EA010427B1 - Preparation for the treatment of prostrate gland diseases - Google Patents

Abstract

The invention relates to medicine and pharmacology, in particular, to providing novel medicaments for the treatment of diseases of urogenital system.The inventive preparation for the treatment of prostrate gland diseases is manufactured as a suppository comprising a complex of bioregulating peptides of prostrate gland of cattle as powder comprising at least 20% of water soluble peptides, an antimicrobal agent, representing an antibiotic or an antiviral preparation, or an antiprotozoal drug, or a mixture of antiviral and antiprotozoal drug taken in 1:1 ratio and a base with the following component ratio, g per one suppository:Complex of bioregulating peptides of prostrate gland of cattle as powder comprising – 0.05-0.4Antimicrobal agent – not more than 0.7Base – sufficient amount for preparing suppository, mass 2.15-2.35 g.Any pharmaceutically acceptable base, e.g., vitepsol, solid fat, cocoa oil can be used as a base for preparing the proposed preparation.The tests have proved high level of organotropic activity and high level of antimicrobic action using said preparation as suppository.

Description

The invention relates to medicine and the pharmaceutical industry, in particular to the creation of new drugs for the treatment of diseases of the genitourinary system.

At present, diseases of the prostate gland occupy a significant place among urological pathology, tend to increase and acquire ever-increasing social significance.

Prostatitis is one of the most common urological diseases among men.

An important role in the development of prostatitis is played by previously transmitted or currently existing infections, which, in addition to involvement in the pathological process of the urethra, can complicate the course of the inflammatory process in the prostate.

Treatment of patients with prostatitis is aimed at eliminating the infection and normalizing the functions of the prostate gland. A comprehensive treatment program, as a rule, includes antibiotic therapy, therapy with drugs that improve vascular tone, physiotherapeutic procedures, restorative agents, as well as surgical intervention.

Currently, one of the promising areas in the treatment of prostatitis is the use of funds aimed at stimulating the nonspecific reactivity of the body, in particular the use of drugs of natural origin. For the treatment of prostatitis, herbal preparations (herbal medicine), enzymes and immunomodulators, in particular cytomedines, are used.

Cytomedins are peptides with a molecular weight of 1000-10000 Yes. They have the ability to restore the specific functions of those organs and tissues that are the source material for their production, which are disturbed as a result of the pathological process or aging.

The presence of immunomodelling properties in the peptides under consideration is essential.

In addition, cytomedins do not have molecular species-specificity, as a result of which the drugs obtained with their use do not have antigenic properties and, as a result, side effects, which makes it possible to relatively freely vary dosages and courses of treatment.

One of the representatives of the cytomedine class is bioregulatory peptides of the prostate gland of cattle (cattle) with a content of water-soluble peptides of at least 20%.

The pharmacological effect of the complex of bioregulatory peptides of the prostate gland of cattle allows the pathogenetic treatment of diseases of the prostate gland and functionally related organs, since bioregulatory peptides have an organotropic effect on the prostate.

The known compositions of various drugs containing a complex of bioregulatory peptides of the prostate gland of cattle.

One of such remedies is the Raveron preparation, which is an extract from the prostate gland of sexually mature animals, freed from androgenic and estrogenic hormones and proteins. The drug is used in the initial phase of prostate adenoma and in chronic non-specific prostatitis, is available as an injection. The disadvantage of this drug is a long course of treatment and with a tendency to allergic reactions, “Raveron” is contraindicated (Mashkovsky MD Medicines. M: Medicine, 1994, v. 2, p. 190).

A rectal agent is known for the treatment of prostatitis of various etiologies, containing as a biologically active substance liquid purified cattle prostate extract and excipients: gelatin, glycerin and sodium carbonate-bicarbonate buffer (RF patent 2152204 for “Rectal agent”). This drug helps to increase circulation and improve the outflow of secretion from the prostate gland in the correction of disorders accompanying any changes in blood circulation and trophic prostate gland, i.e., exhibits organotropic properties, but this drug does not solve the problem of eliminating the infection.

A rectal agent for the treatment of chronic prostatitis of various etiologies is also known, containing a complex of bioregulatory peptides of the prostate gland of cattle, which uses a concentrate of liquid purified extract of the prostate gland of cattle and a component with human α-interferon activity, a stabilizer and excipients: gelatin, glycerin and sodium carbonate bicarbonate buffer (RF patent 2160114 on "Rectal agent for the treatment of chronic prostatitis"). This drug is intended for the treatment of chronic prostatitis of various etiologies, proceeding against the background of immunodeficiency. The tool is a complex preparation containing two biologically active agents, which ensures its multifunctionality, but does not solve the problem of eliminating the infection.

The closest to the claimed tool for the combination of essential features is a drug for the treatment of prostate diseases "Vitaprost" (RF patent 2112504 for "Treatment for prostate diseases Vitaprost").

The known tool is a suppository containing a complex of bioregulatory peptides of the prostate gland of cattle in the form of a powder with a content of water-soluble peptides of at least 20% and a base. The tool has an organotropic effect on the prostate and is used to treat diseases of the prostate gland and organs functionally associated with it. but

- 1 010427 the level of organotropic activity of the drug is limited by the content in it of a complex of bioregulatory peptides of the prostate gland of cattle, which is due to the technological process. In addition, the tool does not have an antimicrobial effect.

The objective of the invention is the creation of a comprehensive drug in the form of a suppository for the treatment of diseases of the prostate gland, with a high level of organotropic activity and a high level of antimicrobial activity.

The technical result from the use of the proposed tool is to increase its organotropic activity and a significant increase in antimicrobial action, which allows the implementation of etiotropic and pathogenetic therapy of bacterial prostatitis.

The problem is solved by the proposed tool containing a complex of bioregulatory peptides of the prostate gland of cattle in the form of a powder with a content of water-soluble peptides of at least 20% and the base, according to the invention, it additionally contains an antimicrobial agent, which is an antibiotic or antiviral agent, or an antiprotozoal agent, or a mixture of an antibiotic and an antiprotozoal agent taken in a 1: 1 ratio, or a mixture of an antiviral and antiprotozoal agent taken in 1: 1 ratio, with the following ratio of components per candle: Complex of bioregulatory peptides of the prostate gland of cattle 0.05-0.4 g Antimicrobial agent not more than 0.7 g

The basis is a sufficient amount to obtain a suppository weighing 2.15-2.35 g

Preferably, the antibiotic is an antibiotic from the group of fluoroquinolones, for example, lomefloxacin, ofloxacin, or from the group of penicillins, such as amoxicillin, ampicillin, or from the group of cephalosporins, such as cefaclor, cefixime, or from the group of tetracyclines, such as doxycycline, tetracycline, sulfonamides, for example cotrimoxazole.

Preferably, as an antiviral agent, for example, ribavirin, lamivudine are used.

Preferably, as an antiprotozoal agent, an antiprotozoal drug from the group of nitroimidazoles is used, for example metronidazole, ornidazole, tinidazole.

It is preferable that any pharmaceutically acceptable base is used as a base, which makes it possible to obtain a suppository, for example Witepsol, solid fat, cocoa butter.

Introduction to the proposed tool at the same time a complex of bioregulatory peptides of the prostate gland of cattle and an antimicrobial agent allows you to get the tool in the form of a suppository with a high level of organotropic activity, an increase which is achieved, on the one hand, due to an increase in the quantitative content of the complex of bioregulatory peptides of the prostate gland of cattle, and on the other hand, due to the synergistic effect due to the fact that the antimicrobial agent accelerates the delivery of bioregulatory peptides cattle prostate gland to the affected organ, since the antimicrobial agent relieves edema and improves the rheological properties of blood;

with a high level of antimicrobial action, which is achieved, on the one hand, due to the introduction of an antimicrobial agent with bactericidal and bacteriostatic effects on a wide range of pathogens, and on the other hand, due to the synergistic effect due to the fact that the bioregulatory peptides of the prostate gland, improving microcirculation, neutrophic and immune processes in the tissues of the prostate, contribute to more effective absorption and enhance the action of antimicrobial agents.

Thus, the action of the proposed agent is complex, affecting both the pathogen and all pathological processes in the affected organ, which leads to an increase in the effectiveness of the treatment of bacterial inflammation of the prostate gland and organs functionally associated with it.

The content of therapeutic substances in the candle mass (2.15-2.35 g) was established experimentally. The content of the complex of bioregulatory peptides less than 0.05 g per suppository does not provide the required therapeutic effect.

