infection is characterized by the presence of sputum containing levels of nitrates at least 250 microns. In some embodiments, the bacterial infection of the lung is defined as having levels of nitrates contained in the sputum of at least 250 microns.

In some embodiments a method of treating a bacterial infection of the lungs does not include the introduction of a therapeutically effective amount of an antibiotic selected from the group consisting of tobramycin, amikacin and aztreonam.

In some embodiments, no other antibiotics are not administered in therapeutically effective amounts for the treatment of bacterial infections of the lungs. In some embodiments ftorhinolonovy antibiotic is administered through intra-lungs shipping. In some embodiments a therapeutically effective amount of a fluoroquinolone is more than about 5 mg. In some embodiments a therapeutically effective amount of a fluoroquinolone is not more than about 150 mg

In some the embodiments, a method for suppressing bacteria growing under anaerobic conditions, including the effect on these bacteria number fluoroquinolone antibiotic that is effective to inhibit the growth of these bacteria.

Bacteria in some embodiments is exposed to a mixture containing at least about 0.75 mg/l fluoroquinolone antibiotic. In some embodiments bacteria include Pseudomonas aeruginosa. In some embodiments the bacteria is defined as growing in anaerobic conditions.

Some embodiments of the method include the analysis of a sample of these bacteria to determine grow any bacteria in anaerobic conditions. In some embodiments, the sample of bacteria is characterized by levels of nitrates at least 250 microns.

In some embodiments ftorhinolonovy antibiotic represents levofloxacin. In some embodiments ftorhinolonovy antibiotic represents ofloxacin.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

In Fig.1 presents a table showing the definition of the IPC (minimum overwhelming concentration) of various antimicrobial agents in aerobic and anaerobic conditions.

In Fig.2A is a diagram of the distribution of values of the IPC levofloxacin (LVX) for P. aeruginosa in aerobic and anaerobic conditions.

In Fig.2B is a diagram of the distribution of values of the IPC tobramycin (THAT is) for P. aeruginosa in aerobic and anaerobic conditions.

In Fig.2C is a diagram of the distribution of values of the IPC amikacin (AMK) for P. aeruginosa in aerobic and anaerobic conditions.

In Fig.2D is a diagram of the distribution of values of IPC aztreonam (ATM) for P. aeruginosa in aerobic and anaerobic conditions.

In Fig.3A is a diagram of the average log CFU/ml P. aeruginosa over a period of time for the strain REM wild-type.

In Fig.3B is a diagram of the average log CFU/ml P. aeruginosa over a period of time for the strain RAM nalB.

In Fig.3C is a diagram of the average log CFU/ml P. aeruginosa over a period of time for the strain RAM nalB gyrA.

In Fig.3D is a diagram of the average log CFU/ml P. aeruginosa over a period of time for the strain RAM nalB gyrA (Thr83lle).

A DETAILED DESCRIPTION of the PREFERRED EMBODIMENTS

Cystic fibrosis is a hereditary disease that leads to frequent bacterial infections of the lungs, requiring treatment with antibiotics. The publication of the patent application U.S. No. 2006/0276483, which is incorporated in this description by reference in its entirety, the proposed aerosol fluoroquinolones and their use for the treatment of bacterial infections of the lungs.

Some types of bacteria that may be present in bacterial infections of the lungs, can grow in anaerobic conditions. It was shown that in dense pulmonary secret to easy the x CF patients, there are areas with low oxygen pressure. Thus, when a bacterial infection of the lungs can be bacteria growing under anaerobic conditions. Hypoxic conditions that can be detected in patients with CF, can interfere with the effectiveness of certain classes of antibiotics, and therefore requires improved methods of treatment.

Unexpectedly, it was found that fluoroquinolones exhibit similar activity against bacteria, growing in both aerobic and anaerobic conditions.

Definition

The term "microorganism" refers to microscopic organisms such as bacteria or fungi. Thus, any disclosure of this term also implies that the features related to a more narrow class of "bacteria". For example, descriptions related to antimicrobial compounds, also implies the use of antibiotics.

