Method of obtaining of agent possessing diuretic and anti-inflammatory activity

FIELD: medicine; pharmacology.

SUBSTANCE: perform extraction by the water purified using the method of fractional maceration of the dried up leaves of garden wild strawberry - Fragaria ananassa, this. Rosaceae which crush till the sizes of particles from >1.0 mm to ≤3 mm. Perform extraction three times for 30 minutes in the ratio 1:10 (raw materials - extracting agent), in a reactor from stainless steel with a false bottom capacity of 100 l, supplied with an anchor mixer, a steam shirt and a sleeve for the thermometer. Aggregate the water extractions. Clearing of incorporated water extraction is performed by filtration through the druk-filter and separation. Evaporation of the incorporated water extraction is performed in circulating vacuum-evaporating device to 0.1 of the initial volume. Drying is performed on the spray-type dryer.

EFFECT: invention allows to realise the specified method.

8 tbl, 1 dwg

 

The invention relates to medical and pharmaceutical industry and can be used in medicine for the development of drugs with diuretic and anti-inflammatory activity.

One of the urgent problems of medical science and practical health care is the prevention and treatment of diseases of the urinary tract, which in prevalence in second place after ARD in Russia. For such diseases are often chronic in nature and require long-term use of medications. The social significance of this problem is due to a wide spread and severity of disease. In this regard, the search and development of new safe and effective drugs and substances from vegetable raw materials with low toxicity, is an important task.

Among the plants that are widely used in science and medicine, the famous wild strawberry - Fragaria vesca. The leaves of this plant are used as antispasmodic, diuretic and tonic [Plant resources of the USSR. - Leningrad: Nauka. - 1987. - P.48-49].

A method of obtaining an aqueous extract of the leaves of the wild strawberry [the State register of medicines. - Moscow. - 2001. - S], which is used as a diuretic and SP is politicheskogo means, and also for the treatment of gall and kidney stones, gout. It is established that a 10%aqueous extract of the leaves of the wild strawberry increases diuresis, lowers blood pressure, changes the amplitude and frequency of contractions of the heart, dilates blood vessels [Konopleva M., Sadikov VK Pharmacological properties of the wild strawberry. / Modern aspects of theory and practice of pharmacy: Sat. scient. Tr. /The 1st Leningrad medical Institute n.a. Pavlov, - 1988. - S-148]. Also have hypoglycemic activity of extract from the leaves of the wild strawberry [Bubenikova V.N., I. Drozdova, Vorotyntseva NI Study of hypoglycemic activity of representatives of the genera of the mallow, the stock rose, strawberry. / Human health: Sat. scient. Tr., Kursk. - 2000, Issue 3. - S-332].

This way it is advisable to take for the prototype due to the presence of common operations, similar biological activity Botanical affinity raw sources.

The prototype has the following disadvantages:

low content of flavonoids, oxidizable substances and ascorbic acid is the main active substances of strawberry leaves (table 1);

- low diuretic activity of aqueous extracts and the absence of data on anti-inflammatory activity (table 5);

- lack of options standardization and quality control of infusion;

- on the found term storage of aqueous extracts (2 days).

The aim of the present invention is to increase the yield of active substances and the establishment of the anti-inflammatory action from a new natural source of biologically active substances from plant materials that have a sufficient resource base.

The objective is achieved by the fact that as a source of raw materials use leaves of strawberry - Fragaria ananassa L. the Air-dried leaves crushed to particle size of 3 mm and extracted with 3 times 30 minutes of purified water in the ratio of raw materials-extractant 1:10 in the reactor of stainless steel with a false bottom with a capacity of 100 liters, equipped with anchor stirrer, a steam jacket and liner for a thermometer. Water extract combine. Cleaning combined aqueous extracts performed by filtering through Druk air filter and separation. Evaporation of the United water extraction is carried out in a circulating vacuum evaporation apparatus to 0.1 volume. Drying is conducted to the spray dryer. The yield is 20% by weight of vegetable raw materials.

The parameters of standardization of the final product

The content of oxidizable substances, ascorbic acid, humidity determined by the methods GFH [State Pharmacopoeia of the USSR. - XI ed. - M.: Medicine. - Vol. 1, 2 (1987, 1990)].

Analysis on the content of flavonoids

Qualitative detection

To 0.5 ml of a solution of a substance (RAS is a thief), obtained to quantify, add 1 ml of a 5%alcohol solution of aluminum chloride; appears yellow staining.

The UV spectrum of the solution B, prepared for the quantitative determination, in the region of from 380 to 450 nm has a maximum absorption at a wavelength of 405±2 nm (see drawing).

Quantitative determination of flavonoids

About 0.15 g (accurately weighed) of dry extract is placed in a volumetric flask with a capacity of 50 ml, dissolved in 25 ml of purified water (70°C)bring to the mark with water and mix (solution A).

2 ml of the solution And placed in a volumetric flask with a capacity of 25 ml, add 5 ml of a 5%alcohol solution of aluminum chloride, 1 ml of 3%acetic acid and adjusted to 70%alcohol to the mark (solution B).