The content of the complex of bioregulatory peptides of more than 0.4 g and an antimicrobial agent of more than 0.7 g complicates the manufacturing process of the suppository mass.

The method of obtaining the proposed tool.

Separately, concentrates of the complex of bioregulatory peptides of the cattle prostate are prepared in the form of a powder with a content of water-soluble peptides of at least 20% and an antimicrobial agent with part of the base, taken with a 1: 1 base. The resulting concentrates are mixed with the remaining base at a temperature of 38-40 ° C. The homogeneous mass is poured into the blister strip packaging from a polyvinyl chloride film and cooled, which subsequently allows to obtain suppositories that meet the requirements of the State Pharmacopoeia, XI ed.

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The following are examples of the manufacture of the proposed funds in the form of suppositories.

Example 1

The base - Vitepsol in the amount of 1.862 kg is melted at a temperature of 55-65 ° C with stirring. A complex of bioregulatory peptides of the prostate gland of cattle in the form of a powder with a content of water-soluble peptides of at least 20% in an amount of 0.596 kg is mixed with part of the molten witepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. Powder antibiotic - lomefloxacin in the amount of 1.042 kg is mixed with part of the molten witepsol taken in a ratio of 1: 1. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. The resulting concentrates are loaded into the remaining vitepsol with stirring until a homogeneous mass is obtained. The finished mass is poured into cells from a polyvinyl chloride film and cooled.

Get suppositories weighing 2.35 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle 0.4 g

Lomefloxacin 0.7 g

Basis Else

Example 2

Carried out analogously to example 1, but with the following amounts of components:

The complex of bioregulatory peptides of the prostate gland of cattle 0,081 kg

Lomefloxacin 0.813 kg

Base 2.606 kg

Get suppositories weighing 2.15 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle 0.05 g

Lomefloxacin 0.5 g

Basis Else

Example 3

Carried out analogously to example 1, but with the following amounts of components:

The complex of bioregulatory peptides of the prostate gland of cattle 0.622 kg

Lomefloxacin 0.777 kg

Base 2,101 kg

Get suppositories weighing 2.25 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle 0.4 g

Lomefloxacin 0.5 g

Basis Else

Example 4

Carried out analogously to example 1, but with the following amounts of components:

The complex of bioregulatory peptides of the prostate gland of cattle 0.077 kg

Lomefloxacin 1.088 kg

Base 2,335 kg

Get suppositories weighing 2.25 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle

Lomefloxacin

The basis

0.05 kg

0.7 kg

Rest

Example 5

Carried out analogously to example 1, only as loxacin, and as a base - solid fat.

Example 6

Carried out analogously to example 2, only as loxacin, and as a basis, solid fat.

Example 7

Carried out analogously to example 3, only as loxacin, and as a base - solid fat.

Example 8

Carried out analogously to example 4, only as loxacin, and as a base - solid fat.

antimicrobial agent composition contains ofantimicrobial agent composition contains ofantimicrobial agent composition contains ofantimicrobial agent composition contains of- 3 010427

Example 9

Carried out analogously to example 1, only as an antimicrobial agent does the composition contain amoxicillin, and cocoa butter as a base.

Example 10

Carried out analogously to example 2, only as an antimicrobial agent does the composition contain amoxicillin, and cocoa butter as a base.

Example 11

Carried out analogously to example 3, only as an antimicrobial agent does the composition contain amoxicillin, and cocoa butter as a base.

Example 12

Carried out analogously to example 4, only as an antimicrobial agent does the composition contain amoxicillin, and cocoa butter as a base. Example 13

Carried out analogously to example 1, picillin.

Example 14

Carried out analogously to example 2, pitsillin.

Example 15

Carried out analogously to example 3, pitsillin.

Example 16

Carried out analogously to example 4, picillin.

Example 17

Carried out analogously to example 1, phaclor. Example 18

Carried out analogously to example 2, phaclor. Example 19

Carried out analogously to example 3, phaclor. Example 20

Carried out analogously to example 4, phaclor. Example 21

Carried out analogously to example 1, fix. Example 22

Carried out analogously to example 2, fix. Example 23

Carried out analogously to example 3, fix. Example 24

Carried out analogously to example 4, fix. Example 25. Carried out analogously to example 1, only sicyclin.

Example 26

Carried out analogously to example 2, only sicycline.

Example 27

Carried out analogously to example 3, only sicycline.

Example 28

Carried out analogously to example 4, only sicycline.

Example 29

Carried out analogously to example 1, only only as only as only only as only as only as as only as as only as as only as as only as an antimicrobial agent the composition contains am antimicrobial agent composition contains am antimicrobial composition contains am antimicrobial composition contains am antimicrobial composition contains antimicrobial composition contains antimicrobial it contains an antimicrobial agent composition contains an antimicrobial agent composition contains an antimicrobial agent contains an antimicrobial agent contains an antimicrobial agent contains an antibiotic as an antimicrobial agent contains a dock as an antimicrobial agent contains a dock as an antimicrobial agent contains a dock as an antimicrobial agent, the composition contains a dock as an antimicrobial agent, the composition contains a tet

- 4 010427 racycline.

Example 30

Carried out analogously to example 2, only as an antimicrobial agent, the composition contains tetracycline.

Example 31

Carried out analogously to example 3, only as an antimicrobial agent, the composition contains tetracycline.

Example 32

Carried out analogously to example 4, only as an antimicrobial agent, the composition contains tetracycline.

Example 33

Carried out analogously to example 1, only as an antimicrobial agent the composition contains cotrimoxazole.

Example 34

Carried out analogously to example 2, only as an antimicrobial agent, the composition contains cotrimoxazole.

Example 35

Carried out analogously to example 3, only as an antimicrobial agent, the composition contains cotrimoxazole.

Example 36

Carried out analogously to example 4, only as an antimicrobial agent the composition contains cotrimoxazole.

Example 37

Carried out analogously to example 1, only as an antimicrobial agent the composition contains ribavirin.

Example 38

Carried out analogously to example 2, only as an antimicrobial agent, the composition contains ribavirin.

Example 39

Carried out analogously to example 3, only as an antimicrobial agent, the composition contains ribavirin.

Example 40

Carried out analogously to example 4, only as an antimicrobial agent, the composition contains ribavirin.

Example 41

Carried out analogously to example 1, only as an antimicrobial agent the composition contains lamivudine.

Example 42

Carried out analogously to example 2, only as an antimicrobial agent, the composition contains lamivudine.

Example 43

Carried out analogously to example 3, only as an antimicrobial agent, the composition contains lamivudine.

Example 44

Carried out analogously to example 4, only as an antimicrobial agent, the composition contains lamivudine.

Example 45

Carried out analogously to example 1, only as an antimicrobial agent the composition contains metronidazole.

Example 46

Carried out analogously to example 2, only as an antimicrobial agent does the composition contain metronidazole.

Example 47

Carried out analogously to example 3, only as an antimicrobial agent does the composition contain metronidazole.

Example 48

Carried out analogously to example 4, only as an antimicrobial agent does the composition contain metronidazole.

Example 49

Carried out analogously to example 1, only as an antimicrobial agent the composition contains tinidazole.

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Example 50

Carried out analogously to example 2, only as an antimicrobial agent the composition contains tinidazole.

Example 51

Carried out analogously to example 3, only as an antimicrobial agent, the composition contains tinidazole.

Example 52

Carried out analogously to example 4, only as an antimicrobial agent the composition contains tinidazole.

Example 53

The base - Vitepsol in the amount of 1.862 kg is melted at a temperature of 55-65 ° C with stirring. A complex of bioregulatory peptides of the prostate gland of cattle in the form of a powder with a content of water-soluble peptides of at least 20% in an amount of 0.596 kg is mixed with part of the molten witepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. The antibiotic powder - lomefloxacin in an amount of 0.521 kg is mixed with part of the molten witepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. An antiprotozoal agent, metronidazole in the form of a powder in the amount of 0.521 kg, is mixed with part of the molten vitepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. The resulting concentrates are loaded into the remaining vitepsol with stirring until a homogeneous mass is obtained. The finished mass is poured into cells from a polyvinyl chloride film and cooled.