The term "introduction" or "enter" refers to the application of the dose of the antimicrobial pharmaceutical composition of the vertebrate animal. The preferred method of administration can vary depending on various factors, such as components of pharmaceutical compositions, localization of potential or ongoing bacterial infection, microorganism involved and the severity of the current microbial infection.

The term "mammal" is used in its usual biological sense. Thus, he bound the maintain includes people cattle, horses, dogs and cats, but also includes many other types.

The term "microbial infection" refers to an undesirable proliferation or the presence of invasion of pathogenic microorganisms in the body is the master. It includes excessive growth of microorganisms that are normally present in the body or on the body of a mammal or other organism. More generally, microbial infection can be any case, when the presence of the microbe(s) population(s) causes harm to the mammal host. Thus, microbial infection occurs when there is an excessive number of microbial populations in the body or on the body of a mammal, or when the presence of the microbe(s) population(s) is damaging the cells or other tissue of a mammal.

With regard to the reaction of the microorganism, such as bacteria, antimicrobial agent, the term "sensitivity" refers to the susceptibility of the microorganism to the presence of the antimicrobial agent. Therefore, the increased sensitivity means that the microorganism is suppressed lower concentration of antimicrobial agent in the environment surrounding the bacterial cell. This is equivalent to saying that the organism is more sensitive to the antimicrobial agent. In most cases, the minimum inhibitory concentration (MIC) of this antimicrobial the agent will be reduced.

The term "therapeutically effective amount" or "pharmaceutically effective amount" mean number of fluoroquinolone antimicrobial agent that has a therapeutic effect. Dose fluoroquinolone antimicrobial agent, which are useful in the treatment, represent a therapeutically effective amount. Thus, used here, the term "therapeutically effective amount" means such amount of fluoroquinolone antimicrobial agent to provide the desired therapeutic effect, as defined from the results of clinical trials and/or studies in animal models of infection. In specific embodiments ftorhinolonovy antimicrobial agent is introduced into a predetermined dose, and, therefore, therapeutically effective amount will be an amount of injected dose. This number and the number of fluoroquinolone antimicrobial agent can be determined in the usual way by a specialist in the art and will vary depending on several factors such as the particular involved a strain of microorganism. This amount can also depend on the growth of the patient, body weight, sex, age and medical history. For preventive treatment a therapeutically effective amount is such to icesto, which will be effective to prevent microbial infection.

"Therapeutic effect" facilitates, to some extent, one or more than one symptom of an infection and includes curing the infection. "Cure" means that symptoms of active infection is resolved, including the complete or substantial removal of excessive numbers of viable cells of microorganisms involved in the infection, prior to or below the detection limit using traditional measurements. However, some long-lasting or permanent consequences of infection can occur even after the onset of treatment (such as extensive tissue damage). Used here, the term "therapeutic effect" is defined as a statistically significant decrease in bacterial load on the host organism, the expression of resistance or relief of symptoms of infection, as determined by the results of clinical trials on human or animal studies.

The terms "treat", "treatment" or "cure" used in this description refer to the introduction of a pharmaceutical composition for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a patient who is not yet infected, but which is susceptible to a particular infection or, in other words, has the risk of such infecti is. The term "therapeutic treatment" refers to treatment of a patient already suffering from infection. Thus, in preferred embodiments the treatment is an introduction to a mammal (either therapeutic or prophylactic purposes) therapeutically effective amounts of fluoroquinolone antimicrobial agent.

The method of treatment

Some embodiments disclosed here are methods of treating bacterial infections of the lungs, which includes the introduction of a therapeutically effective amount of an aerosol fluoroquinolone antimicrobial agent, where the bacterial infection of the lungs includes bacteria growing under anaerobic conditions.

