Prostaglandin derivatives for treating gastrointestinal disorders

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to gastroenterology, and concerns treating gastrointestinal disorders. That is ensured by administration of the effective amount of a halogenated prostaglandin compound and/or its tautomer.

EFFECT: method provides effective treatment in patients of any age and sex without involving electrolyte balance even in long-term introduction for 1 to 6 months and more.

54 cl, 8 tbl, 14 dwg, 6 ex

 

The technical field to which the invention relates.

The invention relates to method and composition for long-term treatment of gastrointestinal disorders in humans.

In addition, the present invention relates to method and composition for treatment of gastrointestinal disorders in women as well as men.

The present invention also relates to a method and composition for treatment of gastrointestinal disorders in people aged 65 years and over.

In addition, the present invention relates to method and compositions for improving the quality of life of people with gastrointestinal disorders.

Prior art

Constipation is usually defined as a rare and difficult passage of stool. According to medical estimates one out of every 50 people in the U.S. suffer from constipation. Therefore, this violation is one of the main problems of the inhabitants of the United States. Most likely that constipation affects women more often than men and is more common in the elderly, showing the exponential growth of the disease in people older than 65 years. The actual number of cases of constipation, apparently, exceed the number of messages about this violation, because a large number of people suffer from it at home and not turn to professional help.

Although in some cases, constipation may be calling the n obstruction, the greatest number of violations of this kind may be due to factors such as diet with insufficient amounts of soluble and insoluble fiber, lack of exercise, and medications (especially opium analgesics, anticholinergic antidepressants, antihistaminic agents and Vinca alkaloids), bowel disorders, neuromuscular disorders, metabolic disorders, low abdominal pressure or muscular atony.

Accurate quantification of constipation it's hard to give what is due to the wide concept of "normal" activity of the intestine, as well as a variety of symptoms and signs associated with constipation. It should be noted that the FDA has recognized the need for mandatory treatment of cases of periodic constipation.

Prostaglandins (hereinafter PGs) belong to the class of organic carboxylic acids contained in the tissues or organs of a human or other mammal with a broad physiological activity. Natural PGs (primary PGs), with the frame postanowi acid represented by the formula (A)

(α-chain)

(ω-chain)

PGs are classified into several types depending on the structure and substituents in the five-membered ring, for example:

Prostaglandins series A (PGAs)

About taglandin series (PGBs)

Prostaglandins series (process gas chromatographs)

The D-series prostaglandins (PGDs)

Prostaglandin E series (PGEs)

Prostaglandins of the F series (PGFs)

etc. in Addition, they are divided into group PG1S containing the 13,14-double bond; PG2s containing 5,6 - and 13,14-double bond; and PG3s containing 5,6-, 13,14 - and 17,18-double bond. It is known that PGs possess various pharmacological and physiological activities, such as vasodilatation, including inflammation, platelet aggregation, stimulation of the muscles of the uterus, muscle stimulation of intestinal antiulcer effect and other Major prostaglandin produced in the gastro-intestinal tract (GI) belong to the series E, I and F (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management. (WB Saunders Company, 1998); Robert, discrimination of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-244 (Churchill Livingstone, 1988); Hawkey et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart et al., Gastroenterology, 109: 285-301 (1995)).

In normal physiological conditions endocannabinoid prostaglandins play an important role in maintaining the functions GI, including the regulation of intestinal motility and passage of contents through the intestines and regulation of the consistency of the Ala (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management. (WB Saunders Company, 1998); Robert, discrimination of Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-244 (Churchill Livingstone, 1988); Hawkey et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976); Main et al., Postgard Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet, et al., Am J Physiol., 250 (3 pt I): G302-G308 (1986); Gaginella, in Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990)). It is shown that when taken in pharmacological doses as PGE2and PGFstimulate the passage of contents through the intestines and cause diarrhea (Robert, discrimination of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-344 (Churchill Livingstone, 1988); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976)). In addition, the most commonly known side effects of misoprostol, similar PGE1developed for the treatment of gastric ulcers and duodenal ulcers, diarrhea is a (Monk et al., Drugs 33 (1): 1-30 (1997)).

PGE or PGF is able to stimulate the activity of the intestines and cause it to shrink, but they have little influence on the ability to concentration of feces in the intestine. Thus, PGEs or PGFs cannot be used as a laxative agent because of the side effects associated with gastric pain caused by contractions of the intestine.

It is reported that multiple mechanisms, including modificar the bathrooms reactions intestinal nerves, the change of contraction of smooth muscle, stimulation of mucus secretion, stimulation of cellular ion transport (in particular the electrogenic transport of Cl-), and an increase in gastric fluid, contribute to the effects of prostaglandins in the GI (Robert, discrimination of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Rampton, Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids 323-244 (Churchill Livingstone, 1988); Hawkey et al., Gastroenterology, 89: 1162-1188 (1985); Eberhart et al., Gastroenterology, 109: 285-301 (1995); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976); Main et al., Postgrad Med J, 64 Suppl 1: 3-6 (1988); Sanders, Am J Physiol, 247: G117 (1984); Pairet et al., Am J Physiol, 250 (3 pt 1): G302-G308 (1986); Gaginella, in Textbook of Secretory Diarrhea 15-30 (Raven Press, 1990); Federal Register Vol.50, No.10 (GPO, 1985); Pierce et. al, Gastroenterology 60 (1): 22-32 (1971); Beubler et al., Gastroenterology, 90: 1972 (1986); Clarke et al., Am J Physiol 259: G62 (1990); Hunt et al., J Vet Pharmacol Ther, 8 (2): 165-173 (1985); Dajani et al., Eur J Pharmacol, 34 (1): 105-113 (1975); Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management (WB Saunders Company, 1998)). It was also shown that prostaglandins have cytoprotective effects (Sellin, Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis and Management (WB Saunders Company, (1998): Robert, discrimination of the Gastrointestinal Tract 1407-1434 (Raven, 1981); Robert, Adv Prostaglandin Thromboxane Res, 2: 507-520 (1976); Wallace et al., Aliment oil displayed pure Pharmacol Ther 9: 227-235 (1995)).

US Patent No.5317032 registered Ueno et al., describes laxatives on the basis of a prostaglandin analogue, including bicyclic tautomers, and US Patent No.6416016 registered Ueno, describes bicyclic tautomers prostaglandin analog obladaushi is expressed on anticonstitutional activity. Bicyclic tautomers prostaglandin analog, substituted at position C-16 by one or more halogen atoms, especially fluorine atoms, can be used in small doses to relieve symptoms of constipation.

In US Patent publication No.2003/0130352 registered Ueno et al., described that prostaglandin connection opens and activates chloride channels, especially ClC-channels, and mainly, ClC-2 channels.

US Patent publication No.2003/0119898 registered Ueno et al., describes the special composition of halogenated prostaglandin analogue used for the treatment and prevention of constipation.

In US Patent publication No.2004/0138308 registered Ueno et al., described that the bleach activator of the channel, in particular the connection prostaglandin nature, can be used for treating discomfort in the abdomen, as well as for the treatment of functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia.

MiraLax™ (polyethylene glycol 3350, NF powder for solution) is a synthetic polyglycol with an average molecular weight of 3350 and is used for the treatment of recurrent constipation. This tool is usually used within two weeks. Prolonged, frequent or excessive use of MiraLax™ can lead to electrolyte imbalances and the emergence of dependingthe laxatives (see the liner in the package MiraLax™). MiraLax™ acts as an osmotic agent that creates an imbalance in the intestinal lumen and osmotically retractor liquid. The increased level of the liquid softens the stool and promotes bowel movements.

Also assume that the above activators ClC-2-chloride channel function by stimulating the secretion of chloride ions into the lumen of the intestine, resulting in water by an osmotic mechanism enters the lumen of the intestine, which, in turn, promotes bowel movements. Given that the specific prostaglandin compound is an activator ion channels, and is thought to work mainly by an osmotic mechanism is analogous to the MiraLax™, it can be assumed that the continued application of the specified prostaglandin compound has the same drawbacks as in the case of MiraLax™. In this regard, its use is limited almost a couple of weeks, as and when using MiraLax™.

Zelnorm® (Tegaserod maleate) is indicated for the short-term treatment of women suffering from irritable bowel syndrome (IBS), the primary symptom is constipation. When conducting two randomized, placebo-controlled studies conducted double-blind method involving 288 volunteers-men, there were no significant differences in reactions to receiving placebo and Zelnom®. He established the safety and effectiveness of taking Zelnorm® men with IBS, accompanied by constipation. In addition, a subgroup analysis of patients aged 65 years and older showed no significant therapeutic effect of Zelnorm® in comparison with the placebo. In other words, is not established the effectiveness of Zelnorm® in patients aged 65 years and older with chronic constipation of unknown origin. Moreover, when you stop taking Zelnorm® symptoms may return within 1 or 2 weeks (instructions in the package Zelnorm®).