Get suppositories weighing 2.35 g, having the following composition:

The complex of bioregulatory peptides

cattle gland 0.4 g Lomefloxacin 0.35 g Metronidazole 0.35 g The basis Rest Example 54 Carried out analogously to example 53, but with the following amounts of components The complex of bioregulatory peptides cattle gland 0.081 kg Lomefloxacin 0.244 kg Metronidazole 0.244 kg The basis 2,931 kg

Get suppositories weighing 2.15 g, having the following composition: Complex of bioregulatory peptides

cattle gland 0.05 kg Lomefloxacin 0.15 kg Metronidazole 0.15 kg The basis Rest Example 55 Carried out analogously to example 53, but with the following amounts of components The complex of bioregulatory peptides cattle gland 0.622 kg Lomefloxacin 0.233 kg Metronidazole 0.233 kg The basis 2,412 kg

Get suppositories weighing 2.25 g, having the following composition: Complex of bioregulatory peptides

cattle gland 0.4 kg Lomefloxacin 0.15 kg Metronidazole 0.15 kg The basis Rest Example 56 Carried out analogously to example 53, but with the following amounts of components The complex of bioregulatory peptides cattle gland 0.077 kg Lomefloxacin 0.544 kg Metronidazole 0.544 kg The basis 2,335 kg

Get suppositories weighing 2.25 g, having the following composition:

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The complex of bioregulatory peptides of the prostate gland of cattle 0.05 kg

Lomefloxacin 0.35 kg

Metronidazole 0.35 kg

Basis Else

Example 57

Carried out analogously to example 53, only as an antibiotic, the drug contains ofloxacin. Example 58

Carried out analogously to example 54, only as an antibiotic, the product contains ofloxacin. Example 59

Carried out analogously to example 55, only as an antibiotic, the drug contains ofloxacin. Example 60

Carried out analogously to example 56, only as an antibiotic, the drug contains ofloxacin. Example 61

Carried out analogously to example 53, only as an antibiotic, the product contains amoxicillin. Example 62

Carried out analogously to example 54, only as an antibiotic, the product contains amoxicillin. Example 63

Carried out analogously to example 55, only as an antibiotic, the product contains amoxicillin. Example 64

Carried out analogously to example 56, only as an antibiotic, the product contains amoxicillin. Example 65

Carried out analogously to example 53, only as an antibiotic, the drug contains ampicillin. Example 66

Carried out analogously to example 54, only as an antibiotic, the drug contains ampicillin. Example 67

Carried out analogously to example 55, only as an antibiotic, the drug contains ampicillin. Example 68

Carried out analogously to example 56, only as an antibiotic, the drug contains ampicillin. Example 69

Carried out analogously to example 53, only as an antibiotic, the product contains cefaclor. Example 70

Carried out analogously to example 54, only as an antibiotic, the product contains cefaclor. Example 71

Carried out analogously to example 55, only as an antibiotic, the product contains cefaclor. Example 72

Carried out analogously to example 56, only as an antibiotic, the product contains cefaclor. Example 73

Carried out analogously to example 53, only as an antibiotic, the product contains cefixime. Example 74

Carried out analogously to example 54, only as an antibiotic, the product contains cefixime. Example 75

Carried out analogously to example 55, only as an antibiotic, the product contains cefixime. Example 76

Carried out analogously to example 56, only as an antibiotic, the product contains cefixime. Example 77

Carried out analogously to example 53, only as an antibiotic, the drug contains doxycycline. Example 78

Carried out analogously to example 54, only as an antibiotic, the drug contains doxycycline. Example 79

Carried out analogously to example 55, only as an antibiotic, the drug contains doxycycline. Example 80

Carried out analogously to example 56, only as an antibiotic, the drug contains doxycycline. Example 81

Carried out analogously to example 53, only as an antibiotic, the product contains tetracycline. Example 82

Carried out analogously to example 54, only as an antibiotic, the product contains tetracycline. Example 83

Carried out analogously to example 55, only as an antibiotic, the product contains tetracycline. Example 84

Carried out analogously to example 56, only as an antibiotic, the product contains tetracycline.

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Example 85

The base - Vitepsol in the amount of 1.862 kg is melted at a temperature of 55-65 ° C with stirring. A complex of bioregulatory peptide prostate gland peptides in the form of a powder with a content of water-soluble peptides of at least 20% in an amount of 0.596 kg is mixed with part of the molten witepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. The antibiotic powder - lomefloxacin in an amount of 0.521 kg is mixed with part of the molten witepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. An antiprotozoal agent - tinidazole in the form of a powder in the amount of 0.521 kg is mixed with part of the molten witepsol taken in a 1: 1 ratio. The concentrate is prepared by grinding the powder on a three-roll grinding machine up to 40 microns at least 95%. The resulting concentrates are loaded into the remaining vitepsol with stirring until a homogeneous mass is obtained. The finished mass is poured into cells from a polyvinyl chloride film and cooled.

Get suppositories weighing 2.35 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle 0.4 g

Lomefloxacin 0.35 g

Tinidazole 0.35 g

Basis Else

Example 86

Carried out analogously to example 85, but with the following amounts of components:

The complex of bioregulatory peptides of the prostate gland of cattle 0.081 g

Lomefloxacin 0.244 g

Tinidazole 0.244 g

Foundation 2,931

Get suppositories weighing 2.15 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle 0.05 g

Lomefloxacin 0.15 g

Tinidazole 0.15 g

Basis Else

Example 87

Carried out analogously to example 85, but with the following amounts of components:

The complex of bioregulatory peptides of the prostate gland of cattle 0.081 g

Lomefloxacin 0.244 g

Tinidazole 0.244 g

Foundation 2,931

Get suppositories weighing 2.15 g, having the following composition:

The complex of bioregulatory peptides of the prostate gland of cattle 0.05 g

Lomefloxacin 0.15 g

Tinidazole 0.15 g

Basis Else

Example 88

Carried out analogously to example 85, but with the following amounts of components:

The complex of bioregulatory peptides of the prostate gland of cattle 0.077 g

Lomefloxacin 0.544 g

Tinidazole 0.544 g

Base 2,335

Get suppositories weighing 2.25 g, having the following composition: Complex of bioregulatory peptides of the prostate gland of cattle 0.05 g

Lomefloxacin 0.35 g

Tinidazole 0.35 g

Basis Else

Example 89

Carried out analogously to example 85, only as an antibiotic, the drug contains ofloxacin. Example 90

Carried out analogously to example 86, only as an antibiotic, the drug contains ofloxacin.

- 8 010427

Example 91

Carried out analogously to example 87, only as an antibiotic, the drug contains ofloxacin. Example 92

Carried out analogously to example 88, only as an antibiotic, the drug contains ofloxacin. Example 93

Carried out analogously to example 85, only as an antibiotic, the product contains amoxicillin. Example 94

Carried out analogously to example 86, only as an antibiotic, the product contains amoxicillin. Example 95

Carried out analogously to example 87, only as an antibiotic, the product contains amoxicillin. Example 96

Carried out analogously to example 88, only as an antibiotic, the product contains amoxicillin. Example 97

Carried out analogously to example 85, only as an antibiotic, the drug contains ampicillin. Example 98

Carried out analogously to example 86, only as an antibiotic, the drug contains ampicillin. Example 99

Carried out analogously to example 87, only as an antibiotic, the drug contains ampicillin. Example 100

Carried out analogously to example 88, only as an antibiotic, the drug contains ampicillin.

Example 101

Carried out analogously to example 85, only as an antibiotic, the product contains cefaclor. Example 102

Carried out analogously to example 86, only as an antibiotic, the product contains cefaclor. Example 103

Carried out analogously to example 87, only as an antibiotic, the product contains cefaclor.

Example 104

Carried out analogously to example 88, only as an antibiotic, the product contains cefaclor.

Example 105

Carried out analogously to example 85, only as an antibiotic, the product contains cefixime. Example 106

Carried out analogously to example 86, only as an antibiotic, the product contains cefixime. Example 107

Carried out analogously to example 87, only as an antibiotic, the product contains cefixime. Example 108

Carried out analogously to example 88, only as an antibiotic, the product contains cefixime. Example 109

Carried out analogously to example 85, only as an antibiotic, the drug contains doxycycline.

Example 110

Carried out analogously to example 86, only as an antibiotic, the drug contains doxycycline. Example 111

Carried out analogously to example 87, only as an antibiotic, the drug contains doxycycline.

Example 112

Carried out analogously to example 88, only as an antibiotic, the drug contains doxycycline. Example 113

Carried out analogously to example 85, only as an antibiotic, the product contains tetracycline.

Example 114

Carried out analogously to example 86, only as an antibiotic, the product contains tetracycline.