Therapeutically effective amount may include, for example, at least about 5 mg, at least about 10 mg, at least about 20 mg, or at least about 50 mg. Similarly, a therapeutically effective amount may include, for example, not more than about 150 mg; no more than about 140 mg; no more than about 125 mg, or not more than about 100 mg

Because fluoroquinolones are active against bacteria growing under anaerobic conditions, the method may include analysis of a bacterial infection of the lungs for the presence of bacteria growing or will grow in anaerobic conditions. For example, the PR, the infection can be allocated to culture and identify the type of bacteria present. If there are bacteria able to grow under anaerobic conditions, can be used in the treatment, including the introduction of a fluoroquinolone. Moreover, the application of this analysis can be used other criteria to determine whether the treatment, including the introduction of a fluoroquinolone. Fluoroquinolone may be appropriate when there are bacteria growing under anaerobic conditions, using a nitrite or nitrate, or alternatively, when the bacteria are Pseudomonas aeruginosa.

Various fluoroquinolones can be used to treat bacterial infections of the lungs. In one embodiment, the fluoroquinolone is selected from the group consisting of levofloxacin and ofloxacin. In another embodiment of the fluoroquinolone can be a levofloxacin. In yet another embodiment of the fluoroquinolone can be a ofloxacin. Fluoroquinolones may be in an aerosol form to ensure internal-lung delivery.

In some embodiments, the method does not include the treatment of bacterial infections of the lungs a therapeutically effective amount of tobramycin, amikacin or aztreonam. In another embodiment of no other antimicrobial agent is not administered in therapeutically effective amounts for the treatment of bacterial infections of the lungs.

The type of lung infections, which are subjected to a treatment, the spiral is however not limited. Lung infection may include infection, detected in a patient with cystic fibrosis. Also the method can be used to treat bacterial infections of the lungs, which is characterized by the presence of sputum containing average levels of nitrates at least about 250 microns or at least about 500 microns. Finally, the method can be used to treat bacterial infections of the lungs in which there is at least a portion of bacteria growing under anaerobic conditions.

Moreover, when treating discusses the various types of bacteria, provided that the bacteria grow or can grow in anaerobic conditions. For example, bacteria may be a Pseudomonas aeruginosa. In one embodiment, the treatment includes bacteria, growing or is able to grow anaerobically using nitrate or nitrite.

EXAMPLES

Embodiments of the present application are disclosed in more detail in the following examples, which are not intended to limit the scope of the invention.

Bacterial strains and antibiotics

One hundred and fourteen isolates of P. aeruginosa from CF patients were obtained to test the sensitivity of the CF Referral Center for Susceptibility & Synergy Studies at Columbia University (New York, NY), and two laboratories CF Therapeutics Development Network (TDN) (Seattle Children's Hospital, Seattle, WA and University of North Carolina at Chapel Hill, Chapel Hill, NC). Approximately sixty percent is accounted for fresh isolates (2004-2007), and the remaining forty percent of the allocated between 1980 and 2004.

Strains of P. aeruginosa PAM1020 (wild type), RAM (nalB), RAM (nalB gyrA (Asp87Tyr)) and RAM (nalB gyrA (Thr83lle)) represent specific resistance mechanisms associated with efflux and mutation of the target genes and were used in the analysis of activity of levofloxacin at time of death.

The antibiotics used in these studies included tobramycin, levofloxacin, amikacin and aztreonam, which are used or are under development as aerosol therapy for the treatment of CF. To determine the antimicrobial sensitivity in aerobic conditions levofloxacin hydrochloride, tobramycin sulfate and amikacin disulfate acquired LKT Laboratories (St. Paul, MN), and aztreonam a base acquired in MP Biomedicals (Solon, OH). All antibiotics used to determine antimicrobial sensitivity in anaerobic conditions, was acquired in the laboratory of the United States Pharmacopeia (Rockville, MD).