Measure the optical density of solution B over 30 minutes using a spectrophotometer at a wavelength of 405 nm in a cell with a layer thickness of 10 mm

As the reference solution using solution consisting of 2 ml of solution a and 1 ml of 3%acetic acid, brought to the mark with 70%alcohol in a volumetric flask with a capacity of 25 ml

In parallel under the same conditions to measure the optical density of a solution containing 1 ml of 0.05%solution of rutin, prepared similarly to the subject an solution.

As the reference solution using 1 ml of 0.05%solution of rutin and 1 ml 3%acetic acid, brought up to the mark 70%ethanol in a volumetric flask with a capacity of 25 ml

The content of total flavonoids rutin in substance in percent (X) is calculated by the formula:

where D is the optical density of the test solution;

D0- the optical density of the solution, working standard sample routine;

m0exact mass routine, taken for solution preparation of working standard sample, g;

m - the exact weight of the drug, g;

W is the loss in weight on drying substance, %.

Found 5,12±0,17%

The proposed method for simple and allows to obtain a product of constant composition. The way to get approved by OJSC "Biochimmash" in Moscow and can be implemented at the enterprises for manufacture of medicinal drugs.

To prove the materiality of the proposed signs studied the influence of the method of extraction, the nature of the extractant, the degree of grinding of raw materials, temperature, frequency and duration of extraction on the output BAS of investigational medicinal plants.

Quantitative evaluation was carried out according to the output amount of flavonoids (rutin standard), the amount of oxidizable substances and ascorbic acid.

Selection of optimal conditions for obtaining extraction was conducted on the combined sample of leaves earthlings the key garden varieties "festival", "Daisy festival", "Found", "Fairy", "Ruby pendant, harvested in the territory of the Plant "Savina" Perm region June 16 and August 20, 2002

The nature of the extractant used for the extraction of biologically active substances, plays a significant role. Properly selected extractant increases the speed and completeness of extraction of compounds from plant material. In addition, you must focus on a number of biologically active substances and their pharmacological efficacy.

Extraction was performed using purified water and ethyl alcohol in various concentrations by heating the flask on a water bath under reflux for 1 hour.

From the table 2 data shows that the maximum number of flavonoids moves in 40% alcohol, the amount of oxidizable substances in water at 70°and the output of ascorbic acid does not depend on the nature of the extractant. As the optimal extractant we chose water as it better go oxidizable substances, ascorbic acid and other water-soluble components (glycosides of flavonoids, polysaccharides, minerals, amino acids).

It is well known the influence of particle size of the raw plant material to the intensification of the extraction process and the yield of biologically active substances. The result is e grinding significantly increases the specific surface of the processed material, due to the increasing speed of extraction. With decreasing particle size of medicinal plants is increasing the number of damaged cells, from which substances quickly extracted by simple washing. To study the effect of particle size of raw materials to the intensity of the extraction process, we used the leaves of the strawberry. Raw material crushed in the laboratory to a size of 7 mm, 5 mm, 3 mm, 2 mm, 1 mm, Results of the analysis are shown in table 2.

The results of the analysis showed that the maximum yield of biologically active substances is observed when the particle size of raw materials 3 mm Grinding less than 3 mm leads to poor wettability of raw materials and ultimately slows down the extraction process. When using a large powder extraction study of biologically active substances is reduced (the amount of flavonoids rutin from 0.21% to 0.11%, the amount of oxidizable substances from 23.2% to 21.4%, of ascorbic acid with 184,7 mg % to 164,7 mg %)becomes long, resulting in removing a large number of related substances and adsorption valuable BAS meal.

Was studied the dependence of the output amounts of the flavonoids rutin, the amount of oxidizable substances and ascorbic acid by extraction with purified water in different ratios to the amount of raw materials. The results of the analysis provide the Lena in table 2.

The experimental data presented in the table indicate that the maximum yield of biologically active substances is observed when the ratio of raw materials-extractant 1:10 for a single Bay of raw materials. Further increase in the volume of the extractant is impractical because not achieved the efficiency of extraction, because there has been no increase in the yield of extracted substances.

It is known that increasing the temperature of the extractant increases the speed of the process of extraction of biologically active substances. Data reflecting the dependence of the yield amounts of flavonoids, the amount of oxidizable substances and ascorbic acid on the temperature of the extractant, is presented in table 2.

The results of the analysis showed that with increasing temperature of the extractant increases the output amounts of flavonoids, the amount of oxidizable substances and ascorbic acid and most complete recovery is achieved when the temperature of the extractant 75°C. Considering that medicinal plant raw materials are thermolabile substances, heated above 80°inappropriate.

To determine the duration and the ratio of the number of extraction was studied while the equilibrium concentration in the system raw material:extractant (table 3). For this sample plant materials were drawn with purified water (80� (C) in a ratio of 1:10 under stirring for 30 minutes. The process was repeated three times, pouring raw new portion of the extractant in the amount equal to the slit extraction. The completeness of the extraction was carried out by the method of chromatography was carried out on paper. Every 15 minutes during each of the contact phase was collected 30 ml for quantifying the amount of flavonoids rutin, the amount of oxidizable substances and ascorbic acid.