Example 115

Carried out analogously to example 87, only as an antibiotic, the product contains tetracycline.

Example 116

Carried out analogously to example 88, only as an antibiotic, the product contains tetracycline. Example 117

Carried out analogously to example 53, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 118

Carried out analogously to example 54, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 119

Carried out analogously to example 55, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

- 9 010427

Example 120

Carried out analogously to example 56, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 121

Carried out analogously to example 85, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 122

Carried out analogously to example 86, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 123

Carried out analogously to example 87, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 124

Carried out analogously to example 88, only instead of the antibiotic, the product contains the antiviral agent ribavirin.

Example 125

Carried out analogously to example 53, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 126

Carried out analogously to example 54, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 127

Carried out analogously to example 55, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 128

Carried out analogously to example 56, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 129

Carried out analogously to example 85, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 130

Carried out analogously to example 86, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 131

Carried out analogously to example 87, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

Example 132

Carried out analogously to example 88, only instead of the antibiotic, the product contains the antiviral agent lamivudine.

The content of water-soluble peptides is determined by spectrophotometric method. Determination of the content of antibiotic, in particular lomefloxacin, is carried out by high performance liquid chromatography (HPLC) on a liquid chromatograph company \ Wa1sg5 (or similar) with a spectrophotometric detector.

The test for microbiological purity of suppositories was carried out in accordance with the requirements of Global Fund XI, issue 2, p. 193 and Amendments 3, category 3A. The results obtained comply with regulatory requirements.

The resulting suppositories have a color from white or almost white to light cream with a grayish tint, torpedo-shaped. In appearance, suppositories satisfy the requirements of Global Fund XI, issue 2.

In order to determine the general toxic effect and evidence of the effectiveness of the proposed tool, its preclinical trials were conducted on the basis of the central research laboratory of the Nizhny Novgorod State Medical Academy in October 2004.

For testing, a tool was presented in the form of a suppository containing, as active substances, a complex of bioregulatory peptides of the cattle prostate gland and lomefloxacin as an antimicrobial agent. The content of components in 1 mg per suppository is presented in table. one.

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Table 1

The composition of the proposed funds for one suppository, mg

The complex of bioregulatory peptides of the prostate gland of cattle (samprosta substance (prostate extract)) (FSP 42-0179-2983-02 or another, registered in the Russian Federation, of similar quality) in terms of 20% content of water-soluble peptides - one hundred Lomefloxacin hydrochloride (ND 42-10824-00 or another, registered in the Russian Federation, of similar quality) -400 Suppository Basics: Vitepsol (TU 3-2004 or another, approved by M3 of the Russian Federation for the production of medicines of similar quality) - a sufficient amount to obtain a suppository weighing 2.25 g

Toxicological studies were carried out in accordance with the guidelines “Guidelines for the experimental (preclinical) study of new pharmacological substances”, 2000.

The materials of the experiments were subjected to statistical processing by the conventional student method. The report presents experimental data obtained from 10-11 animals in each of the groups.

The determination of acute toxicity of the studied dosage form is technically rectally impossible and inappropriate by other methods of administration.

The duration of the subchronic experiment for 30 days was chosen for a new combination of components used in clinical practice.

A subchronic experiment was carried out on randomly bred white male rats weighing 204 ± 5 g. Animals were kept in plastic cages with an area of 2150 cm ² , each containing 7-8 individuals, under natural light conditions, fed with briquetted and natural foods in accordance with the norms approved by the M3 of the Russian Federation.

All experimental animals were divided into 3 groups of 11 animals each. Groups were formed by random numbers using body weight as a leading feature. The experimental design is shown in table. 2.

Table 2 Scheme of a subchronic toxicological experiment in white rats

№№ groups Animal sex The number of animals in the group Dose, mg / kg Dates for taking indicators one males eleven 14 mg / kg Background, 1 month 2 males eleven 140 mg / kg 3 males eleven the control

The proposed tool was administered rectally daily once, for 1 month at doses of 14 (therapeutic) and 140 mg / kg, ten times the therapeutic dose for rats and 70 times for humans in mg / kg. Interspecific dose calculation was carried out according to Epepeyuy Ε.Ι. et al.

The general condition of the experimental animals was evaluated by their appearance, behavioral reactions, and integral indicators (feed and water intake, body weight dynamics).

The state of the cardiovascular system was studied using electrocardiography (ECG) in the second standard lead without anesthesia on the ECCHMP-N3051 at a paper draw speed of 200 mm / s and a correspondence of 1 mV - 20 mm.

After 30 days of administration of the proposed drug, it did not cause statistically significant changes on the part of the studied electrocardiogram parameters in experimental animals (Tables 3, 4).

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Table 3

Rat ECG parameters before exposure, proposed agent (M ± t; n = 10)

No. No. gru pp Floor Dose mg / kg Amplitude of teeth, mv Duration of intervals, sec heart rate in minutes R TO. 5 t RO OB5 rt QC one b 14.0 0.103 ± 0.004 0.356 ± 0,021 0.017 ± 0.011 0,089 ± 0.005 0.0408 ± 0.000 8 0.0183 ± 0.000 4 0,0562 ± 0.001 one 0.1 112 ± 0.001 2 540.1 ± 5.9 2 <3 140.0 0.102 ± 0.004 0.376 ± 0,022 0.009 ± 0.009 0,094 ± 0.003 0.0389 ± 0.000 nine 0.0187 ± 0.000 4 0,0568 ± 0.001 5 0.1 122 ± 0.000 8 535.0 ± 3.6 3 <3 the control 0.103 ± 0.005 0.364 ± 0,029 0,045 ± 0,038 0,084 ± 0.005 0,0403 ± 0,000 nine 0.0184 ± 0.000 6 0,0556 ± 0.001 5 0.1 108 ± 0.001 5 542.4 ± 7.0

Table 4 Parameters of the ECG of rats after 30 days of administration of the proposed drug (M ± t; p = 10)

No. No. gru pp Floor Dose mg / kg Amplitude of teeth, mv Duration of intervals, sec Heart rate in minutes R to 5 T R <E <? t K.R one <3 14.0 0,096 ± 0.004 0.383 ± 0.016 0.024 ± 0.018 0,091 ± 0.006 0.0408 ± 0.000 9 0.0189 ± 0.000 6 0.0584 ± 0.001 2 0.1128 ± 0.0 (11 3 532.5 ± 6.0 6 2 3 140.0 0.197 ± 0.005 0.372 ± 0,024 0,021 ± 0.011 0,089 ± 0.007 0.0409 ± 0.001 2 0.0203 ± 0.000 4 0.0591 ± 0.001 4 0.1154 ± 0.001 one 520.4 ± 5.0 6 3 3 the control 0.102 ± 0.003 0.386 ± 0,020 0,067 ± 0,033 0,087 ± 0.004 0.0415 ± 0,000 6 0.0196 ± 0.000 7 0,0583 ± 0.001 nine 0.1136 ± 0,0 (11 5 529.0 ± 7.0 8

The state of peripheral blood was judged by the number of red blood cells and leukocytes (counting in Goryaev’s cell), platelets (counting in blood smears) and reticulocytes (counting in blood smears stained with diamond cresyl blue), leukogram (counting in blood smears stained according to Romanowski-Giemsa ), hemoglobin (measurement on a GF3 hemoglobinometer), blood coagulation parameters (coagulograph N-334).

When exposed to the proposed agent for 30 days in the peripheral blood of rats of all experimental groups, there were no significant differences from the control of the studied parameters (red blood cells, white blood cells, hemoglobin, reticulocytes, platelets, white blood cell count). The data are presented in table. 5, 6.