Brief description of the invention

Despite the predominance of osmotic mechanism of action, the inventor unexpectedly found that with long-term use of certain halogenated prostaglandin compounds of patients-people with no redistribution of electrolytes.

The inventor also found that halogenated prostaglandin compounds are effective in long-term care, and even after the cessation of long-term treatment specified connection is basically not happening resume symptoms.

The inventor also found that halogenated prostaglandin compounds improve the quality of life of patients with gastrointestinal disorders and is equally effective in the treatment of both women and men and even patients in age is 65 years and older.

That is, the present invention provides a method long-term treatment of gastrointestinal disorders in humans comprising the administration to a patient an effective amount of prostaglandin compounds represented by formula (I), and/or tautomer

where Wi and Ws are

,or(a)

R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;

X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;

R2represents hydrogen or alkyl;

Y represents a saturated or unsaturated C2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;

A represents a-CH2HE PINES2HE, -COOH or its functional derivative;

R1represents a saturated or unsaturated, linear-chain, branched-chain, or collabrasuite lower hydrocarbon which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy what Ruppel; lowest cycloalkyl; lower cycloalkane; aryl; or aryloxy;

the bond between C-13 and C14 is a double or single bond and the steric configuration of the position-15 represents the R, S configuration or a mixture.

The present invention also provides a method of treating gastrointestinal disorders in men or in men aged 65 years or older, which includes an introduction to a patient in need of treatment an effective amount of prostaglandin compounds having the formula (I), and/or tautomer.

In addition, the present invention provides a method for improving the quality of life of subjects with gastrointestinal disorders which comprises administration to a patient in need of treatment an effective amount of prostaglandin compounds having the formula (I), and/or tautomer.

In each embodiment of the method of the present invention, the total daily dose of PG-connection can preferably be 6-96 mcg.

The method of the present invention can be carried out by introducing a patient in need of treatment a pharmaceutical composition that includes the above prostaglandin compound and/or its tautomer. Accordingly, in another aspect, the present invention provides a pharmaceutical composition for long-term treatment of gastro-intestinal narushenie person, includes (i) an effective amount of prostaglandin compounds having the formula (I), and/or tautomer and (ii) a pharmaceutically acceptable filler.

In addition, the present invention provides a pharmaceutical composition for treating gastrointestinal disorders in patients as male or female, or in people aged 65 years or older, and the composition includes (i) an effective amount of prostaglandin compounds having the formula (I), and/or tautomer and (ii) a pharmaceutically acceptable filler.

The present invention also provides a pharmaceutical composition for improving the quality of life of a person with gastrointestinal disorders, which includes (i) an effective amount of prostaglandin compounds having the formula (I), and/or tautomer and (ii) a pharmaceutically acceptable filler.

In another aspect the present invention provides the use of prostaglandin compounds having the formula (I), and/or tautomer for the production of pharmaceutical compositions specified above.

Brief description of drawings

Figure 1 is a graph showing the severity of constipation during treatment within 6 months.

Figure 2 is a graph showing the severity of constipation during leczenia 12 months.

Figure 3 is a graph showing the evaluation bloating during treatment within 6 months

Figure 4 is a graph showing the evaluation bloating during treatment within 12 months.

Figure 5 is a graph showing the assessment of discomfort in the abdomen during treatment within 6 months.

Figure 6 is a graph showing the assessment of discomfort in the abdomen during treatment within 12 months.

Figure 7 is a graph showing the effect on the number of defecations per week.

Figure 8 is a graph showing the effect on bloating.

Figure 9 is a graph showing the effect on the discomfort in the abdomen.

Figure 10 is a graph showing the effect on the severity of constipation.

Figure 11 is a graph showing the influence on the degree of natureline when urinating.

Figure 12 is a graph showing the effect on stool consistency.

Figure 13 is a comparative graph showing the effect on defecation in patients, male and female.

Figure 14 is a graph showing the influence of patient age on defecation.

Detailed description izobreteny the

In the present invention, the term "effective amount" may be determined taking into account age, weight, condition of the patient, the desired therapeutic effect, the method of application, period of treatment, etc. In accordance with the present invention, the quantity of injected patient prostaglandin compounds may be about 0.001-1000 μg/kg body weight, more preferably 0.01 to 100 μg/kg body weight and most preferably 0.1 to 10 mg/kg of body weight per day. The frequency of injection can be one or more doses per day, preferably two or more doses per day. The usual amount of drug introduced to the patient, is 6-96 mcg per day. In accordance with the description and claims of the input quantity or dose set for a patient with an approximate body weight of 60 kg

Used in the text, the term "approximately"related to the unit of measurement can be defined as +/-30%, preferably +/-20%, particularly preferably +/-10% from measured values. For example, the total daily dose of about 6-96 µg preferably has a ratio to between 5.4 105,6 mcg. The preferred dose is in the range 6-72 mcg. In a more preferred embodiment, the dose is in the range of 6-60 mcg. For example, the dose of halogenated compounds may be about 8-48 m is,

(i) a Prostaglandin compound having the formula (I)

In the present invention is applied prostaglandin compound having the formula (I)

where W1and W2are:

,or(a)

R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;

X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;

R2represents hydrogen or alkyl;

Y represents a saturated or unsaturated With2-10hydrocarbon chain, which is unsubstituted or substituted by exography, halogen, alkyl, hydroxy or aryl;

A represents a-CH2OH, the PINES2HE, -COOH or its functional derivative;

R1represents a saturated or unsaturated, linear-chain, razvetvlenno-chain or collabrasuite lower hydrocarbon which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy; lower cycloalkyl; lower cycloalkane; aryl; or aryloxy;

the bond between C-13 and the 14 is a double or single bond, and

steric configuration of the position-15 represents the R, S configuration or a mixture.

In the above formula, the term "halogen" includes fluorine atoms, chlorine, bromine and iodine. Particularly preferred halogen atoms for the substituents X1and X2are fluorine atoms.

The term "unsubstituted"used in the definition of the substituents R1and Y includes at least one or more double bonds and/or triple bonds that are between carbon atoms in the main and/or side chain and which can be isolated, separated and arranged periodically. In accordance with the accepted nomenclature of unsaturated linkage between two consecutive positions is determined by specifying a smaller number of the two provisions, and the unsaturated bond between two remote from each other regulations determined by specifying both positions.

Used in the description and the claims, the term "lower" includes a group containing 1-6 carbon atoms, if there is no special reservations.

The term "ring" refers to the lower cycloalkyl, lower cycloalkane, aryl or aryloxy.

The term "lower alkyl" refers to linear or branched chain saturated hydrocarbon groups containing 1-6 carbon atoms, and includes, for example, methyl, ethyl, about the sludge, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term "lower alkoxy" refers to the group of lower alkyl-O-, in which lower alkyl is defined as above.

The term "lower alkanoyloxy" refers to a group represented by the formula RCO-O-, in which RCO is an acyl group such as acetyl formed from oxidation of the lower alkyl group as described above.

The term "lower cycloalkyl" refers to a cyclic group formed in the cyclization of the above lower alkyl groups, but containing three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "lower cycloalkane" refers to the group of lower cycloalkyl-O-, in which the lower cycloalkyl defined as indicated above.

The term "aryl" refers to unsubstituted or substituted aromatic carbocyclic or heterocyclic groups (preferably monocyclic groups, such as phenyl, naphthyl, tolyl, xylyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furanyl, pyranyl, pyridyl, pyridil, pyrimidyl, Persil, pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidine, piperazinil, morpholino, indolyl, benzothiazyl, hinely, ethanolic, uril, hintline, carbazolyl, acridines, phenanthridines, benzimidazolyl, benzimidazolinyl, benzothiazolyl and phenothiazinyl. Examples of the substituents may be a halogen atom, halo(lower)alkyl, where the halogen atom and lower alkyl is defined as above.

The term "aryloxy" refers to a group represented by the formula ArO-, in which Ar is aryl, the definition of which was given above.

The term "functional derivative" includes salts, preferably pharmaceutically acceptable salts), ethers and esters and amides.