The equilibrium state of the system is achieved through 30, 30 and 30 minutes at 1, 2 and 3 contacts phases, respectively.

When used in the extraction process all selected us optimal conditions achieved a fairly high yield of biologically active substances. The results are presented in table 4. The results of the analysis indicate that when triple extraction in an aqueous extract of the leaves: the amount of flavonoids rutin - 98%, the amount of oxidizable substances - 99%, of ascorbic acid 86% of the initial content in raw materials.

Optimal conditions were the basis of the extraction process.

Way to obtain is illustrated by the following example: 6 kg leaf strawberry crushed to particle sizes of raw materials 3 mm, are placed into the reactor through the upper hatch, fill it with water purified in the ratio of raw material and solvent of 1:10 and taking into account the coefficient vodopad is osenia raw materials.

Extracted under stirring at a temperature of 80±5°C for 30 minutes. The first extract is drained, simultaneously filtering, dipstick and guide the next stage of the process.

In a similar way to spend two more extraction 30 and 30 minutes, giving each time in the reactor water clean in the amount equal to the amount drained extract.

The obtained extract combine, filter and served in circulation vacuum apparatus for parki. Oparka carried out at the temperature of the reaction mass to 60±5°C and a pressure of 0.01 kgf/cm2(9,81 hPa) to approximately 1/10 of the initial volume. As a result, parki get 10 litres of water VAT residue (density 1,043 g/cm3). One stripped off the extract purified by separation. Get the purified extract (density 1,043 g/cm3and sediment ballast substances in quantities of 0.005 kg, which is not used. The purified extract is dried in the spray dryer "Niro Atomazer" (Denmark).

The aqueous extract is fed to the spray dosing pump and atomized into small droplets. Dehumidification occurs due to contact with hot air coming into the camera. Next, the powder together with the air enters the cyclone high performance, where the separation of the powder from the air and collecting it in a container. Mode of operation: tempera is ur air inlet - 130-140°C, the outlet temperature is 70-80°C. the feed Rate of the mixture to 2.0 to 2.5 l/h, pressure of compressed air to 5.2 kgf/cm2(0,52 MPa).

Get the dry weight of 1.2 kg, which is 20% of the mass of absolutely dry raw material. The loss in weight on drying of 3.4%.

The dry extract is a powder from yellow-green to brownish-green color with a faint odor and a bitter, slightly astringent taste. The content of flavonoids - 5,12±0,17%, oxidizable substances - 82,3±8,5%, ascorbic acid - 1,1±0,12%, humidity - 3,5±0,3%.

Diuretic activity

Diuretic activity was investigated at 24 outbred rats of both sexes weighing 220-280 g Rats during the day before the experience was deprived of food and water. Water load carried per os just before experience of 25 ml/kg of the urine produced after 5 and 24 hours after the water load [hazura V.V. Methods of primary pharmacological studies of biologically active substances. / Resources affecting diuresis. - M, - 1974. - C-105]. The study drugs were administered per os at a dose of 150 mg/kg

As a result of the experiments revealed that in control animals after 5 hours after water load diuresis was 2.4 ml, and in a day and 2.9 ml. of Increase of diuresis for 19 hours was not.

Infusion of wild strawberry in a dose of 150 mg/kg showed diuretic action is selected. This is evidenced by the increase in urine output in 24 hours, and the increase in the volume of urine for 19 hours at 1.7 ml (table 5), which corresponds to literature data [Konopleva M., Sadikov VK study of the diuretic action of phenolic compounds in strawberry. / Circulatory failure. - L., 1986. - S-177]. It should be noted that the infusion of wild strawberry has not changed a five-hour urine output.

Extract strawberry dry at a dose of 150 mg/kg had a diuretic effect, which is manifested by increased urine output in 24 hours, and the increase in the volume of urine for 19 hours 2.9 ml (table 5). Extract strawberry dry also not changed a five-hour urine output.

Thus, the extract from the leaves of the strawberry dry increased daily diuresis by 75.9%, while the infusion of the leaves of the wild strawberry only 31.0%.

Anti-inflammatory activity

Anti-inflammatory activity was determined in 18 rats of both sexes weighing 220-280 g Animals were kept on a normal diet. Investigational drugs strawberry leaves forest - infusion (official drug) and garden - dry extract (promising substance) was administered at a dose of 150 mg/kg orally one hour prior modeling carragenine inflammation. Carrageenophyte swelling caused subplanetary the introduction of the 0.1% solution carragenine [Methodical recommendations for the study of the new non-steroidal drugs. /Guidance on experimental (preclinical) study of new pharmacological substances. - CJSC "JJA "Remedium", 2000. - P.236]. About anti-inflammatory activity was assessed by the change in the severity of inflammation in the dynamics. Inflammatory edema was detected ecometrics after 3 and 5 hours after modeling inflammation. Control rats were injected equiano amount of solvent.

Infusion of leaves of wild strawberry in the tested dose had no significant influence on the development and course of carragenine inflammation (table 6).

The leaf extract of strawberry dry at a dose of 150 mg/kg showed anti-inflammatory activity. This is evidenced by significant inhibition of inflammatory edema at 3 and 5 h of observation.