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Table 5

The condition of the peripheral blood in rats before the introduction of the proposed funds (M ± t; n = 10)

№№ one 2 3 Floor in <5 <? Dose mg / kg 14.0 140.0 the control Hemoglobin, g / l 121.00 ± 3.75 120.25 ± 4.26 118.50 ± 3.65 Red blood cells, T / L 7.87 ± 0.44 6.91 ± 0.44 8.02 ± 0.49 Color display tel 0.797 ± 0.065 0.905 ± 0.066 0.764 ± 0.050 Reticulocytes,% 28.30 ± 1.76 29.00 ± 1.92 30.30 ± 1.94 Platelets, g / l 537.40 ± 34.24 449.62 ± 31.85 555.48 ± 43.95 White blood cells, g / l 14.16 ± 0.97 12.94 ± 1.07 14.11 ± 0.93 Leukogram (g / l) I ³ "th o · © <a PO Box 0.214 ± 0,028 0.181 ± 0,026 0.198 ± 0.029 s / i 1.810 ± 0.289 1,818 ± 0.202 2.185 ± 0.283 lymphocytes 11.82 ± 0.75 10.73 ± 0.95 11.50 ± 0.72 monocytes 0.135 ± 0.049 0.129 ± 0.046 0.125 ± 0.035 eosinophils . 0.188 ± 0,042 0.088 ± 0.044 0,101 ± 0,030

Table 6

The state of peripheral blood in rats after 30 days of administration of the proposed drug (M ± t; n = 10)

№№ one 2 3 Floor in in Dose mg / kg 14.0 140.0 the control G emoglobin, g / l 127.40 ± 4.63 127.25 ± 3,53 127.40 ± 4.01 Red blood cells, T / L 8.71 ± 0.17 8.77 ± 0.24 8.74 ± 0.23 Color indicator 0.736 ± 0.035 0.715 ± 0.027 0.734 ± 0.032 Reticulocytes,% 24.20 ± 1.81 22.10 ± 2.67 23.70 ± 2.62 Platelets G / l 584.55 ± 16.97 569.32 ± 23.33 573.62 ± 21.83 White blood cells, g / l 16.99 ± 0.32 16.34 ± 0.63 16.38 ± 0.59 Leukogram (g / l) a s O) f PO Box 0.273 ± 0,029 0.212 ± 0.025 0.227 ± 0.025 s / i 2,544 ± 0.194 2,348 ± 0.273 2,043 ± 0.210 lymphocytes 14.01 ± 0.23 13.51 ± 0.50 13.85 ± 0.50 monocytes 0.050 ± 0.026 0.103 ± 0,046 0.147 ± 0.052 eosinophils 0.121 ± 0,027 0.166 ± 0.043 0.116 ± 0.034

Within 30 days of the experiment, the proposed tool did not affect the state of blood coagulation of experimental animals, judging by the parameters of the coagulogram (table. 7).

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Table 7

The state of blood coagulation in rats after 30 days of administration of the proposed drug (M ± t; n = 10)

No. No. gru pp Floor Dose mg / kg Coagulation, sec. Clotting speed Start the end Duration in 1 min for 2 min for 3 min one <3 14.0 121.70 ± 14.4 4 305.70 ± 13.8 nine 184.00 ± 21.51 0.800 ± 0.125 0.420 ± 0.124 0.080 ± 0.055 2 in 140.0 120.00 ± 20.3 0 279.00 ± 60.0 6 159.00 ± 42.99 1,680 ± 0,403 0.510 ± 0.203 0.290 ± 0.116 3 in ! 120.90 ^K0H ', ± 17.9 trol 2 300.30 ± 24.0 3 179.40 ± 13.15 0.830 ± 0.166 0.690 ± 0.157 0.210 ± 0.142

The study of the general toxic effects of the proposed tool included a set of tests to evaluate liver function. The excretory and absorption functions of the liver were studied by the BSF test, the protein synthesizing function by the total protein content using a biuret reaction, the lipid function by the total lipid content using the colorimetric method with a reagent consisting of vanillin and phosphoric acid, and total cholesterol by the Ilk method. The antitoxic function of the liver was evaluated by the duration of hexenal sleep.

The introduction of the proposed funds within 30 days did not affect the excretory, absorption and protein synthesizing function of the liver in all experimental animals (tables. 8, 9).

Table 8

The state of absorption and excretory function of the liver of rats after 30 days of administration of the proposed drug (M ± t; n = 10)

Group No. py Floor Dose mg / kg Retention of BSF in the blood (%). one 14.0 14.53 ± 0.29 2 140.0 14.13 ± 0.22 3 3 the control 14.42 ± 0.48

Table 9

The effect of the proposed tool on the concentration of total protein in the blood serum of rats (M ± t; n = 10)

Group No. Floor Dose mg / kg Total serum protein (g / l) Before the introduction After 30 days of administration one in 14.0 85,20 86.69 ± 2.59 ± 1.30 2 140.0 85.07 ± 2.01 90.37 ± 1.53 3 <3 the control 85.73 ± 1.57 88.34 ± 1.62

The lipid function of the liver and blood glucose in all experimental groups did not differ from the control (tab. 10, 11).

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Table 10

The effect of the proposed tool on the content of total lipids in the serum of rats (M ± t; n = 10)

№№ groups Floor Dose mg / kg Total lipids (g / l) Before the introduction After 30 days, enter niya one 14.0 2,542 ± 0.101 2,036 ± 0.115 2 <3 140.0 2,553 ± 0,076 1,988 ± 0,103 3 <3 the control 2,578 ± 0,091 1.939 ± 0.116

Table 11

The effect of the proposed funds on the glucose content

in good condition blood stream (M ± t; n = 10) №№ Floor Dose Serum Glucose (mM / L) groups mg / kg Before the introduction After 30 days of administration one 14.0 3,807 ± 0,085 3,865 ± 0,097 2 <3 140.0 3,759 ± 0,101 3.833 ± 0.131 3 (3 the control 3,837 ± 0,098 3.702 ± 0.112

The proposed tool did not have a noticeable effect on the concentration of total cholesterol in the blood serum of animals of all experimental groups (Table 12).

Table 12

The effect of the proposed tool on the concentration of total cholesterol in the blood serum of rats (M ± t; n = 10)

Group No. Floor Dose mg / kg Total cholesterol (mM / L) Before the introduction After 30 days of administration one 14.0 1.81 ± 0.08 1.82 ± 0.08 2 (3 140.0 1.78 ± 0.09 1.76 ± 0.08 3 <3 the control 1.85 ± 0.08 1.76 ± 0.08

Judging by the duration of hexenal sleep, the antitoxic function of the liver in all experimental animals did not differ from the control (Table 13).

Table 13

The state of antitoxic function of rat liver (M ± t; n = 10)

groups Floor Dose mg / kg The duration of "hexenal" sleep, min one <3 14.0 22.60 ± 2.17 2 <3 140.0 19.00 ± 2.31 3 <3 the control 21.00 ± 3.05

The functional state of the pancreas and indirectly the carbohydrate function of the liver were determined by the glucose content in the blood serum by the glucose oxidase method.

The function of the excretory system was studied according to the following program: spontaneous diuresis in 18 hours, specific gravity of the urine by the gravimetric method, urine pH, urea in blood serum and urine by the diacetyl monoxime method, followed by calculation of the standard urea purification coefficient (SCOM); the content of creatinine in blood serum and urine according to the Jaffe reaction and the determination of creatinine clearance as an indicator of glomerular filtration; the content of potassium and sodium ions in serum cro

- 15 010427 vi and their excretion with urine by flame photometry at PFM-1; phenol red load as an indicator of secretory function of the kidneys.

Under the influence of the drug, the functional state of the kidneys in all experimental animals remained practically unchanged (Table 14-20).

Table 14

Indicators of the excretory system of rats before the introduction of the proposed funds (M ± t; n = 10)

Group No. Floor Dose mg / kg Diuresis for 18 h „ ML urine pH, units The specific gravity of urine, g / cm · ¹ Urea concentration, mM / L The urea content in urine, mm / 18 hours skom in the batch. blood in urine one 14.0 2.29 ± 0.18 6.6 ± 0.1 1,038 ± 0,003 7.00 ± 0.16 40.49 ± 0.95 0,092 ± 0.006 0.264 ± 0.008 2 <? 140.0 2,39 ± 0.26 6.6 ± 0.1 1,041 ± 0.002 7.39 ± 0.17 40.63 ± 0.88 0,098 ± 0.011 0.257 ± 0.018 3 <? the control 2,51 ± 0.28 6.6 ± 0.1 1,043 ± 0.003 7.20 ± 0.13 40.79 ± 0.98 0.103 ± 0.013 0.270 ± 0.018

Table 15

The rat excretory system after 30 days of administration of the proposed drug (M ± t; n = 10)

№№ corpse py Floor Dose mg / kg Diuresis in 18 ml h _m urine pH, units The specific gravity of urine, g / cm ’ Urea concentration, mM / L The urea content in urine, mm / 18 hours SCOM In the event. blood in urine one <5 14.0 3,410 ± 0.421 6.7 ± 0.1 1,041 ± 0.001 7.08 ± 0.18 39.83 ± 0.87 0.135 ± 0.016 0,309 ± 0.019 2 b 140.0 3,140 ± 0.334 6.7 ± 0.1 1,043 ± 0.002 7.15 ± 0.18 40.15 ± 1,02 0.128 ± 0.016 0.301 ± 0.021 3 8 the control 3,640 ± 0.499 6.8 ± 0.1 1,041 ± 0.002 7.22 ± 0.17 40.40 ± 0.76 0.148 ± 0,021 0.322 ± 0,029