Suitable "pharmaceutically acceptable salts" include traditionally used non-toxic salt, such as salt inorganic bases, such as alkali metal salt (e.g. sodium and potassium salt), salt, alkaline earth metal (for example, a salt of calcium and magnesium), ammonium salt; or a salt of organic bases such as amine salt (such as salt of methylamine, dimethylamine salt, salt cyclohexylamine, salt benzylamine, salt, piperidine salt, Ethylenediamine, ethanolamine salt, diethanolamine salt, triethanolamine salt, salt of Tris(hydroxymethylamino)ethane, salt monomethyl-monoethanolamine salt of procaine salt and caffeine), salt of the basic amino acids (such as salt arginine and lysine salt), salt of a tetraalkylammonium and the like, These salts can be obtained traditional the mi methods, for example, from the corresponding acids and bases, or salt exchange.

Examples of ethers include alkalemia esters, for example lower alkalemia ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl methyl ether, pentalogy ether and 1-cyclopropylethyl ether; and secondary and higher alkalemia esters, such as oktilovom ether, diethylhexyl ester, lauric ether and cetyl ether; unsaturated ethers such as alerby ether and linalilovy ether; lower alkenilovyh esters, such as vinyl ether, allyl ether; lower alkinilovymi esters, such as atinlay ether and ether propenyloxy; esters of hydroxy(lower alkyl) such as hydroxyethyloxy ether and hydroxyisopropyl ether; esters of lower alkoxy(lower alkyl), such as methoxymethyl ether and 1-methoxyethylamine ether; optionally substituted akrilovye ethers such as phenyl ether, tailby ether, tert-BUTYLPEROXY ester, salicylic ether, 3,4-dimethoxyphenyl ether and benzamidophenyl ether; and esters of aryl(lower alkyl), such as benzyl ether, trailovic ether and benzhydrylamine ether.

Examples of esters include aliphatic esters, for example lower alkalemia ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, subutility ether, tert-butyl ether, pentalogy ether and 1-cyclopropylethyl ester; compound alkenilovyh esters, such as vinyl ether and allyl ether; such complex alkinilovymi esters, as atinlay ether and propenyloxy ether; an ester of hydroxy(lower alkyl), as hydroxyethyloxy ether; esters of lower alkoxy(lower alkyl), such as methoxymethyl ether and 1-methoxyethoxy ester; and optionally substituted complex akrilovye ethers such as phenyl ether, tallowy ether, tert-BUTYLPEROXY ester, salicylic ether, 3,4-dimethoxyphenyl and benzamidophenyl ether; and the ether aryl(lower alkyl), such as benzyl ether, trailovic ether and benzhydrylamine ether.

Amide part a refers to a group represented by the formula-CONR'R”, in which each of R' and R” represents hydrogen, lower alkyl, aryl, alkyl - or arylsulfonyl, lower alkenyl and lower quinil, and includes, for example, the lowest alkylamide, such as methylamide, ethylamide, dimethylamide and diethylamide; such acrylamide as anilide and toluidin; and alkyl - or arylsulfonate, such as methylsulfonylamino, ethylsulfonyl and tolilsulfonil.

Examples of Y include, for example, the following groups:

-CH2-CH2-CH2-CH2-CH2-CH2-,

-CH2-CH=CH-CH2-CH2-CH2-,/p>

-CH2-CH2-CH2-CH2-CH=CH-,

-CH2-C≡C-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-O-CH2-,

-CH2-CH=CH-CH2-O-CH2-,

-CH2-C≡C-CH2-O-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH2-CH2,

-CH2-CH=CH-CH2-CH2-CH2-CH2,

-CH2-CH2-CH2-CH2-CH2-CH=CH-,

-CH2-C≡C-CH2-CH2-CH2-CH2,

-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-,

-CH2-CH2-CH2-CH2-CH(CH3)-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2,

-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2,

-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-,

-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-and

-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-.

In addition, at least one carbon atom in the aliphatic hydrocarbon fragment Y is optionally substituted by oxygen, nitrogen or sulfur.

Suppose the equipment And represents-COOH or its pharmaceutically acceptable salt, or ester.

Preferred radicals X1and X2can represent halogen atoms, and more preferably fluorine atoms.

Preferred W1is a =O.

Preferred W2represents a

or(a)

where both radicals R3and R4are hydrogen atoms.

Preferred Y is an unsubstituted, saturated or unsaturated hydrocarbon chain containing from 6-8 carbon atoms.

Preferred R1represents a hydrocarbon residue containing 1-6 carbon atoms, more preferably 1-4 carbon atoms. In R1when one carbon atom may be present one or two side chains.

R2preferably represents hydrogen.

The most preferred embodiment of the invention is a prostaglandin compound having the formula (I)in which a represents a-COOH; Y is (CH2)6; W1represents =O; W2represents a

or(a)

where both radicals R3and R4are hydrogen; R2represents hydrogen; X1and X2represent fluorine; and R1depict is to place a (CH 2)2CH3or CH2CH(CH3)CH2CH3.

The active compound of this invention or the connection PG having the formula (I), exists in the form of bicyclic compounds in the solid state, but when dissolved in a solvent, the connection part forms a tautomeric form. In the absence of water, the compound represented by formula (I), is mainly in the form of a bicyclic structure. Assume that in the aqueous medium, a hydrogen bond between the water molecule and, for example, a ketone group in position C-15, which complicates the formation of a bicyclic ring. In addition, assume that the atoms of halogen in position C-16 contribute to the formation of a bicyclic ring. As shown below, the tautomerism between the hydroxy-group in position C-11 and geography in position C-15 plays a particularly important role in the case of compounds containing 13, 14-single bond and two fluorine atom at position C-16.

Thus, the present invention may include halogenated isomers of prostaglandin compounds. Below, in the example shown monocyclic the tautomers, containing ketogroup in position C-15 and the atoms of halogen in position C-16.

In accordance with generally accepted nomenclature of prostaglandins monocyclic the preferred form of the program of the present invention can be named, as 13,14-dihydro-15-keto-16,16-debtor-PGE1.

(ii) a Pharmaceutically acceptable filler

In accordance with the present invention the pharmaceutical composition may be formulated in any form. Therefore, the pharmaceutically acceptable excipient can be selected depending on the desired form of the composition. In accordance with the invention, the term "pharmaceutically acceptable excipient" means an inert substance that is used in conjunction with the active ingredient of the invention and is suitable for obtaining the desired shape.

For example, the solid composition of the present invention for oral administration may include tablets, drugs, granules, etc. In such solid compositions one or more active ingredients may be mixed with at least one inert diluent, e.g. lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate of magnesium aluminate, and the like In accordance with conventional practice, the composition in addition to the inert diluent may contain additives, such as a lubricating substance, such as magnesium stearate; dezintegriruetsja substance, such as fibrous calcium gluconate; stabilizer such as cyclodextrin for example α,β - or γ-cyclodextrin; the esterified cyclade the Stryn, such as dimethyl-α-, dimethyl-β-, trimethyl-β - or hydroxypropyl-β-cyclodextrin; a branched cyclodextrin, such as glycosyl, multiselection; formirovanii cyclodextrin; cyclodextrin containing sulfur; a phospholipid, etc. When using the above cyclodextrins can sometimes occur in the formation of compounds include, increasing the stability of the product. Alternative sometimes for the formation of liposomes can be applied phospholipid, which also improves stability.

If necessary, tablets or pills may be coated with a membrane, soluble in the stomach or intestines, such as sugar, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose. In addition, you can get them in the form of capsules with absorbable substances such as gelatin. Preferably the composition is in the form of soft gelatin capsules with liquid content of the halogenated prostaglandin compounds and triglycerides with medium chain fatty acids. Examples of triglycerides with medium chain fatty acids used in the present invention include a triglyceride with saturated or unsaturated fatty acid containing 6-14 carbon atoms, which may have a branched structure. Preferred fatty acid represents Yanou saturated fatty acid, for example, Caproic acid (C6), Caprylic acid (C8), capric acid (C10), lauric acid (C12) and myristic acid (C14). In addition, you can apply a mixture of two or more triglycerides medium chain fatty acids. Other suitable fillers are described in published PCT application WO 01/27099.

Liquid composition for oral administration may be in the form of an emulsion, solution, suspension, syrup or elixir, and includes a generally used inert diluent. In addition to the inert diluent, this composition may contain additives such as lubricants, sweeteners, flavorings, preservatives, soljubilizatory, antioxidants and other Additives can be selected from those described in any General guidance for the pharmaceutical industry. Liquid compositions can be directly placed in soft capsules. The composition of the present invention can be applied in the form of suppositories, enemas, etc. They can be in the form of a sterile aqueous or nonaqueous solutions, suspensions, emulsions and the like, Examples of the filler for an aqueous solution, suspension or emulsion may include distilled water, physiological solution and ringer's solution.

Examples of fillers for non-aqueous solution, suspension or emulsion may include propylene glycol, polyethylene glycol, a triglyceride with germanically, vegetable oil, such as olive oil, alcohols such as ethanol, Polysorbate and the like, the composition may contain additives, for example preservatives, moisturizer, emulsifier, dispersant, antioxidant, etc.