Comparison of severity of anti-inflammatory activity of leaf extract of strawberry dry and indometacin (functional equivalent) showed that the herbal drug is not inferior to a typical non-steroidal anti-inflammatory agent.

Statistical processing of data of pharmacological experiment was performed by student's criterion. The effect was considered significant at p≤0,05 [Belenky, M. elements of a quantitative evaluation of the pharmacological effect. 2nd ed., HP: the Medical literature, 1963].

Acute toxicity

Acute toxicity was determined on two VI the Ah Mature laboratory animals: 150 mice (males and females with weight 18-20 g) and 90 Wistar rats of both sexes weighing 160-180 g The animals were kept on a normal diet, before chronic experiences were clinically healthy. Dry extract from the leaves of the strawberry was introduced in the form of a 5-10% aqueous suspensions prepared ex tempore in volume 0,3-10,0 ml per animal. The duration of observation of the animals was 14 days. In the experiment, followed by behavior, appearance, motor activity, reaction of animals to external stimuli. The clinical presentation of acute poisoning in laboratory animals registered with the introduction of the extract in doses close to srednesemennyh. Determination of the toxicity parameters in a single laboratory animals was carried out using the method of Dahmane and Les Blank with indicative sredneseriynoe dose [Arzamastsev E.V. et al. (1973)] and the method of probit analysis according to Litchfield and Wilcockson [Belenky, M. elements of a quantitative evaluation of the pharmacological effect. 2nd ed.. L.: the Medical literature, 1963]. Intraperitoneal injection of the extract from the leaves of the strawberry dry the male mice in the dose range of 700-1000 mg/kg of body weight after 5 minutes was noted symptoms of Central nervous system: anxiety, motor excitement; after 10-15 minutes grooming, hyperemia of the vessels of the ears and tail, "cramps". After 20 minutes, shortness of breath, after 30 minutes it was reduced physical the activity, lethargy. The death of individual animals registered on the following day after administration of the extract. Intraperitoneal administration of the extract to mice females picture of acute intoxication were consistent with that described above in males, but was manifest from the introduction of a few large doses of the substance.

Intraperitoneal administration of the studied extract to rats of both sexes at doses of from 1100 to 2000 mg/kg caused concern, motor excitation, after 15-20 minutes, the blood vessels of the ears and tail, after 30 minutes grooming, shortness of breath, "cramps". 40-50 minutes it was reduced physical activity and sleep. The death of individual animals registered on the following day after administration of the extract.

Intragastric administration of the studied extract to mice (males and females) in doses up to 8000 mg/kg caused them to decrease motor activity, anxiety, therasense, after 15-20 minutes - shortness of breath, cyanosis of the ears and tail. The death of mice registered on the third day after the introduction of the dry extract.

After a single intraperitoneal administration of the extract from the leaves of the strawberries dry mice and rats males and females set the following parameters: LD50: 850±70 and 1500±120 mg/kg (males); 1008±105 and 1900±180 mg/kg (females), respectively. With the introduction of the extract from the leaves of the strawberry dry in the RCU mice and rats indicators srednesemennyh doses increase on the average 5-7 times and are respectively equal to: 6000± 570 and 7200±600 mg/kg (males); 7400±530 and 9200±850 mg/kg (females), respectively.

After intragastric administration of the extract of strawberry leaves dry rats of both sexes at doses up to 10,000 mg/kg, was observed symptoms of poisoning similar to that described in mice, but they came in later observations and from the introduction of large doses. Table 7 presents the parameters of the toxicity of the extract of strawberry leaves dry in a single laboratory animals. Analysis of the results shows that after a single intraperitoneal administration of the investigated extract mouse was more sensitive laboratory animal species to the action of the substance of the drug compared with rats. Males showed greater sensitivity to the extract as compared with females.

Thus, the extract of wild strawberry dry in a single laboratory animals can be attributed to toxic substances.

Chronic toxicity

Chronic toxicity was determined in 45 rats male Wistar rats weighing 200-220, the Animals were kept on a normal diet, before chronic experiences were clinically healthy. Dry extract from the leaves of the strawberry animals were injected intragastrically, a probe in the form of 2-10% aqueous solutions prepared immediately before introduction, the volume is 1.5 to 5.0 ml in the rat at doses 72 and 720 mg/kg, once a day for 3 months [Manual on experimental (preclinical) study of new pharmacological substances, M., 2005, p.41-122]. During the experiment, rats were noted General condition, physical activity, appetite, dynamics of body weight, coat condition, response to external stimuli. After 1 and 3 months after the start of injection of the extract in animals conducted a study of hematological parameters of peripheral blood: the total number of erythrocytes, leukocytes, platelets, hemoglobin, hematocrit, mean hemoglobin in the erythrocyte, the average concentration of hemoglobin in the erythrocyte, the average volume of erythrocytes distribution width red cell volume, hemo-grams; biochemical indices of blood serum: total protein, albumin, total cholesterol, total bilirubin, urea, glucose, creatinine, as well as the activity of some enzymes in the blood serum: alkaline phosphatase, alanine and aspartaminotransferazy. At the end of 1 and 3 months were determined by the state of the cardiovascular system of rats on the electrocardiograph, Heart Mirror". On renal function of rats was judged by the results of diuresis in conditions 3% water load, and the Central nervous system - on behavioral tests and estimated responses in the "open field". After 3 months of the introduction of animal extract the x were subjected to euthanasia in CO 2the camera. They determined the coefficients of mass and performed the histopathological examination of the internal organs. Extract from strawberry leaves dry, had no General toxic effects and does not irritate the mucous membranes of the gastrointestinal tract of experimental animals.