Table 16

Rat kidney secretory function after 30 days of administration

P the proposed funds (M ± t; n = 10) №№ Floor Dose Phenol Red Excretion groups mg / kg mg / 2 hours one 14.0 40.18 ± 1.64 2 in 140.0 39.77 ± 1.71 3 in the control 38.23 ± 0.86

Table 17 Indicators of mineral metabolism of rats before the introduction of the proposed funds (M ± t; p = 10)

№№ corpse py Floor Dose mg / kg Potassium Sodium Νη ⁺ / Κ ⁺ serum, mmol / l Urine mm / 18 h serum, mmol / l Urine mm / 18 h one <5 14.0 6.60 ± 0.16 0.49 ± 0.05 167.04 ± 5.16 0.43 ± 0.05 25.3 / 1 2 in 140.0 6.59 ± 0.36 0.47 ± 0.06 170.52 ± 4.14 0.45 ± 0.07 25.8 / 1 3 <5 the control 6.50 ± 0.31 0.52 ± 0.06 173.13 ± 4.93 0.50 ± 0.07 26.6 / 1

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Table 18

Rat mineral metabolism after 30 days of administration of the proposed drug (M ± t; n = 10)

№№ group py Floor Dose mg / kg Potassium Sodium 14a ⁺ / K ⁺ serum, mmol / l Urine serum, mmol / l Urine mm / 18 h mm / 18 h one 3 14.0 6.44 ± 0.34 0.66 ± 0.09 179.18 ± 6.36 0.97 ± 0.14 27.8 / 1 2 in 140.0 6.44 ± 0.34 0.60 ± 0.07 187.05 ± 7.70 0.89 ± 0.08 29.0 / 1 3 the control 6.60 ± 0.39 0.69 ± 0.11 182.74 ± 6.60 0.98 ± 0.16 27.7 / 1

Table 19 Glomerular filtration of the kidneys of rats before the introduction of the proposed funds (M ± t; p = 10)

№№ group py Floor Dose mg / kg Diuresis in 18 hours ml Creatine concentration on, Creatinine clearance, ml / min μM / L mm / l in blood serum in urine one 3 14.0 2.29 ± 0.18 69.60 ± 2.16 10.26 ± 0.24 0.3163 ± 0,0284 2 <3 140.0 2.39 ± 0.26 70.76 ± 2.77 9.98 ± 0.26 0.3124 ± 0,0327 3 3 the control 2,51 ± 0.28 71.34 ± 2.94 10.21 ± 0.18 0.3346 ± 0.0377

Table 20 Glomerular filtration of the kidneys of rats after 30 days of administration of the proposed drug (M ± t; p = 10)

№№ group py Floor Dose mg / kg Diuresis in 18 hours, ml Creatinine concentration, Creatinine clearance, ml / min μM / L mm / l in blood serum in urine one 3 14.0 3.67 ± 0.44 71.66 ± 3.62 10.29 ± 0.16 0.4832 ± 0.0541 2 3 140.0 3.14 ± 0.33 70.52 ± 3.29 9.95 ± 0.24 0.4035 ± 0.0360 3 3 the control 3.64 ± 0.50 73.65 ± 2.07 10.39 ± 0.25 0.4750 ± 0,0658

The functional state of the nervous system was assessed by the open field method according to Boissier in its own modification, by spontaneous motor activity, which was recorded using an Idot VaShe actometer and by a sum-threshold indicator.

30 days after the start of administration, the parameters of the open field did not differ significantly from the control (Tables 21, 22).

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Table 21

Functional indicators of the state of the nervous system of rats before the introduction of the proposed funds (M ± t; n = 11)

Group No. one 2 BUT Floor 3 in Dose mg / kg  14.0 140.0 the control Open field Intersection of squares 46.0 ± 9.4 37.4 ± 4.8 63.5 ± 13.1 Racks 14.8 ± 2.3 10.2 ± 2.4 18.5 ± 4.0 Face wash 2.8 ± 1.0 5, O ± O, 7 4.6 ± 0.9 Purges 1.4 ± 0.4 1.7 ± 0.7 2.3 ± 0.6 Shaking off 2.1 ± 0.6 1.3 ± 0.6 0.9 ± 0.4 Bowel movements 4.3 ± 0.5 4.7 ± 0.7 4.6 ± 0.5 Mink reflex 1-5 min 4.2 ± 1.0 3.5 ± 1.6 8.2 ± 2.0 6-10 min 2.6 ± 1.3 1.4 ± 0.8 3.0 ± 0.9 in 10 min 6.8 ± 1.9 4.8 ± 2.3 11.2 ± 2.6

Table 22

Functional indicators of the state of the nervous system of rats after 30 days of administration of the proposed drug (M ± t; n = 11)

Ν ·. · No. Floor Dose mg / kg Open field Mink reflex Intersection of squares Racks Face wash Clean ki Shaking off Defenations 1-5 min 6-10 min for 10 min one <3 14.0 47.7 ± 11.9 9.3 ± 2.0 3.4 ± 0.7 1.3 ± 0.6 1,1 ± 0.6 2.7 ± 0.6 1.8 ± 0.6 2.0 ± 0.6 3.2 ± 0.9 2 <3 140.0 45,2 ± 14.5 9.9 ± 3.1 3.7 ± 0.8 1.3 ± 0.7 1,1 ± 0.6 3.3 ± 0.6 1,5 ± 0.9 1.5 ± 0.6 2.9 ± 1.4 3 b the control 30.9 ± 12.5 8.3 ± 2.4 1.8 ± 0.6 1,1 ± 0.5 1.4 ± 0.7 3.4 ± 0.8 1,0 ± 0.4 1.6 ± 0.7 2.6 ± 0.9

After 1 month of administration of the proposed drug, indicators of general motor activity and emotional state did not significantly differ from control. The data are given in table. 23.

Table 23

The effect of the proposed tool on the motor activity of rats (M ± t; n = 11)

No. No. FU pp Floor Dose mg / kg Locomotion Bowel movements Before introduction After 14 days of administration Before introduction After 14 days on denia one <3 14.0 173.45 ± 10.91 127.09 ± 17.43 3.09 ± 0.73 2.55 ± 0.59 2 <3 140.0 162.27 ± 8.90 120.45 ± 20.56 3.91 ± 0.72 3.64 ± 0.64 3 3 the control 188.18 ± 17.43 165.27 ± 20.06 2.36 ± 0.96 1.82 ± 0.92

The proposed tool after 30 days of rectal administration did not cause significant changes in the SPP (table. 24).

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Table 24

The impact of the proposed tool on the sum-threshold indicator of rats (M ± t; n = 11)

№№ corpse py Floor Dose mg / kg Sum of the threshold indicator Before introduction After 30 days of administration one 14.0 3.75 ± 0.15 3.42 ± 0.14 2 <3 140.0 3.95 ± 0.16 3.65 ± 0.23 3 3 the control 3.76 ± 0.10 3.36 ± 0.17

During the experiment, the death of animals was not observed. Examination of the animals showed that they are all well-fed, have the correct physique, are neat, the hairline and natural openings are clean.

At the end of the experiment, the experimental animals were killed (dislocation), opened, the relative mass of organs was determined.

A visual examination during autopsy from the internal organs showed no significant differences between the experimental and control rats. The organs are correctly located, there is no free fluid in the chest and abdominal cavities. No visual signs of pathology of organs and tissues were found.

Heart muscle and valves unchanged. The gleams of the trachea and large bronchi are free. The lung tissue is airy, pink in color, without signs of edema. The mucous membrane of the stomach, duodenum 12, small and large intestines, appendix without ulceration and hemorrhage. The capsule of the kidneys is easily removed, on the cut the cortical and medulla are clearly distinguishable. The thymus is gray-pink, not enlarged. The thyroid gland is pink in color with a clearly visible parathyroid gland. Adrenal glands unchanged. Shells of the brain are not strained, convolutions are well defined. Genitals without any abnormalities.