In accordance with the present invention the pharmaceutical composition may be intended for parenteral or oral administration, and preferred is a composition for oral administration. In the example, the active ingredient is preferably dissolved in a triglyceride with a medium chain fatty acid and the solution is filled capsules.

In accordance with the method of the invention the composition of the present invention can be entered systemically or locally by means of oral or parenteral administration, including parenteral administration via suppository, enemas, etc. Composition of the present invention can enter from one to several times a day.

Preferably, the total daily dose of prostaglandin compounds of the present invention is about 6-96 μg, more preferably about 6-72 μg, even more preferably about 6-60 mcg and particularly preferably 8-48 mcg. The dose may vary at the discretion of therapist, depending on age and body weight of the patient's condition, therapeutic effect, the route of administration, the PE the iodine treatment, etc.

Used in the text the term "no significant electrolyte shift" means that electrolyte imbalance during treatment is expressed to a much lesser extent than under the action of known means, inducing electrolyte imbalance. In addition, the term "no significant electrolyte shift" refers to the level of serum electrolyte in a patient undergoing treatment, which, as should be clear to clinicians, is in the region of normal clinical values. As noted above, MiraLax™is used to treat constipation that can cause electrolyte imbalance, which, among other things, can lead to dangerous cardiac problems. On the other hand, as shown in the following example, prostaglandin compound used in the present invention, practically does not cause electrolyte shift even during prolonged administration of the drug.

The following examples also illustrate the fact that the pharmaceutical composition of the present invention practically does not cause a resumption of symptoms of constipation or other undesirable conditions after the termination of long-term treatment with the composition. Thus, as a consequence, the composition of the present invention may be useful in long-term care.

Moreover, assessment of the quality of life of patients, traduse constipation and IBS, led to the conclusion that the connection has improved the quality of life of patients.

In accordance with the present invention is represented by compounds may be useful in long-term treatment of gastro-intestinal disorders. They have the same efficacy in the treatment of patients, both male and female. In addition, they are useful in the treatment of patients aged 65 years or older.

Used in the text, the term "gastrointestinal disorders" includes, but is not limited to the above, acute or chronic constipation, functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, stomach ulcer, ulcer of the colon and small intestine and discomfort in the abdominal area.

Different types of constipation to be treated include, but are not limited to the mentioned above, functional constipation, such as relaxing constipation, spastic constipation, rectal constipation and post-operative ileus; organic constipation caused by bowel disease and stenosis due to postoperative adhesions; and constipation, caused by the action of drugs such as opioid.

In addition to the mitigation or prevention of constipation, the composition of the present invention can be applied to prevent natureline when urinating in a patient suffering from a hernia or serdechno-vascular disease, or to soften the stool of a patient with anorectal diseases. In addition, the present composition can be used for cleansing the gastrointestinal tract in preparation for endoscopy or for diagnostic or surgical procedures, such as colonoscopy, barium enema x-ray studies and intravenous pyelography, or in case of urgent procedures such as emergency washing of the gastrointestinal tract in order to remove poisons, etc. Thus, the invention encompasses embodiments in which the composition of the present invention is used for cleansing the gastrointestinal tract in men or people aged 65 years or older.

Used in the text, the term "treatment" includes any means of control such as prevention, care of patients, withdrawal symptoms, relieving symptoms and stop disease progression. Used in the text the term "long-term treatment" refers to the introduction of the connection, at least for two weeks. The connection may be taken daily throughout the treatment period or interval in one or more days.

Described below are details of the present invention will be made with reference to experimental examples, which, however, do not limit the scope of the present invention.

Information, a confirmation is origaudio the possibility of carrying out the invention

Example 1

Method

A multicenter open study was conducted to assess the safety of taking 48 μg of compound A (13,14-dihydro-15-keto-1B,16-debtor PGE1) (24 μg compound A b.i.d.) when given daily for 24 weeks (6 months) or 48 weeks (12 months) patients suffering from periodic constipation. Registered patients who in the past had chronic constipation for at least for 3 months (less than 3 SBMs per week) and at least one associated symptom, such as hard stools, incomplete evacuation, natureline. After a 14-day washout period in the absence of drugs, patients received 48 μg of compound A (24 µg connection And b.i.d.) orally for 48 weeks.

This study evaluated the following parameters.

1. Electrolyte balance

The concentration of ions of sodium, potassium, chlorine, calcium, magnesium and phosphorus in the serum of patients (n=299) were measured before treatment and after 6, 12, 18, 24, 30, 48 and 50 weeks after starting treatment with compound A.

Laboratory standard values set electrolytes were taken from the normal range of values of the Central laboratory.

2) the severity of the constipation, 3) bloating and 4) discomfort in the abdomen.

Each parameter (the severity of constipation, bloating and discomfort in the abdomen) has been evaluated in patients during a 6-month (n=246) or 12 months (n=30) treatment according to the following scale: 0 (no), 1 (weak)2 (moderate), 3 (severe) and 4 (very severe).

Results

1. Electrolyte balance

As follows from Table 1, treatment with compound a had no effect on the concentration of ions of sodium, potassium, chlorine, calcium, magnesium and phosphorus in the serum of patients. The results show that compound a does not cause a significant shift of electrolytes during long-term administration of the drug.

Table 1
The average results of chemical analysis of blood serum
WeekSodium (mmol/l)Potassium (mmol/l)Chloride (mmol/l)Calcium (mg/DL)Magnesium (mg/DL)Phosphorus (mg/DL)
0141,004,28103,08being 9.612,18the 3.65
6142,254,28103,009,902,23 3,20
12139,784,20103,089,712,243,57
18141,504,40105,50of 9.302,353,55
24139,214,19102,569,77of 2.213,61
30136,004,30100,009,102,302,50
36138,944,18102,519,672,19to 3.58
48139,594,20102,889,662,143,50
50139,114,49102,67for 9.472,313,54
Laboratory standard135-1483,5-5,596-109of 8.5 to 10.61,6-2,6*
* Women: 15-19 2.5 to 5.3 mg/DL, ≥ 20 years of 2.5-4.5 mg/DL
Men: 15-19 2.5 to 5.6 mg/DL, ≥ 20 years of 2.5-4.5 mg/DL

2) the severity of constipation (6 and 12 months), 3) bloating (6 and 12 months) and 4) discomfort in the abdomen (6 and 12 months) are shown in figures 1-6, respectively.

As shown in figures 1-6, the compound a is effective in the treatment for 6 and 12 months.

Example 2

Method

Multi-purpose, double-blind, randomized, placebo-controlled study was conducted to evaluate the response after treatment in some patients, after four (4) weeks of active treatment (total daily dose of a compound A - 48 µg) and three (3) weeks of randomized withdrawal period of treatment. Registered patients who in the past had chronic constipation for at least 6 months (less than 3 SBMs per week) and, hence, is her least one associated symptom, such as hard stools, incomplete evacuation, natureline. After a 14-day washout period in the absence of drugs, patients received 48 μg of compound A (total daily dose) orally for 28 days, and then 0 or 48 μg of compound A (total daily dose) for 21 days.

This study evaluated the following parameters:

1) the number of defecations per week;

2) bloating;

3) discomfort in the abdomen;

4) the severity of constipation;

5) natureline;

6) consistency.

Each parameter (bloating, discomfort in the abdomen, the severity of constipation or natureline) was evaluated in patients according to the following scale: 0 (no), 1 (weak)2 (moderate), 3 (severe) and 4 (very severe). Consistency was evaluated on a scale of 0 (very loose), 1 (loose), 2 (normal), 3 (tight) and 4 (very dense, small balls).

Results

1) the number of defecations per week 2) bloating, 3) discomfort in the abdomen, 4) severity of constipation, 5) natureline and 6) the consistency shown in figures 7-12, respectively.

As shown in figures 7-12, after discontinuation of treatment with compound a were not observed resume symptoms, and the effectiveness of the connection And continued even after cessation of treatment.

This result indicates that the introduction of the connection is the patients ' quality of life improves.

Example 3

Method

Patients suffering from irritable bowel syndrome (IBS), was attended by 48 μg of compound A (24 μg compound A b.i.d.) within 48 weeks.

This study evaluated the following parameters:

1) discomfort in the abdomen;

2) bloating;

3) the severity of constipation.

And discomfort in the stomach, and bloating of the patients were evaluated according to the scale: 0 (no), 1 (weak)2 (moderate), 3 (severe) and 4 (very severe). The severity of constipation in patients was assessed according to the scale: 0 (very weak). 1 (weak), 2 (normal), 3 (severe), 4 (very severe).