As shown, the extract from the leaves of the strawberry dry possesses self-diuretic and anti-inflammatory action, and is superior to similar plant origin (infusion of leaves of the wild strawberry) and not inferior to the intensity of the pharmacological effect of a typical non-steroidal anti-inflammatory agent (indomethacin). Phyto has no acute or chronic toxicity. Identified pharmacological properties of a new herbal drug, derived from a new type of raw material (leaves of strawberry), indicate the availability of this raw material as a source of various dosage forms and their implementation in the Arsenal of effective medicines of natural origin for the treatment of diseases accompanied by swelling and inflammation.

Comparative characteristics of the claimed method with the selected prototype is presented in table 8.

The proposed method is compared with the known allows you to obtain the product of constant composition is higher diuretic activity in combination with an anti-inflammatory effect by increasing the content of active substances; allows you to control the technological process of getting and standardize the target product; allows you to get a drug that is convenient for storage and transport.

The foregoing advantages, in combination with the proposed scheme of obtaining contribute to rational way of using medicinal plants, the expansion of the range of natural medicines with diuretic and anti-inflammatory activity and offer the prospect of implementation of this method in the pharmaceutical industry.

Literature

1. Belenky, M. elements of a quantitative evaluation of the pharmacological effect. 2nd ed., HP: the Medical literature, 1963.

2. Bubenikova V.N., I. Drozdova, Vorotyntseva NI Study of hypoglycemic activity of representatives of the genera of the mallow, the stock rose, strawberry. / Human health: Sat. scient. Tr., Kursk. - 2000, Issue 3. - S-332.

3. Hazura V.V. Methods of primary pharmacological studies of biologically active substances. / Resources affecting diuresis. - M, - 1974. - S-105.

4. The state register of medicines. - Moscow. - 2001. - S.

5. State Pharmacopoeia of the USSR. - XI ed. - M.: Medicine. - Vol. 1, 2 (1987, 1990).

6. Konopleva M., Sadikov VK study of the diuretic action of phenolic compounds in strawberry. / Failure bravobride the Oia. - L., 1986. - C-177.

7. Konopleva M., Sadikov VK Pharmacological properties of the wild strawberry. / Modern aspects of theory and practice of pharmacy: Sat. scient. Tr. / The 1st Leningrad medical Institute n.a. Pavlov, - 1988. - S-148.

8. Methodical recommendations for the study of new non-steroidal drugs. /Guidance on experimental (preclinical) study of new pharmacological substances.- CJSC "JJA "Remedium", 2000. - P.236.

9. Plant resources of the USSR. - Leningrad: Nauka. - 1987. - P.48-49.

10. Manual on experimental (preclinical) study of new pharmacological substances, M., 2005, p.41-122.

Table 1

The quality indicators of leaves and preparations strawberry
Drugs strawberryFlavonoids, %Oxidizable substances, %Ascorbic acid, mg %Humidity, %
The leaves of the strawberry2,5±0,4031,2±8,5291,2±8,17,56±0,5
The aqueous extract of 1:100,21±0,0323,3±3,23 184,66±8,7-
Dry extract (extractant water)5,12±0,1782,3±8,51100±20,63,5±0,3
Table 2

The content of biologically active substances in the extract from the leaves of the strawberry depending on the investigated factor
FactorThe content of BAS
the amount of flavonoids rutin, %The amount of oxidizable substances, %Ascorbic acid, mg %
The extractantwater0,21±0,0323,27±3,23184,66±8,72
alcohol 10%0,27±0,0219,31±2,10178,55±7,98
alcohol 20%0,38±0,0316,58±2,60179,8±8,23
alcohol 30%0,52±0,0214,95±3,10180,69 8,13
alcohol 40%0,79±0,0311,99±2,70182,58±8,55
The particle size of raw material, mm7,00,11±0,0321,4±0,9164,7±8,7
5,00,8±0,0428,2±4,5170,3±10,04
3,00,21±0,0325,2±3,2204,7±8,7
2,00,16±0,0120,6±5,9176,0±11,4
1,00,18±0,0820,8±1,08200,0±10,8
The ratio of raw material:extractant1:50,25±0,0218,38±2,9159,87±8,14
1:100,55±0,032,32± 3,2185,65±8,72
1:150,49±0,0221,45±2,7183,71±7,95
1:200,48±0,03to 22.35±3,1180,52±8,21
The temperature of extraction, °200,15±0,0315,85±3,0179,85±8,5
300,17±0,0217,90±2,8179,99±8,3
400,19±0,0318,85±2,7180,55±7,9
500,21±0,0219,95±2,9182,63±8,1
600,22±0,0321,05±2,7185,76±7,5
750,28±0,0325,38±2,9195,9ଘ,3
800,22±0,0226,45±3,2180,6±8,2