For pathomorphological studies, the following organs were taken from experimental animals of all groups: brain, heart, lymph nodes, spleen, thyroid and parathyroid glands, thymus, adrenal glands, pituitary gland, stomach, small and large intestines, pancreas, liver, lungs, kidneys, testes, prostate gland.

The determination of the relative mass of the organs of the experimental animals did not reveal significant differences from the control when exposed to the proposed agent in the indicated doses (Table 25).

Table 25 The relative mass of organs of rats in an experiment to study the general toxic effects of the proposed tool (M ± t; n = 10)

№№ one 2 3 Floor 3 from? 3 Dose mg / kg 14.0 140.0 the control -------------------------------------------------- --------------------------------'----------------- ---------'---------------------------------------- --'----------------------------------------------- -------------------------------------------------one The ratio of body weight to body weight (%) Liver 3.76 ± 0.16 3.87 ± 0.12 3.71 ± 0.10 A heart 0.380 ± 0.017 0.383 ± 0.014 0.356 ± 0.013 Spleen 0.588 ± 0.044 0.494 ± 0.045 0.501 ± 0.055 Kidney left 0.402 ± 0.017 0.403 ± 0.007 0.392 ± 0.015 right 0.401 ± 0.016 0.403 ± 0.007 0.384 ± 0.014 Adrenal glands left 0.0137 ± 0.0023 0.0115 ± 0,0006 0.0101 ± 0,0007 right 0.0155 ± 0.0022 0.0137 ± 0.0013 0.0113 ± 0.0010 testicles left 0.5165 ± 0.0188 0.5229 ± 0,0201 0.5111 ± 0.0199 right 0.5169 ± 0.0174 0.5227 ± 0.0173 0.5137 ± 0.0199 Thyroid 0.0066 ± 0.0011 0.0076 ± 0,0008 0.0080 ± 0,0003 Brain 0.618 ± 0,025 0.679 ± 0.019 0.661 ± 0,033 Pituitary 0,00347 ± 0.00008 0,00352 ± 0.00014 0,00356 ± 0.00019

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The morphological structure of the studied organs of control animals corresponds to the norm.

Compared with the control group, animals of the 2nd group (140 mg / kg) showed a small macrophage reaction in the brain layer of lymph nodes, well-defined reactive centers.

In the adrenal glands, a small and moderate venous plethora of the cerebral layer. There are no pathological changes at the injection site of the proposed agent.

To study the specific pharmacological action of the proposed remedy in the form of rectal suppositories, experiments were carried out using sexually mature outbred white rats (Stolbovaya nursery, State Institution Scientific Center BMT RAMS). The keeping of animals corresponded to the rules for the design, equipment and maintenance of experimental biological clinics (vivariums). They fed animals with natural and briquetted feeds in accordance with the approved standards. Animals were quarantined and acclimatized in vivarium for 14 days. Experimental groups of animals were formed by random sampling, taking into account body weight as a determining indicator.

The experiments were conducted in October 2004.

The order of identification of individuals: animal labeling in groups was carried out using notches on the auricle and stained with dyes (eosin and methylene blue) of the surface of the tail according to the developed schemes according to the available recommendations.

Method of animal euthanasia: decapitation.

The number of animals in the study groups is 10.

To evaluate the effectiveness, the effect of the proposed drug on rectal administration was studied. The proposed tool was introduced in the form of specially made small rectal suppositories containing the active and excipients in the appropriate dosage, which is laid down in the regulatory documentation for this drug. As a control substance for rectal use, suppositories specially made from the base of the drug were used.

Rectal suppositories were administered to rats 1 time per day after bowel movement.

The choice of doses of the drug for the study was carried out taking into account the intended course of application of the proposed funds in humans. The duration of drug administration to animals during the experiment was 10 days.

When calculating the doses, we proceeded from the daily dose of the drug Lomefloxacin: 400 mg per person weighing 70 kg and taking into account the conversion factor in rats of 5.9. Thus, the equitherapeutic dose for lomefloxacin is 400 / 705.9 = 33.7 mg / kg.

The specific pharmacological effect of the drug was studied in modeling septic prostatitis in rats.

Before prostatitis modeling, the bacterostatic and bactericidal activity of the drug was determined in the ίη νίΐτο test. To determine the severity of the bactericidal effect of the drug in the ίη νίΐτο systems, we studied its effect on sensitive microorganisms specified in the regulations of the manufacturer. Typical strains were used in the experiments: 81Alb1lossoss aigeis strain 7M (NNIEM, N. Novgorod) and Ezepepsia11 strain 18M (Department of Microbiology and Immunology, GOU VPO NizhGMA).

To grow staphylococci and Escherichia coli, meat-peptone broth (MPB) and meat-peptone agar (MPA) were used. A suspension of microorganisms containing 10 ⁷ microbial bodies in 1 ml (initial concentration) was prepared by washing with a buffered saline solution (pH 7.2-7.4) of a 24-hour agar culture. The microbial suspension was standardized according to the turbidity standard of the L. A. Tarasevich State Control Institute of Medical Biological Preparations for bacteria.

The study of bactericidal and bacteriostatic activity was carried out in accordance with the previously described recommendations in their own modification.

The method of serial dilutions. The suppository material was diluted in a nutrient medium. For this, the drug was dissolved in meat and peptone broth in a ratio of 1:30. In tubes with medium (3 ml) containing the drug and without the drug (control), 0.3 ml of a suspension of microorganisms was added to obtain various final concentrations (1 · 10, 1 · 10 ⁶ , 1 · 10 ⁵ , 1 · 10 ⁴ , 1 · 10 ³ ). The tubes were incubated (37 ° C, 24 hours). All experiments were performed in triplicate. Tubes in which microorganism growth was observed were taken into account.

Diffusion method. The method was used to detect the bactericidal activity of the native substance of rectal suppositories on Epeploxa co11, one of the leading causative agents of pyogenic urogenital infections. Simple agar was poured into Petri dishes (20 ml per cup). After solidification in the center of the agar 4 holes were punched (diameter 5 mm). On the surface of the agar was placed 0.1 ml of a suspension of Epeploxa11 strain 17 M (initial concentration 1 · 10 ⁹ ) and seeded with a continuous lawn according to the Drigalski method. Then, 100 mg of suppository substance was added to each well. The agar plates were thermostated (37 ° C, 24 hours). The results were taken into account by measuring the diameter of the zone (mm) of growth retardation of mushrooms around

- 20 010427 wells with the drug. All experiments were performed in triplicate. The average experimental result was taken into account.

To simulate septic prostatitis, the microorganisms Exxepius soy were selected as the most probable causative agents of infectious prostatitis, since other representatives of the family Eexbepepaeae and Rkebiotopak kr are much less common.

As a material for infection, we used a suspension of the drug susceptible (according to the tests of ίη ugo) of the Ekiepsis strain 18 M in physiological saline (1-10 ⁹ CFU / ml). The felt disks used for the experiment, 2x1x1 mm in size, were immersed in a physiological solution of suspended bacteria. Under nembutal anesthesia (40 mg / kg), an operation was performed to open the abdominal cavity of experimental animals and suturing a felt disk saturated with microorganisms to the prostate gland. After 3 days, septic prostatitis developed, and in the experimental groups treatment began with the proposed agent, rectal suppositories (OJSC Nizhpharm, Russia); treatment was carried out for 10 days. After completing the full course of treatment, a biopsy of the prostate (100 mg of tissue) was taken from the animals and thoroughly triturated and diluted 1:10, 1: 100 in sterile saline. Sow 0.1 ml of the diluted suspension on selective Endo agar according to the method of Drigalski (solid lawn). All experiments were performed in triplicate. The average experimental result was taken into account. Counted the number of CFU E. soy after incubation (24 h, 37 ° C).

Assessment of the condition of animals and the development of experimental prostatitis without treatment and during treatment was carried out daily according to the parameters of the appearance of the animals, and on the 3rd, 7th and 14th day of the development of prostatitis by parameters of body weight, analysis of blood phagocytic activity, counting white blood cells and leukocyte formula, total protein in serum, pathological studies of the prostate.

The analysis of blood phagocytic activity was carried out using the method of luminol-dependent chemiluminescence. The method is based on the release of reactive oxygen species by stimulated cells. A bright outbreak of chemiluminescence is accompanied by the reaction of the interaction of luminol with hypochlorite. By the value of the integral indicator 8 (light sum), the number of formed forms of oxygen is estimated, this value is proportional to phagocytic activity.