Results

1) discomfort in the abdomen, 2) bloating and 3) the severity of constipation are presented in tables 2-4, respectively.

As shown in tables 2-4, the connection And effectively within a 12-month treatment of patients suffering from IBS.

Table 2
Analysis of discomfort in the abdomen
WeekConnection As Mean±SD(N)Connection
Mean±SD(N) Median
MedianInt
Int P value*
Baseline1,95±0,850 (183)Deviation from baseline
2.00
0,00-4,00
12-week1,16 ±0,836 (135)-0,79±0,993 (135)
1,00-1,00
0,00-4,00-3,00-2,00
<0,001#
Week 180,98±0,874 (111)-0,97±1,031(111)
1,00-1,00
0,00-3,00-4,00-3,00
<0,001#
24-week1,09±0,917 (107)-0,82±1,035 (107)
1,00-1,00
0,00-4,00-4,00-3.00
<0,001#
The 36th week0,93±0,799 (57) -0,77±0,926 (57)
1.00-1,00
0,00-3,00-4,00-2,00
<0,001#
48-week0,87±0,929 (52)-0,81±0,908 (52)
1,00-1,00
0,00-4,00-2,00-2,00
<0,001#
The end of the treatment1,28±1,020 (183)-0,66±1,112 (183)
1,00-1,00
0,00-4,00-4,00-2,00
<0,001#
Follow-up1,40±0,996 (121)be 0,55±1,080 (121)
1,00-1,00
0,00-4,00-4,00-2,00
<0,001#
* p value from sign-rank criterion of an eye the Sona

Table 3
Analysis bloating
WeekConnection As Mean±SD(N)Connection
MedianMean±SD(N) Median
IntInt
P value*
Baseline2,23±0,927 (183)Deviation from baseline
2,00
0,00-4,00
12-week1,43±0,919 (135)-0,84 ±1,045 (135)
1,00-1,00
0,00-4,00-3,00-3,00
<0,001#
Week 181,19±0,837 (111)-1,07±1,068 (111)
1,00-1,00
0,00-3,00-3,00-3,00
<0,001#
24-week1,26±0,915 (107)of 0,95±1,102 (107)
1,00-1,00
0,00-4,00-4,00-3,00
<0,001#
The 36th week1,05 ±0,854 (57)-1,00±1,134 (57)
1,00-1,00
0,00-3,00-4,00-2,00
<0,001#
48-week1,12±0,832 (52)-0,94±0,802 (52)
1,00-1,00
0,00-4,00-3,00-1,00
<0,001#
The end of the treatment1,50±1,005 (183)-0,73±1,075 (183)
1,00-1,00
0,00-4,00-4,00-2,00
<0,001#
Follow-up1,55±0,957 (121)-0,69±1,109 (121)
2,00-1,00
0,00-4,00-3,00-3,00
<0,001#
* p value from sign-rank criterion of Wilcoxon signed

Table 4
The analysis of the severity of constipation
WeekConnectionConnection And
Mean±SD(N)
Mean±SD(N) MedianMedian
IntInt
P value*
Baseline2,95±0,751(183)Change baseline
3,00
1,00-4,00
12-week1,76±1,003 (135)-1,16±1,099(135)
2,00-1,00
0,00-4,00-4,00-2,00
<0,001#
Week 181,33±0,985(111)-1,59±1,148 (111)
1,00-2,00
0,00-4,00-4,00-3,00
<0,001#
24-week1,50±0,965 (107)-1,40±1,036 (107)
1,00-1,00
0,00-4,00-3,00-2,00
<0,001#
The 36th week1,39±0,921(57)-1,33±1,123(57)
1,00-1,00
0,00-4,00-4,00-2,00
<0,001#
48-week1,37±0,894 (51)-1,37±1,095 (51)
1,00-1,00
0,00-3,00-3,00-1,00
<0,001#
The end of the treatment1,84±1,120 (183)-1,11±1,148 (183)
2,00-1,00
0,00-4,00-4,00-2.00
<0,001#
Follow-up2,07±0,946 (121)-0,88±1,122 (121)
2,00-1,00
0,00-4,00-4,00-2,00
<0,001#
* p value from sign-rank criterion of Wilcoxon signed

Example 4

Method

Multi-purpose, parallel-group, double-blind, placebo-controlled study was conducted to compare the activity of a compound And the weekly number of SPONTA the data defecation in patients, male and female. Patients of both sexes suffering from periodic constipation, took 48 mg (total daily dose) connection And (24 μg compound A b.i.d.) within 4 weeks. During treatment patients were registered cases of bowel movements.

Results

Data on the comparative influence of 48 µg connection And the weekly number of spontaneous bowel movements in patients, male and female are presented in figure 13.

As shown in figure 13, the connection And possessed considerable efficiency in the use of both men and women. We detected no significant differences between the effects of the drug on men and women.

Example 5

Method

Multi-purpose, parallel-group, double-blind, placebo-controlled study was conducted to compare the activity of a compound And to improve (increase) the weekly number of spontaneous bowel movements in patients of different ages suffering from periodic constipation. Patients took 48 mg (total daily dose) connection And (24 μg compound A b.i.d.) within 4 weeks. During treatment patients were registered cases of bowel movements.

Results

The results are shown in figure 14. As shown in figure 14, the connection And had significant efficacy in all age groups, even among patients aged 65 years and over.

Example 6

Method

<> 48-week multi-purpose research was conducted to evaluate the safety and efficacy of reception of 48 mg (total daily dose) connection And patients suffering from periodic constipation. Registered patients who in the past had chronic constipation for at least for 3 months (less than 3 SBMs per week) and at least one associated symptom, such as hard stools, incomplete evacuation, natureline. After a 14-day washout period in the absence of drugs, patients received 48 µg connection And a day (24 μg of compound A, b.i.d.) within 48 days.

Patients filled consisting of 36 items short form (SF-36) final medical research (MOS), i.e. the traditional evaluation form QOL, at check-in (baseline) and after treatment (48-week). Components form the MOS SF-36 (Med Care 30(6), 473-483, 2000) is given below.

Physical component: physical function, role-physical component, somatic pain, and General health status.

Mental component: vitality, social function, role emotional component and mental health

Each of the 8 components were evaluated in accordance with the guidelines of the publisher, including directives regarding the use of the missing variables. Deviation from the baseline in each of the 8 components at the end of the Le is to be placed (48-week) were recorded and evaluated using paired t-test.

Results

As shown in table 5, to evaluate each of the 8 components of the average value of the baseline is 47-52, which suggests that the study population was mostly healthy. The average deviation from the baseline for the assessment of each component at the 48th week is characterized by a small increase, which indicates the improvement of the relevant categories. Improve significantly different from zero values observed for 48 week for physical function, role physical components, somatic pain, General health, vitality, social function and mental health.

The results show that the connection And improves QOL of patients.

Table 5
The final results SF36
Component/score scale
Physical functionRole-physical componentSomatic painGeneral healthViable Role-emotional componentMental health
Social function
Basic
line
N320320319319319320319319
Average49.0449,7547,5351,5250,6150,1249,5250,60
(std)9,817 9,4579,7659,0699,9409,7789,9739,829
48-weeka)
N153153151151151152151151
Averageb)2,48**1,95**3,38**1,47*2,89**2,22**1,221,97**
(Std)8,4317.4039,8837,8279,1638,9739,560 9,201
a) the Values given at week 48, illustrate the deviation from the baseline.
b) *p<0,05, **p<0,01 (paired T-test)

Example 7

Method

12-week, double-blind, randomized study was conducted to evaluate the safety and efficacy of oral administration of 16 mg, 32 mcg and 48 mcg (total daily dose) connection And patients with irritable bowel syndrome (IBS).

Patients answered a questionnaire IBS QOL at the beginning of treatment, at week 4 of treatment, 12-week treatment and at the completion of treatment, and the results of the survey were evaluated in accordance with IBS QOL User's manual (A Quality of Life Measure for Persons with Irritable Bowel Syndrome (IBS-QOL): User's Manual and Scoring Diskette for United States Version. Seattle, Washington: University of Washington; 1997). In all analyses used the rating scale, and the assessment was calculated in accordance with the manual according to the following formula:

Score scale = {[Amount positions IBS QOL - lowest possible score] / the possible interval of the original reference} x 100.

Deviations from baseline to week 4, week 12 and at the end of the study were evaluated with respect to the average aggregate score and the average domain estimates (dysphoria, impaired activity, the body schema, anxiety associated with health status, refusal of food is a social response, sexual response and dependence).

Results

In tables 6-8 summarizes the average deviation of the estimates of the IBS-QOL from baseline analyzed without LOCF (accounting data of the last observation).