Table 6

Anti-inflammatory drugs leaves of the wild strawberry and garden
MedicationDose, mg/kgThe number of animalsThe inhibition of inflammatory edema, %
Infusion of leaves of the wild strawberry150610,5± and 4.98,7±3,5
The leaf extract of strawberry dry150636,9±3,5***1***240,9±3,3***1***2
Indometacin10630,2±2,4***1***252,1±2,6***1***2
Note: * p<0,05; ** p<0,01; *** p<0,001

***1- sravnenie the control

***2compared with infusion of the leaves of the wild strawberry
Table 7

Indicators of toxicity of the extract of strawberry leaves dry in a single laboratory animals
Species and sex of animalsRoute of administrationThe toxicity parameters, mg/kg
LD16LD50±mLD84
Mouse maleintraperitoneally670850±701240
Mouse femaleintraperitoneally8001008±1051600
Rats malesintraperitoneally11001500±1201800
Rat femalesintraperitoneally12001900±1802300
Mouse malein the stomach50006000±5707500
Mouse female in the stomach52007400±5308400
Rats malesin the stomach61007200±6008500
Rat femalesin the stomach71009200±85012000

Table 8

Comparative characteristics of the claimed method with the selected prototype
№ p/pOption compareThe known methodThe claimed method
1Vegetable raw materialsthe leaves of the wild strawberrythe leaves of the strawberry
2The extractantWaterwater
3Clean-filtration separation
4Concentration-evaporation of circulating vacuum evaporation apparatus
5Drying-in the spray dryer
6The yield of the target productOn the one dry extract 20%
7The content of BAS,%
- flavonoids0,215,12
- oxidizable substance23,382,3
- ascorbic acid0,181,10

The method of obtaining funds, possessing diuretic and anti-inflammatory activity, including extraction of plant materials the leaves of strawberry, crushed >1.0 mm to ≤3.0 mm method fractional of maceration water purified in the ratio of raw materials-extractant 1:10, in the reactor of stainless steel with a false bottom with a capacity of 100 liters, equipped with anchor stirrer, a steam jacket and sleeve for thermometer, at time 90 min infusion (triple maceration for 30 min); integration of water extraction, filtration, separation, evaporation of circulating vacuum evaporation apparatus, and drying in the spray dryer.



 

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22 cl, 2 tbl, 17 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, where Q represents optionally substituted with 1-3 substituents, determined in formula, phenyl or pyridyl or pyrodazinyl; R2 represents C1-6alkyl or aminogroup, determined in item 1 of formula or C1-6alkyl, substituted with said aminogroup; bond between oxygen atom O* and adjacent carbon atom C1 or (i) is double bond, which determines carbonyl group [C(=O)], where R6 represents C1-6alkyl or cyclopropyl; or (ii) represents simple bond, where, in case of simple bond, said oxygen atom O*, is in addition bound to group R6 and, taken together with R6 and with adjacent nitrogen atom, determines optionally substituted with C1-6alkyl, oxadiazolyl ring, bond between C1 and adjacent nitrogen atom being double bond.

EFFECT: obtaining medications which are useful in obtaining medications for treatment of conditions connected with p38 kinase and/or in obtaining medications for treatment of inflammatory diseases or conditions in patient.

8 cl, 6 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely described is bis{3-phenyl-1-[N-(3-pyridyl)carboxamido]-1,3-propandionato}cadmium, which has anti-inflammatory activity, of formula: .

EFFECT: obtainin compound with high output, which has expressed anti-inflammatory activity and low toxicity.

1 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: oral introduction of monoacetyldiacylglycerin derivatives detains development of hamster's induced cancer by activation of lymphocytes, monocytes and dendritic cells, as well as apoptosis induction of cancer cells owing to intensified cytotoxicity of immune cells in relation to cancer cells. Besides, induction of septic shock at mice is accompanied with shown 100% survival rate even in 120 hours, reached by immunity control and suppressing apoptosis effect. Monoacetyldiacylglycerin derivatives according to this invention can be effectively applied as agent for sepsis and cancer treatment and as healthy food preventing cancer or autoimmune diseases.

EFFECT: discovers application of monoacetyldiacylglycerin derivatives extracted from antler as agent suppressing cell abnormality resulted from autoresponse.

11 cl, 16 dwg, 11 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: novel chemical compounds of formula (I) or their pharmaceutically acceptable salts possess inhibiting activity with respect to kinase p-38 MAP and kinase FGFR, and can be used in treatment of such diseases as arthritis, obstructive lung disease, Alzheimer's disease or oncological and other diseases. In general formula (I) , R1 is hydrogen, R2 is 6-member oxygen-containing heterocyclyl, aryl, selected from unsubstituted phenyl or phenyl substituted with aliphatic acyl group which contains 1-6 carbon atoms, halogen cyano, hydroxyl, C1-6alkylsulfinyl, C1-6alkylsulfonyloxy, C1-6alkylsulfonyl, C1-6alkylsulfanyl, tret-butydimethylsilanyloxy, 6-member heterocyclyl, containing 1-2-heteroatoms, selected from nitrogen and oxygen, R3 is C1-6alkyl, Ar1 is phenyl, substituted with 1-2 substituents, selected from atoms of halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, X1 is oxygen and X2 is chemical bond.