Testing sensitivity

The edge values of the IPC antibiotics were obtained by using the method of microdesmidae in a liquid nutrient medium according to the CLSI reference method (Institute for clinical laboratory standards). Cm. Clinical and Laboratory Standards Institute. Methods for Dilution AntiMnKrobial Susceptibility Tests for Bacteria That Grow Aerobically - Seventh Edition: Approved Standard M7-A7. CLSI, Wayne, PA, USA, 2006. Antibiotics were serially diluted until the next concentrations for testing under aerobic conditions: levofloxacin and tobramycin 0,03-32 mg/l, and amikacin and aztreonam 0,125-128 mg/L. Testing the sensitivity of the anaerobic conditions required the addition of 1% potassium nitrate (KNO3in the cation-balanced broth Mueller-Hinton (SUNW) to ensure anaerobic respiration for P. aeruginosa. To test the sensitivity anaerobically frozen cups to determine the IPC was thawed and placed in an anaerobic chamber overnight to ensure the removal of all oxygen before inoculation of the investigated strains. The range of dilution for all antibiotics was a 0.125-128 mg/l to determine the antimicrobial sensitivity in anaerobic conditions. Could require extended incubation up to 48 hours in anaerobic conditions, and it was necessary for 54% of the isolates.

Bactericidal activity

Analysis of activity time loss in aerobic and hypoxic conditions was performed to determine the bactericidal activity of levofloxacin in concentrations in the range 32-1,024 mg/L. Concentration of levofloxacin ranged from 16-fold to 2,048-fold values of the IPC against isogenic strains of P. aeruginosa PAM1020 (IPC equal to 0.125 mg/l), RAM (IPC ravno mg/l), RAM (IPC equal to 4 mg/l) and RAM (IPC equal to 8 mg/l). Cultures grown in broth Mueller-Hinton (EOM) in aerobic and hypoxic conditions, bred to primary inoculum 1×107-1×10 8CFU/ml Hypoxic conditions were simulated by bringing the EOM volume to maximum in the pressure vessel for growing and exceptions mixing during incubation at 37°C. the growth Rate under these conditions or EOM-treated enzyme system Oxyrase (Oxyrase, Inc., Mansfield, OH) were similar. The final volume of the culture fluid was 10 ml At time 0, 10, 20, 40, 80 and 160 minutes, 0.5 ml samples were taken from each culture liquid, immediately washed twice EOM to minimize residual effects of levofloxacin, serially diluted with saline and were sown on plates with agar Mueller-Hinton (MNA). Cups with agar incubated up to 48 hours at 37°C and evaluated the bactericidal activity. The detection limit was 2 log10CFU/ml the Number of bacteria obtained after incubation and those in the other conditions were compared using paired t-test.

Results

The results of determination of the IPC in aerobic and anaerobic conditions are summarized in the table shown in Fig.1. There has been little change in the activity of levofloxacin in anaerobic conditions; IPC50increased only 2 times, without increase in IPC90. In contrast, under anaerobic incubation increased geometric average IPC values for tobramycin, is mecatina and aztreonam approximately 7, 4 and 6 times, respectively, the values of the IPC50for tobramycin and aztreonam increased in 4 and 16 times, respectively, under anaerobic conditions. For more than 40% of the isolates had an increase in the values of the IPC more than 4 times in tobramycin, amikacin and aztreonam compared to only 4% for levofloxacin.

Fig.2A-D show the distribution of values of the IPC in aerobic and anaerobic conditions for each antibiotic against all 114 isolates of P. aeruginosa. Under anaerobic conditions tobramycin, amikacin and aztreonam showed reduced activity, determined by the shift in the distribution of values of the IPC. In contrast, the distribution of values of the IPC in aerobic and anaerobic conditions for levofloxacin were similar.

Curves death from time built for the determination of bactericidal activity of high concentrations of levofloxacin achieved after aerosol administration, against isogenic strains of P. aeruginosa in aerobic and hypoxic conditions to simulate the gradient of partial pressure of oxygen in the lungs of patients with CF. Rapid and sustained bactericidal activity in vitro within 10 minutes was observed for each strain at each concentration of levofloxacin in those and other conditions (p>0,05), as shown in Fig.3.