The data obtained showed that the deviation from the baseline is significantly different from zero in all groups. In General, the treated group, and 16 µg compounds And were characterized by the most pronounced improvement relative to baseline in all groups in each specific area and for all QOL.

N
Table 6
The resulting representation of the deviation from the baseline QOL in IBS (16 µg)
Component/score scale
General QOLDysphoriaViolation activityThe body schemaAnxiety about healthRefusing to eatSocial reactionSexual responseDependence
Baseline
N515151515151515151
average55,6653,1965,8241,4237,7446,0863,9764,9567,81
(Std)21,16527,33322,54422,87723,11330,01624,54633,91325,367
4th week
N454545454545454545
average14,7**17,85**10,87**accounted for 10.39**22,41**13,89**11,94**13,33**a 10.74**
(Std)14,84218,48314,89919,86720,24122,33219,43925,05717,463
12-week
424242424242424242
average18,54**23,51**13,95**22,32**23,81**15,28**14,58**16,67**15,47**
(Std)17,69820.94918,39221,70122,12926,79221,54829,6221,897
The end of the study
N494949 494949494949
Average16,82**21,62**11,95**20,41**21,94**13,95**13,78**14,03**of 14.28**
(Std)17,14520,45118,34921,49121,56225,76220,5728,49520,692

Table 7
The resulting representation of the deviation from the baseline QOL in IBS (32 mcg)
Component/score scale
General QOLDysphoriaViolation activityThe body schema Anxiety about healthRefusing to eatSocial reactionSexual responseDependence
Baseline
N494949494949494949
average60,1459,6969,8243,3744,3852,2166,8468,6270,23
(Std)22,0524,7923,38524,38724,67232,175 28,56231,36723,385
4th week
N363636363636363636
average11,25**14,58**? 7.04 baby mortality**15,28**16,9**8,33**9,9**8,68**of 7.64**
(Std)16,27720,3917,75318,26417,53423,99816,4618,13118,831
12-week
N333333333333333333
average13,08**15,25**9,42**17,99**19,44**11,36**10,8**10,98**a 9.09**
(Std)13,52715,28518,05215,2121,61523,4614,17318,42420,87
The end of the study
N444444444444444444
average12,58**14,77**8,2**17,47**17,61**10,79**11,08**10,23**10,79**
(Std)12,62114,42916,72615,34422,31721,90614,3216,89420,139

Table 8
The resulting representation of the deviation from the baseline QOL in IBS (48 g)
Component/score scale
General QOLDysphoriaViolation activityThe body schemaAnxiety about healthRefusing to eatSocial reactionSexual responseDependence
Baseline
N454545454545454545
average59,8555,8168,2545,6944,0750,37 66,8171,9475,18
(Std)21,66426,80223,39621,39623,27431,92727,07430,40422,365
4th week
N343434343434343434
average12,43**17,28**9,14**13,24**19,61**12,01**8,82**8,46**6,87**
(St) 11,61916,84214,47713,56818,56219,5914,02815,60712,558
12-week
N303030303030303030
average14,8**20,83**10,95**17,08**23,33**11,3**914,17**5**6,95**
(Std)13,6518,86315,091 18,41918,09822,15321,14318,15912,202
The end of the study
N434343434343434343
average11,54**16.28 per**7,97**14.24 from**17,05**8,33**12,06**3,49**6,01**
(Std)13,00218,6214,38717,4319,06720,002 18,7217,53512,244
*P < 0,05, **P < 0,01 (paired T-criteria)

1. The way long-term treatment of gastrointestinal disorders in humans comprising the administration to a subject in need of treatment an effective amount of prostaglandin compounds of the formula (I) and/or tautomer:

where W1and W2are:
,or; (a)
R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;
X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;
R2represents hydrogen or alkyl;
Y represents a saturated or unsaturated With2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents a-CH2HE, -COCH2OH, -COOH or its functional derivative;
R1represents a saturated or unsaturated, linear-chain, razvetvlenno-chain or collabrasuite lower hydrocarbon that can be unsubstituted or substituted ha is ogena, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy; lower cycloalkyl; lower cycloalkane; aryl or aryloxy;
the relationship between the provisions of C-13 and C-14) is a double or single bond and the steric configuration of the substituents at position C-15 represents the R, S configuration or a mixture thereof, where prostaglandin connection lead, at least for 4 weeks.

2. The method according to claim 1, in which the specified prostaglandin compound is a monocyclic tautomer formula (I).

3. The method according to claim 1, in which the input quantity specified prostaglandin compound is in the range of about 6-96 mcg per day.

4. The method according to claim 1, in which the input quantity specified prostaglandin compound is in the range of about 6-72 mcg per day.

5. The method according to claim 1, in which the input quantity specified prostaglandin compound is in the range of about 6-60 mg per day.

6. The method according to claim 1, in which the input quantity specified prostaglandin compound is in the range of about 8-48 mg per day.

7. The method according to claim 1, wherein the prostaglandin compound is administered orally.

8. The method according to claim 7, in which the specified prostaglandin compound is injected with oil dissolve the eat as filler.

9. The method of claim 8, wherein said oil solvent is a medium chain fatty acid.

10. The method according to claim 1, in which a represents a-COOH, Y is (CH2)6; W1represents =O; W2represents a
or(a),
where R3and R4represent hydrogen atoms; R2represents a hydrogen atom, X1and X2represent fluorine atoms, a R1represents (CH2)3CH3.

11. The method according to claim 1, in which the specified gastrointestinal disturbance is chosen from the group consisting of constipation, irritable bowel syndrome and functional dyspepsia.

12. The method according to claim 1, in which the specified prostaglandin connection, you must enter at least for 2 months.

13. The method according to claim 1, in which the specified prostaglandin compound is administered at least within 6 months.

14. The method according to claim 1, in which the specified prostaglandin compound is administered at least for 1 year.

15. The method according to claim 1, in which the specified prostaglandin compound is administered continuously.

16. The method according to claim 1, wherein said subject is a human is a human male.

17. The method according to claim 1, wherein said subject person is predstavljaet a person aged 65 years or older.

18. The way to improve the quality of life of the person with gastrointestinal disturbance, which includes an introduction to the human an effective amount of prostaglandin compounds having the formula (I), and/or tautomer:

where W1and W2are:
,or; (a)
R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;
X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;
R2represents hydrogen or alkyl;
Y represents a saturated or unsaturated C2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents a-CH2OH, -COCH2OH, -COOH or its functional derivative;
R1represents a saturated or unsaturated, linear-chain, razvetvlenno-chain or collabrasuite lower hydrocarbon that can be unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy; lower cycloalkyl; ISSI cycloalkane; aryl or aryloxy;
the relationship between the provisions of C-13 and C-14) is a double or single bond and the steric configuration of the substituents at position C-15 represents the R, S configuration or a mixture.

19. Composition for long-term treatment of gastrointestinal disorders in humans, which includes (1) an effective amount of the prostaglandin compounds of the formula (I), and/or tautomer:

where W1and W2are:
,or; (a)
R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;
X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;
R2represents hydrogen or alkyl;
Y represents a saturated or unsaturated With2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents a-CH2OH, -COCH2OH, -COOH or its functional derivative;
R1represents a saturated or unsaturated, linear-chain or razvetvlenno-chain or collabrasuite lower hydrocarbon which is unsubstituted or substituted Gal the genome, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy;
the relationship between the provisions of C-13 and C-14) is a double or single bond and the steric configuration of the substituents at position C-15 represents the R, S configuration or a mixture thereof, and (2) pharmaceutically acceptable excipient, where the specified composition should be introduced for at least four weeks.

20. The composition according to claim 19, in which the specified prostaglandin compound is a monocyclic tautomer.

21. The composition according to claim 19, which is composed so that the patient is given about 6-96 mcg a day specified prostaglandin compounds.

22. The composition according to claim 19, which is composed so that the patient is given about 6-72 mcg a day specified prostaglandin compounds.

23. The composition according to claim 19, which is composed so that the patient is given about 6-60 mg per day specified prostaglandin compounds.

24. The composition according to claim 19, which is composed so that the patient is given about 8-48 mg per day specified prostaglandin compounds.

25. The composition according to claim 19, which should be administered orally.

26. The composition according A.25, in which the pharmaceutically acceptable filler presented yet an oil solvent.

27. The composition according to p in which the specified oil solvent is a medium chain fatty acid.

28. The composition according to claim 19, in which a represents a-COOH; Y is (CH2)6; W1represents =O; W2represents a
or(a),
where both radicals R3and R4represent hydrogen atoms; R2represents a hydrogen atom; X1and X2represent fluorine atoms; a R1represents (CH2)3CH3.