EFFECT: efficient application of invention compounds in pharmaceutical composition.

13 cl, 1 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , in which Ra is H, CH3 or isopropyl, Rb is H, halogen, C1-6alkoxygroup or C1-6alkyl, and or I. R is radical of formula (b) , R4 is 1-pyperasinyl, substituted with CH3 in positions 3 and/or 4, Ra is not H or CH3, when R4 is 4-methyl-1-pyperazinyl; or III. R is remaining part of formula (c) , in which R14 is 1-pyperazinyl, optionally substituted with CH3 in position 3; or 4,7-diase-spiro[2,5]oct-7-yl, R15 is halogen, CF3 or CH3, R15 is not CH3, when R16 stands for CH3, Ra is H or CH3, Rb is H, and R14 is 4-methyl-1-pyperazinyl, and R16 is H, CH3 or CF3, R16 is not H, when R15 is Cl, Ra is H or CH3, Rb is H, and R14 is 4-methyl-1-pyperazinyl, or IV. R is radical of formula (d) , in which R8 is 1-pyperazinyl, 3- methyl-1-pyperazin-l-yl or 4-benzyl-pyperazin-1-yl, or V. R is radical of formula (e) , in which R9 is 4,7-diase-spiro[2,5]oct-7-yl or pyperazin-1-yl, substituted in position 3 with ethyl, or its salt, method of their production, based on them pharmaceutical composition and application for obtaining medication for treatment or prevention of T-lymphocyte and-or "ПКС"-mediated diseases or disorders.

EFFECT: increase of composition and treatment method efficiency.

12 cl, 5 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: nitroxy-derivatives or their salts of general formula (I) R-NR1c-(K)k0-(B)b0-(C)c0-NO2, where c0 represents 1; b0 represents 0; k0 represents 0 or 1; R represents radical of pain-killing agent of formula (II) where: W represents carbon atom; m represents integer from 0 to 1; R0=H or -(CH2)n-COOH, where n represents integer from 0 to 2; R2 with R1 and with W together form saturated ring C6; R1c represents H; K represents (CO); C represents two-valent radical, having formula -Tc-Y-, where Tc=(CO) or O; or Y can be: alkylenoxy group -R'O-, in which R' represents straight-chain or branched C1-C20alkyl, or group of formula where n3 represents integer from 0 to 5 and n3' represents integer from 1 to 3. Also described are pharmaceutical composition based on nitroxy-derivatives and their application as medications for chronic pain treatment.

EFFECT: useful biological properties of compounds.

8 cl, 3 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: means for treatment of chronic prostatitis contains the active substance including a complex of water-soluble peptides, allocated from prostate gland of livestock, and glycine in the ratio 1 : 2; the carrier including dimethyl sulfoxide and a softener, thus it is executed in the form of an ointment, the carrier contains an emulsive basis including softener, distilled monoglycerides and purified water, and in addition contains preservative.

EFFECT: organotropic action in relation to prostate gland, high biological availability and therapeutic effect, preservation of stability throughout long time.

4 cl, 3 ex, 2 tbl

FIELD: medicine; urology.

SUBSTANCE: after suppurative focuses surgical sanitation, and complex anti-inflammatory and antibacterial therapy conducting, biovestin is administered beginning from the first postoperative day, 2-3 doses daily 30 minutes before meal. The course lasts for 10 to 14 days.

EFFECT: optimal stimulation of all immune system components in short time due to certain probiotic selection for patient group in question.

1 ex, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to application of compounds according to formula 1 as a medicine in treatment for urinary bladder hyperactivity, and to pharmaceutical composition containing compound of formula 1 in treatment for urinary bladder hyperactivity.

EFFECT: invention allows mentioned purpose implementing.

20 cl, 10 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: agent for treatment of a senile incontience of urine represents water infusion of a grass bladder campion, obtained by digestion during 3 h. l. of the crushed grass with about 700 ml of water within 10 hours in warm place, thus the water temperature should be 80°C. The spent course of treatment by the declared agent shows positive therapeutic influence of the declared agent for treatment process.

EFFECT: agent does not possess a side effect and shows toning up influence on a bladder musculation.