1. A method of treating bacterial infe the tion of the lungs, involving the introduction of a therapeutically effective amount of an aerosol fluoroquinolone antibiotic selected from the group consisting of levofloxacin and ofloxacin, where bacterial infection of the lungs includes bacteria Pseudomonas aeruginosa growing in anaerobic conditions, and these bacteria Pseudomonas aeruginosa exposed to the specified fluoroquinolone antibiotic in a concentration 0.125-128 mg/L.

2. The method according to p. 1, further comprising before the introduction fluoroquinolone antibiotic analysis of a bacterial infection of the lungs for the presence of bacteria growing under anaerobic conditions.

3. The method according to p. 1, where bacteria are able to grow anaerobically using nitrate or nitrite.

4. The method according to p. 3, further comprising before the introduction fluoroquinolone antibiotic analysis of a bacterial infection of the lungs for the presence of bacteria able to grow under anaerobic conditions using nitrate or nitrite.

5. The method according to any of paragraphs.1-4, further comprising before the introduction fluoroquinolone antibiotic analysis of a bacterial infection of the lungs for the presence of Pseudomonas aeruginosa.

6. The method according to p. 1, where ftorhinolonovy antibiotic represents levofloxacin.

7. The method according to p. 1, where ftorhinolonovy antibiotic represents ofloxacin.

8. The method according to p. 1, where specified bacterial infection easily which x is defined as having at least some of these bacteria, growing under anaerobic conditions.

9. The method according to p. 1, where a bacterial infection of the lungs of the subject with cystic fibrosis.

10. The method according to p. 1, where the infection of the lungs characterized by the presence of sputum containing levels of nitrates at least 250 microns.

11. The method according to p. 1, where specified bacterial lung infection defined as having levels of nitrates contained in the sputum of at least 500 microns.

12. The method according to p. 1, where the said method of treatment of bacterial infections of the lungs does not include the introduction of a therapeutically effective amount of an antibiotic selected from the group consisting of tobramycin, amikacin and aztreonam.

13. The method according to p. 1, where no other antibiotics are not administered in therapeutically effective amounts for the treatment of bacterial infections of the lungs.

14. The method according to p. 1, where ftorhinolonovy antibiotic is administered through intra-lungs shipping.

15. The method according to p. 1, where the specified therapeutically effective amount of a fluoroquinolone is more than about 5 mg.

16. The method according to p. 1, where the specified therapeutically effective amount of a fluoroquinolone is not more than about 150 mg

17. The method of suppressing bacteria Pseudomonas aeruginosa growing in anaerobic conditions, including the effect on these bacteria number fluoroquinolone antibiotic, is effective for baking the population growth of these bacteria, moreover, these bacteria Pseudomonas aeruginosa exposed to the specified fluoroquinolone antibiotic in a concentration 0.125-128 mg/L.

18. The method according to p. 17, where the bacteria is exposed to a mixture containing at least about 0.75 mg/l fluoroquinolone antibiotic.

19. The method according to PP.17 or 18, further comprising prior to exposure to fluoroquinolone antibiotic for these bacteria sample analysis of these bacteria to determine grow any bacteria in anaerobic conditions.

20. The method according to PP.17 or 18, where the sample of bacteria is characterized by levels of nitrates at least 250 microns.

21. The method according to PP.17 or 18, where ftorhinolonovy antibiotic represents levofloxacin.

22. The method according to PP.17 or 18, where ftorhinolonovy antibiotic represents ofloxacin.



 

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8 cl, 3 tbl, 5 ex, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a carrier applicable for the local drug delivery. A drug is enclosed in a carrier, and the carrier comprises a coating able to release an enclosed drug as a result of a local stimulus. The coating additionally surrounds the contrast agent MR 19F which changes its detectability after being released from the carrier. The invention refers to a method for the drug delivery to an MRT-controlled individual, wherein the method involves administering the above carrier into the individual enabling the carrier releasing the drug, and forming MR 19F images with the use of a contrast produced by the contrast agent MR 19F.