29. The composition according to claim 19, in which the specified gastrointestinal disturbance is chosen from the group consisting of constipation, irritable bowel syndrome and functional dyspepsia.

30. The composition according to claim 19, which should be introduced for at least 2 months.

31. The composition according to claim 19, which should be introduced for at least 6 months.

32. The composition according to claim 19, which should be introduced for at least 1 year.

33. The composition according to claim 19, which should be introduced constantly.

34. The composition according to claim 19, when the subject person is a person, male or female.

35. The composition according to claim 19, when the subject person is a person aged 65 years or older.

36. Composition for the improvement of human life quality, suffering from gastrointestinal disorders, which includes (1) an effective amount of the prostaglandin compound represented by formula (I), and/or tautomer:

where W1and W2are:
,or; (a)
R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;
X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;
R2represents hydrogen or alkyl;
Y represents a saturated or unsaturated With2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents a-CH2HE, -COCH2OH, -COOH or its functional derivative;
R1represents a saturated or unsaturated, linear-chain or razvetvlenno-chain or collabrasuite lower hydrocarbon which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy; lower cycloalkyl; lower cycloalkane; aryl or aryloxy; the relationship between the Polo is eniami C-13 and C-14) is a double or single bond and the steric configuration of the position when the position of the C-15 is a R, S configuration or a mixture thereof; and
(2) a pharmaceutically acceptable filler.

37. The use of prostaglandin compounds of the formula (I), and/or tautomer:

where W1and W2are:
,or; (a)
R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;
X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;
R2represents hydrogen or alkyl;
Y represents a saturated or unsaturated With2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents a-CH2HE PINES2HE, -COOH or its functional derivative;
R1represents a saturated or unsaturated, linear-chain or branched-chain or collabrasuite lower hydrocarbon which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy; lower cycloalkyl; lower cycloalkane; aryl or aryloxy;
the relationship between polozheniya-13 and C-14) is a double or single bond and the steric configuration of the position when the position of the C-15 is a R, S configuration or a mixture thereof, for the manufacture of pharmaceutical compositions intended for long-term treatment of gastrointestinal disorders in humans, where the composition should be introduced to a patient in need of treatment, where the specified composition should be introduced for at least four months.

38. The application of clause 37, wherein the specified prostaglandin compound is a monocyclic tautomer having the formula (I).

39. The application of clause 37, wherein the composition is such that the patient is given about 6-96 mcg a day specified prostaglandin compounds.

40. The application of clause 37, wherein the composition is such that the patient is given about 6-72 mcg a day specified prostaglandin compounds.

41. The application of clause 37, wherein the composition is such that the patient is given about 6-60 mg per day specified prostaglandin compounds.

42. The application of clause 37, wherein the composition is such that the patient is given about 8-48 mg per day specified prostaglandin compounds.

43. The application of clause 37, wherein the composition is administered orally.

44. The application of item 43, wherein the composition further includes an oil solvent as filler.

45. The application of item 44, wherein the specified oil solvent p is ecstasy a medium chain fatty acid.

46. The application of clause 37, wherein a represents a-COOH; Y is (CH2)6; W1represents =O; W2represents a
or(a),
where both radicals R3and R4represent hydrogen atoms; R2represents a hydrogen atom; X1and X2represent fluorine atoms; a R1represents (CH2)3CH3.

47. The application of clause 37, wherein the specified gastrointestinal disturbance is chosen from the group consisting of constipation, irritable bowel syndrome and functional dyspepsia.

48. The application of clause 37, wherein the composition is administered at least for 2 months.

49. The application of clause 37, wherein the composition is administered at least within 6 months.

50. The application of clause 37, wherein the composition is administered at least for 1 year.

51. The application of clause 37, wherein the composition is administered continuously.

52. The application of clause 37, wherein the specified subject person is a person, male or female.

53. The application of clause 37, wherein the specified subject person is a person aged 65 years and over.

54. The use of prostaglandin compounds of the formula (I) and/or tautomer:

where W1and W2are:
,or; (a)
R3and R4represent hydrogen; or one of the radicals represents IT, and the other is hydrogen;
X1and X2represent hydrogen, lower alkyl or halogen, provided that at least one of them is a halogen;
R2represents hydrogen or alkyl;
Y represents a saturated or unsaturated With2-10hydrocarbon chain, which is unsubstituted or substituted by oxo, halogen, alkyl, hydroxy or aryl;
A represents a-CH2HE, -COCH2OH, -COOH or its functional derivative;
R1represents a saturated or unsaturated, linear-chain or razvetvlenno-chain or collabrasuite lower hydrocarbon which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkyl, lower alkoxy, lower alkanoyloxy, lower cycloalkyl, lower cycloalkane, aryl or aryloxy; lower cycloalkyl; lower cycloalkane; aryl or aryloxy;
the relationship between the provisions of C-13 and C-14) is a double or single bond and the steric configuration of the position when the position-15 represents the R, S configuration or a mixture thereof, for the manufacture of pharmaceutical com is osili, to improve the quality of life of the person suffering from gastrointestinal disorders, where the composition should be introduced to a subject in need of treatment.



 

Same patents:

FIELD: medicine.

SUBSTANCE: present invention refers to medical products, particularly to large depletion mixture containing the following components per litre of aqueous solution: polyethylene glycol 90 to 150; ascorbic acid and/or ascorbic acid salt 5 to 15; alkaline or earth metal sulphate or mixed alkaline or earth metal sulphates 5 to 10; and electrolyte (sodium chloride, potassium chloride and sodium hydrocarbonate). The mixture agents are chosen so that the osmolarity of the aqueous solution reduced to 1 litre is within 300 to 550 mOsmoles/litre. Besides the invention concerns a cleaning agent, a component set for large intestine depletion, to application of polyethylene glycol as a large intestine depletion agent and to method of large intestine depletion.

EFFECT: higher mixture safety and tolerance.

39 cl, 29 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: IBAT antioxidant application (transport of bilious acids in a iliococcygeus gut), chosen of 1,2,5-benzothiadiazines in treatment and-or prevention of coprostasia at warm-blooded animals, such as the person (versions), corresponding method of treatment and a pharmaceutical composition is described.

EFFECT: increase in quantity of excrements at the expense of strengthening of impellent function of intestines, increase in quantity of water in its bottom part content, softening of the content and decrease in a stretching of walls of intestine, reduction of feeling of pain.

16 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: method involves giving patient to drink 100 ml of lactulose syrup with 250 ml of liquid at the day before examination. 2-3 h later, intestinal lavage is carried out with 10-15% aqueous lactulose solution being prepared as 100 ml of the syrup diluted with water to volume of 1 l, giving 250 ml to drink every 15 min. Next day, intestinal lavage is carried out with 1 l of aqueous polyethylene glycol solution 3-4 h before performing examination.

EFFECT: enhanced effectiveness in cleaning large intestine with smaller volume drugs consumed; improved aged patient tolerance to the procedure.

FIELD: medicine, pediatrics, gastroenterology.

SUBSTANCE: it is necessary to carry out complex therapy of the disease in question and ozonotherapy of the lower department of large intestine. Moreover, 2 h before ozonotherapy one should additionally introduce motilac at the dosage of 2.5 mg for 10 kg/d. Ozonotherapy should be carried out with an ozonator "Ultraton-AMP" due to rectal introduction of a gas-discharge cylindrical electrode for the depth of about 4-6 cm. This procedure should be fulfilled daily at power of 3 W. Impact duration should be prolonged from 5 min up to 10 min. The course lasts for 10 d. The innovation in question provides increased circulation of gastro-intestinal tract and enhanced therapeutic impact of motilac and, as a result, rapid interruption of pain syndrome, inflammatory rectal process and the absence of relapses during 6 mo.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, fitotherapy.

SUBSTANCE: claimed method includes administering of medicative herb powder for 5 days daily from 11 o'clock with 2 h interval. The first composition contains horsetail sprouts, hawthorn flours or fruits, bluebottle, chicory, cowberry leaves, green tea leaves, elecampane, tutsan, hyssop roots and/or leaves, and/or inflorescence. The second composition contains cranberry leaves, nettle leaves, maize stigma, burdock roots, coltstoof leaves and rootstocks, carrot seeds, blowball leaves and inflorescence. The third composition contains buckthorn, parsley, tansy flowers, goosegrass leaves. The forth composition contains sagebrash, motherwort, camomile, milfoil grass, senna leaves. The fifth composition contains milfoil grass, senna leaves, blueberry leaves, cinnamon rose fruits. Then 50-100 g of oily balsam prepared g of refined vegetable oil and 14 g of power of 5 plant composition is administered. In evening of fifth day mixture from juice of 3 lemons, 5 grapefruits, 2 oranges and garlic head, glass of squash cranberry and parsley is diluted with silica water up to 3 l, filtered and administered during the sixth day in amount of 100 g after 30 min. During 7th and 8th days flax seed tea is administered 9-10 times in amount of 100 g after 30 min.