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted indoles of general formula , where: X stands for -S(O)n-, -C(O)-; A stands for C1-C6alkyl, -(CH2)p-NRaRb; R1, R2, R3 and R4 each is independently selected from group including H, halogen, halogen(C1-C6)alkyl, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, NO2, -NRaRb, phenyl, benzyl and benzyloxy, said phenyl cycles are optionally substituted with substituent, selected from group including C1-C6alkyl, halogen, NO2, halogen(C1-C6)alkyl, C1-C6alkoxy; R5 stands for H, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy C1-C6alkyl, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, hydroxyl-(C1-C6)alkyl, hydroxy(C1-C6)alkylamino, halogen, halogen(C1-C6)alkyl-NRaRb, -NRc-( C1-C6)alkylene-NRaRb, or R5 and A together form radical C2-C3alkylene; R6 stands for H, C1-C6alkyl; R' and R" each independently stand for H, C1-C6alkyl; Ra, Rb and Rc each is independently chosen from group including H, C1-C6alkyl, hydroxy(C1-C6)alkyl, C2-C6alkenyl, C3-C6cycloalkyl-(C1-C6)alkyl, or Ra and Rb together with nitrogen atom, to which they are attached, form 5-7 member non-aromatic heterocyclic cycle, optionally containing in cycle O as additional heteroatom; m is equal 1 or 2; n is equal 0, 1 or 2 under condition that, if n is equal 0, R5 does not stand for NRaRb, and p is equal 0, 1 or 2; or their pharmaceutically acceptable salts.

EFFECT: obtaining compounds possessing agonistic activity which allows using them in pharmaceutical composition.

24 cl, 2 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention is referred to medicine, in particular, to therapy and cardiology, and concerns restoration of functional renal reserve. For this purpose define a functional renal reserve on rate of a glomerular filtration at an albuminous load and at augmentation of rate of a glomerular filtration to 10% enter an ACE inhibitor, and at decrease of rate of a glomerular filtration administer α1, β-adrenoblocker.

EFFECT: provision of effective restoration of functional renal reserve at patients with an essential hypertensia.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine. A soft drink on the basis of herbs consists of the concentrated vegetative extract obtained from an admixture of herbs, chosen of Sida sps., Boerhaavia diffusa, Vitis vinifera, Tinospora cordifolia and Withania somnifera, along with green palm sugar, the agent causing a fermentation, and carbonised water, in which proportion Sida sps.: Boerhaavia diffusa: Vitis vinifera: Tinospora cordifolia: Withania somnifera in a powdery admixture makes (15-20 : (5-10 : (15-20 : (5-10 : (5-10); Proportion of wt/wt: green palm sugar: the concentrated vegetative extract makes from 1 : 3 to 1 : 4; wt/wt, a proportion of carbonised water: the admixture of the concentrated vegetative extract, green palm sugar and the agent causing a fermentation, makes from 1 : 3 to 1 : 5. Perform: (a) obtaining of parts of Sida sps., Boerhaavia diffusa, Vitis vinifera, Tinospora cordifolia and Withania somnifera; (b) crushing of parts of plants and their mixing with obtaining of a powdery admixture; (c) water addition to a powdery admixture from a stage (b) for obtaining of a water extract; (d) concentration of a water extract from the stage (c); (e) filtration of the concentrated extract from the stage (d); (f) admixture of green palm sugar to the filtered extract from the stage (e); (g) addition of Sacromyces strain and the agent causing fermentation, to the admixture from the stage (f); (h) fermentation of the admixture from the stage (g) during the period of time from 3 till 6 days; (i) filtration of the fermented admixture from the stage (h); (j) concentration of the fermented filtrate from the stage (i) with obtaining of the basic solution and (k) mixing of the basic solution (j) with the carbonised water in wt/wt proportion from 1 : 3 to 1 : 5 with obtaining of a soft drink on the basis of herbs.

EFFECT: creation of a soft drink on the basis of herbs.

11 cl, 5 tbl, 8 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention concerns carboxylic acid compounds of the formula (I) , where R1 is hydrogen or C1-4alkyl; m is 2 or 3; n is 0-2; R2 is phenyl, naphtyl, benzofuran, benzothiophene; Q is -CH2-O-Cyc1, -CH2-Cyc2, -L-Cyc3, each of R3a and R3b radicals is independently a hydrogen, alkyl, or the R3a and R3b radicals together form tetrahydro-2H-pyran; pharmaceutically acceptable salts, method of obtaining them, and pharmaceutical agent including this compound as active component. Compound of the formula (I) displays antagonistic effect on PGE2 receptor, especially EP3 receptor, which is its subtype, and is applied in prevention and/or treatment of itching, pain, urination disorder or diseases caused by stress.

EFFECT: increased efficiency of compounds.

11 cl, 37 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: invention relates to urology and can be used in post-operation period in patients with acute purulent pyelonephritis. For this purpose patients undergo complex pharmacotherapy with antibacterial and anti-inflammatory medications. Additionally sessions of hypobaric hyperoxygenetion, 45-90 minutes each, with 0.85-0.9 ata and oxygen content in air 70-85% are prescribed. Sessions are performed daily; course consists of 5-7 sessions, starting with the first day of post-operation period.

EFFECT: ensuring stimulation of urodynamics and microcirculation in kidney parenchyma due to immunostimulating and bactericidal action of oxygen, as well as due to increase of lymphatic drainage during hypobaria.

1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new medical product possessing hemorheological and antiplatelet properties represents a dry extract preparation of Amur maackia.

EFFECT: arsenal expansion of the antiplatelet vegetative means, improving rheological properties of blood and an antiplatelet effect.

6 ex, 2 tbl

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