EFFECT: invention enables monitoring the beginning of the drug release from the carrier.

18 cl, 11 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and concerns irinotecan liposomes or its hydrochloride containing irinotecan or its hydrochloride, neutral phospholipid and cholesterol, wherein the weight ratio of cholesterol to neutral phospholipid makes 1:3-5, and a method for preparing them.

EFFECT: liposomes have higher stability.

15 cl, 3 dwg, 10 tbl, 10 ex

FIELD: medicine.

SUBSTANCE: inhalation aerosol formulation for treating respiratory diseases contains salmeterol or salmeterol xinafoate, fluticasone or fluticasone propionate, a propellent modifier representing perfluorodecalin, and a propellent specified in 1,1,1,2 tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HPA-227ea).

EFFECT: higher respirable fraction and effective pulmonary delivery of the active ingredient; the aerosol has higher stability.

1 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: inhalation formulation in the form of aerosol for treating bronchial asthma and chronic obstructive pulmonary disease containing ipratropium bromide monohydrate as an active ingredient, ethanol absolute as a solvent, an aerosol particle size regulator as an adjuvant consisting of triethyl citrate and an acid specified in a group: citric acid, hydrochloric acid, orthophosphoric acid, 1,1,1,4-tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) as a propellant in certain proportions.

EFFECT: increasing the respirable fraction and obtaining an optimised particle size distribution profile.

7 ex

FIELD: medicine.

SUBSTANCE: invention refers to methods of treating a patient suffering from severe and uncontrolled asthma which involve pulmonary administration of a glucocorticoid in the form of a vapour-phase nebulised aerosol in a combination with oral administration of a glucocorticoid. According to one of the declared methods, the nebulised aerosol is administered by inhalation at no more than 20 l/min rate in the total inhalation volume of at least 0.4 l of the vapour phase; t administration of the nebulised aerosol is preceded by administering no more than 150 ml of aerosol-free air. The glucocorticoid is administered in a daily dose of no more than 40 mg of prednisolone and an equivalent dose of another glucocorticoid. The other method of treating the patient involves pulmonary administration of the glucocorticoid in an amount of 400 to 4,000 mcg with using a nebuliser which is used to administer the glucocorticoid aerosol into the lower portion of the lungs at excessive pressure of 40 mbar or less that leads to deposition of more than 200 mcg of the glucocorticoid in the lower portion of the lungs. What is also declared is a method of treating the patient which involves pulmonary administration of the glucocorticoid in the amount of 400 to 4,000 mcg with the aerosol administered by inhalation consisting of three pre-specified periods wherein after the third period, the patient is advised to stop inhaling and exhale; the presented treatment leads to deposition of more than 200 microgram of the glucocorticoid in the lower portion of the lungs.

EFFECT: invention provides improved deposition of the inhaled glucocorticoid in the lower portion of the lungs, min 30% less consumption of oral glucocorticoids and fewer oropharyngeal side effects.

16 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a vesicle-containing composition which is characterised by that it contains: (A) a silicone-based surfactant which is silicon modified with polyoxyalkylene, (B) one or more anionic surfactants selected from polyoxyethylenealkyl(12-15)ether-phosphate, acylmethyltaurate and acylglutamate in amount of 0.001-0.2 wt %, (C) polar oil having IOB of 0.05-0.80 and/or silicone oil, and (D) water, which contains a water-soluble medicinal agent, in amount of 0.5-5 wt % of the weight of the composition, where the silicone-based surfactant (A) forms vesicles; the anionic surfactant(s) (B) is attached to the surface of the vesicles; and the polar oil and/or silicone oil (C) is present inside the bilayer membrane of the vesicles.

EFFECT: disclosed composition has excellent stability even in the presence of high concentrations of a water-soluble medicinal agent.

6 cl, 8 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

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