EFFECT: improved method for body healing.

8 cl, 5 ex, 1 tbl

FIELD: medicine, pharmacology, organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) promoting the defecation. Also, invention relates to a pharmaceutical composition containing these compounds and a method for promoting defecation and a method for treatment or relief of constipation. Proposed compounds possess the enhanced effectiveness.

EFFECT: valuable medicinal properties of pharmaceutical composition.

14 cl, 11 tbl, 55 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the development of a novel vegetable-base agent that can be used in treatment of inflammatory diseases of small pelvis organs and diseases of rectum. Agent used in prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum comprises long turmeric (Curcuma longa L.) rhizome dried extract standardized by curcumin, anesthetic agent and pharmaceutically acceptable excipients. Agent is made as a suppository and comprises benzocaine as an anesthetic agent and vitepsol and cacao butter as a suppository base. Method for preparing agent used in prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum involves mixing long turmeric dried extract standardized by curcumin with anesthetic agent and a pharmaceutically acceptable excipient. Method for prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum involves using the proposed agent.

EFFECT: improved preparing agent, valuable medicinal properties of agent.

9 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: pharmaceutical industry, in particular antacidal and purgative tablet.

SUBSTANCE: claimed tablet for peroral administration contains particles of magnesium oxide as active ingredient, wherein 1) magnesium oxide particles containing in tablet, have average secondary size measured by laser IR-scattering of 0.5-10 mum; 2) tablet contains 99 mass % or more of magnesium oxide particles: 3) tablet is not blacked and essentially has no spots formed in pelletization process; and 4) tablet disintegration time is 10 s or less.

EFFECT: tablets with high content of magnesium oxide particles and short disintegration time.

12 cl, 6 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a purgative agent composition comprising bicyclic compound of the formula (1) and a method providing the purgative effect and using compounds of the formula (1). He composition possesses the enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

42 cl, 3 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention belongs to polymeric container for storage of prostaglandin F2α derivate aqueous preparation. Derivate has at least one fluor atom in its molecule. Polymeric container is made of propylene/ethylene copolymer in which propylene/ethylene ratio varies from 94.0/6.0 to 99.5/0.5. This container provides long time storage of prostaglandin F2α derivate liquid aqueous solution.

EFFECT: long time storable in aforementioned polymeric container product is offered.

5 cl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: in early after-burn period, with underlying antiinflammatory, antibacterial and trophic treatment, additionally alprostadil in single dosing 40 mcg dissolved in 200 mg of physiologic saline is introduced intravenously drop-by-drop within 2 hours.

EFFECT: method allows for conventional and effective treatment of burns of the conjunctiva ensured by effect of alprostadil on pathogenic links of the burn disease.

3 ex

FIELD: medicine.

SUBSTANCE: therapy of the patients suffering from chronic lower limb ischemia involves sampling the autogenic blood cell mass in amount 6-8% of total blood volume by discrete plasmapheresis. Then the autogenic cell mass is incubated with pentoxifylline 10 ml during 20 min at room temperature with ATP 2 ml added. The prepared mass is reinfused to the patient. Thereafter, Vasaprostan is introduced in a dose 40 mkg/day with physiologic saline 200 ml as intravenous infusion during 3 hours. Therapeutic course is 10-15 daily procedures.

EFFECT: higher clinical effectiveness with regard to the pathology due to correction of hemodynamic disorders in an ischemic focus and improvement of rheological properties blood in the absence of absolute indications to surgical procedure or inability thereof.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely surgery, and can be used for treatment of chronic arterial lower limb ischemia. It is ensured by mixing preparation Vasaprostan 20 mkg and human albumin 10% 100 ml. The mixture is incubated in a thermostat within 20 min at temperature 37°C and then slowly introduced to a patient intravenously drop-by-drop within 2-3 hours, once a day. Therapeutic course is 10 days.

EFFECT: incubation of Vasaprostan and albumin in a developed mode provides binding with protein and prolongation of therapeutic effect that in turn allows improving clinical effectiveness with decreasing therapeutic dose of the preparation.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, therapy. The way includes blood sampling and its centrifugation. Then allocation of erythrocyte fraction and plasma removal is carried out. An angiotropic medicinal substance in quantity of an average therapeutic dose on each 200 ml of erythrocyte fraction is administered into the allocated fraction. Then irradiation with low-intensity helium-neon laser radiation with 1.2 mW power within 20 minutes is performed. 100 ml of a normal saline solution on each 200 ml is added in erythrocyte fraction and returned within 1.5-2 hours. The way increases efficiency of treatment at the expense of including activisation of an angiotropic preparation in erythrocyte cells at a laser irradiation of packed red cells.

EFFECT: increase of treatment efficiency at the expense of including activisation of an angiotropic preparation in erythrocyte cells at a laser irradiation of packed red cells.

2 cl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to ophthalmology. Invented is a composition for reducing intraocular pressure, treating glaucoma or ocular hypertension, containing from 0.005 to 0.02 wt %/ bimatoprost mass and from 100 mln-1 to 250 mln-1 benzalkonium chloride, where the said composition is a water based liquid, with content suitable for application into eyes. Invented also is a method which is useful in treating glaucoma or related ocular hypertension.

EFFECT: reduction of active component in the composition while retaining effectiveness of the composition and design of a method of its application for reduction of intraocular pressure when treating glaucoma or ocular hypertension.

17 cl, 5 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly orthopedics and extracorporal treatment methods, and can be applied in aseptic whirlbone necrosis and Perther disease treatment. Method involves venous blood sampling in amount of 300 ml with further blood separation into erythrocyte mass and plasma. Obtained erythrocyte mass is diluted by 200 ml of 0.9% physiological solution and administered intravenously to patient. 100 ml or patient's plasma is placed in thermostat and incubated for 20 minutes at 37°C. Further 20 mg of vasoprostan medicine is added to incubated plasma, and obtained mix is administered to patient by drop infusion for 1.5-2 hours once a day for 10 days.

EFFECT: enhanced efficiency of the pathology treatment due to vasoprostan binding to plasma proteins and prolonged vasoprostan circulation in blood, resulting in arterial blood circulation improvement, venous stasis blocking in aseptic necrosis zone and significant acceleration of whirlbone acceleration.

2 tbl, 2 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly vascular surgery, and can be applied in treatment of critical lower extremity ischemia. Method involves sampling of 400-500 ml of blood from vein. Blood is centrifuged for 15 minutes at 2000 rpm rate. Separated erythrocyte mass is dissolved by 200 ml of 0.9% physiological solution and returned to patient intravenously. 20 mcg of vasaprostan medication is added to 200 ml of plasma. Obtained mix is placed in thermostat and incubated for 20 minutes at 37°C, then injected to patient slowly by intravenous drop infusion for 2-3 hours once per day for 10 days.

EFFECT: elevated peripheral arterial pressure, ischemia grade regress, resulting in larger pain-free walking distance.

1 tbl, 2 ex

FIELD: medicine; phlebology.

SUBSTANCE: to treat chronic indolent trophic ulcers of different genesis, chloroquine is administered during 4 weeks: by 0.5 g during first and second week, and by 0.25 g during third and fourth week. Additionally, prednisolone is injected by 10-15 mg during first and second week, then dose is reduced by 2.5 mg every week until the drug is repealed; as well, vasoprostane intravenous infusion is conducted by 20 mcg in physiologic solution, twice a day, during 10 to 20 days.

EFFECT: effective treatment for chronic indolent trophic ulcers of different genesis due to tissue perfusion increase, humoral and cellular regulating mechanisms activation by complex medicines action.

3 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine area, in particular to ophthalmosurgery. Viscoelastic contains methyl cellulose as a basis, the benzalkonium stabiliser sodium chloridum, Latanoprost and the phosphatic buffer at a certain parity of components. Usage of viscoelastic effectively protects intraocular tissues at intraocular interventions from injuring consequences of surgical manipulations, prevents increase of intraocular pressure in the postoperative period and serves for prevention of the postoperative hypertensia caused by longtime location of polymer in the anterior chamber.

EFFECT: protection of intraocular tissues at intraocular interventions from injuring consequences of surgical manipulations, prevention of increase of intraocular pressure in the postoperative period and prevention of the postoperative hypertensia caused by longtime location of polymer in the anterior chamber.

2 ex

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

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