A latex with a particle diameter of ~ 1 μm was used as a phagocytosis stimulant. Before analysis, 48 mg of luminol was dissolved in 1 ml of 0.1 N. CON. After dissolution, it was made up to 100 ml with distilled water. The next day, filtered through a paper filter. Whole heparinized blood was diluted 100 times (Hanks solution without dye). Latex was washed before use to a clear supernatant. 1 ml of the latex mixture was taken, 10 ml of Hanks solution without dye was added and centrifuged at 3000 vol. 15-20 minutes

In the course of work, 0.7 ml of diluted blood and 0.1 ml of the main solvent were drained. Then, 0.2 ml of luminol and 0.002 ml of latex were added to the cell in the cell compartment.

The measurement was carried out for 15 min, each sample on the instrument "BHL-06", combined with a PC. During this time, the peak was recorded and the area under the peak was calculated (indicator 8) using the specialized LIM program. The peak was recorded in the range of 5-10 min from the start of stimulation and reflected a complete phagocytic response.

Phagocytic activity was evaluated in the values of the 8-integral indicator of the total light sum.

To study the structure of the prostate in chronic prostatitis and treatment with drugs at the end of the experiment, the prostate was excised and fixed in a 10% solution of neutral formalin for 48 hours. After fixation, the prostate samples were washed in running tap water for 12 hours and dehydrated in ascending alcohols. After dehydration, tissue samples were passed through intermediate media (a mixture of 100 ° alcohol + chloroform = 1: 1, chloroform + paraffin = 1: 1), soaked in two portions of paraffin at 1 = 60 ° С and poured into Plast 54 paraffin. Sections with a thickness of 5-7 μm were prepared on a Leyua 8M 2000B sledge microtome, glued onto glass-free Nikiforov mixture (100 ° alcohol + ethyl ether = 1: 1) slides, dried in an thermostat at 1 = 37 ° C for 24 hours. After dewaxing sections were stained with hematoxylin and eosin, dehydrated in ascending alcohols, enlightened in xylene and enclosed in Canadian balsam. Finished histological preparations were kept in a horizontal position for 24 hours until the resin dried out and was examined using a Leu8 ΌΜΕ 8 light microscope at a magnification of 100 and 200.

Methods of statistical data processing. The results were processed on ΙΒΜ PC / AT using the software packages 81ike-ysa 6.0. The probability of differences in the means of the groups was determined using the ΐ Student test. Differences were considered significant at a significance level of p <0.05.

Results and its discussion.

1. The biocidal effect of the proposed funds in the form of rectal suppositories in the test ίη ugo

The results of microbiological studies are presented in table. 26 and 27.

- 21 010427

Table 26

The effect of the proposed product on 81 aryu1ossoss8 aigeya and Eeyepsya soi

Meat-peptone broth (BCH) with the proposed tool BCH without the proposed tool (control) The final concentration of bacteria in the environment 10 ⁷ Ju ⁶ 10 ⁵ w ⁴ 10 ³ 10 ⁷ Growth 8. aigeez 7M - - - - - + Growth bold 18M - - - - - +

- - lack of visible growth of microorganisms.

+ - the presence of growth of microorganisms in the environment.

According to the regulation of studies on the identification of biocidal drugs, the minimum inhibitory concentration of an antimicrobial drug is considered to be dilution that inhibits the growth of microorganisms at a concentration of 10 ⁴ cells / ml and above. As can be seen from the table. 26, a working dilution of the proposed 1:50 agent had a strongly pronounced bactericidal effect on gram-positive and gram-negative flora, suppressing the growth of both 1 1 у и у осс осс осс 8 из из из из из, Е Е and Ezepepsysoi in a final concentration of up to 10 ⁷ cells / ml.

The diffusion test data (Table 27) also confirmed the significant bactericidal activity of the native preparation in relation to the Ezhepsysoi strain, which was subsequently used to infect laboratory animals in order to create a model of chronic prostatitis.

Table 27

Bactericidal activity of the native substance of the proposed remedy in relation to Soybean

The diameter of the zone of growth inhibition (mm) near the hole containing: 1.100 mg 2. Empty well (control) 44.6 ± 3.6 p _2. | <0.05 Lack of growth retardation (continuous growth of Acne sop on agar)

Thus, the proposed tool has a pronounced bactericidal activity in the ίη ugo systems both in relation to gram-positive bacteria (§1aryu1ossoss8 aiguiz) and in relation to gram-negative bacteria (Exeptus soya).

2. The study of the bactericidal action of the proposed tool in the modeling of bacterial chronic prostatitis

The results of microbiological studies of the prostate after treatment of bacterial prostatitis with the proposed tool are presented in table. 28.

Table 28

The number of soybean in the material of the prostate after applying the proposed remedy for 10 days

The studied groups of the abdomen ny: Amount of Soybeans on Endo Agar (CFU per Petri dish) Dilution 1:10 Dilution 1: 100 1. The control group 935, 4 ± 65.6 63.3 ± 14.7 2. After treatment, the proposed tool 466, 3 ± 93.4 p2] <0.05 27.6 ± 5.8 p1 1 <0.05

According to the tests ίη у1уо (tab. 28), after applying the course of treatment with the proposed agent, a decrease in the number of CFU in the sowing material is observed. The presence of bacterial material in the prostate, although smaller than in the control, after treatment for 10 days, is due to the peculiarities of modeling the disease in rats (infection with high doses of Exposure, preservation of the source of infection in the abdominal cavity, anatomical features of rats).

Thus, the treatment with the proposed agent within 10 days almost 2 times reduces the number of bacteria (Espepticus soy) in the tissue of the prostate, which indicates the presence of a bactericidal effect of the proposed means ίη у1уо.

3. The study of anti-inflammatory and organotropic effects of the proposed funds in the modeling of bacterial prostatitis

In the treatment of bacterial prostatitis caused by Exodus soy, a positive effect of the proposed drug on the external condition of animals, food intake, behavior was revealed. The difference in body weight gain was significant on the 4th day of treatment with the proposed remedy as compared

- 22 010427 report with a control series (tab. 29).

Table 29

The change in body weight of rats when modeling experimental bacterial prostatitis and treatment of the proposed tool (M ± t)

Groups of animals Initial data 3 days after surgery (start of treatment) 4th day of treatment (7th day of prostatitis) After 10 days of treatment (14th day of prostatitis) 1. Control 250.21 ± 5.3 247.36 ± 5.13 232.00 ± 4.80 259.84 ± 7.43 2. The proposed tool 251.3 ± 4.51 258.80 ± 4.86 254.04 ± 4.96 p ₂ _] <0.05 263.32 ± 7.47

The dynamics of phagocytic activity against the background of the development of bacterial prostatitis and its treatment with the proposed agent is presented in table. thirty.

Table 30

Blood phagocytic activity (rel. Units) in the treatment of bacterial prostatitis in rats with the proposed agent (M ± t)

Groups of animals Initial data 3 days after surgery (start of treatment) 4th day of treatment (7th day of prostatitis) After 10 days of treatment (14th day of prostatitis) 1. Control 118.2 ± 3.2 242.96 ± 3.2 289.43 ± 3.3 164.2 ± 8.1 2. The proposed tool 114.2 ± 4.8 230.5 ± 4.5 * 157.3 ± 5.6 p ₂ -] <0.05 122.5 ± 4.2 P2-1 <0.05

It was revealed that the rectal use of the proposed agent in modeling bacterial prostatitis caused by Escherichia coli causes a decrease in phagocytic activity already on the 4th day of treatment compared with the control series and completely normalizes the activity indicators of the inflammatory process after 10 days of treatment.

Thus, the proposed tool has a pronounced anti-inflammatory effect according to phagocytic activity.

The study of the dynamics of hematological parameters in the treatment of bacterial prostatitis by the proposed tool also showed the presence of an effective therapeutic anti-inflammatory effect (table. 31).

With rectal administration, the proposed agent after 10 days of treatment, i.e. on the 14th day of bacterial prostatitis, there was a significant decrease in the percentage of neutrophils, monocytes, eosinophils, ESR compared with the control group.

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Table 31

Changes in some hematological parameters when using the proposed drug for the treatment of bacterial prostatitis (M ± t)

Index, units measuring R groups of animals Source data 3 days after surgery (start of treatment) 4th day of treatment (7th day of prostatitis) After 10 days of treatment (14th day of prostatitis) White blood cells (10 ⁹ ) 1. Control 2. The proposed tool 5.8 + 0.41 5.9 + 0.72 8.72 ± 0.43 7.38 ± 0.47 6.86 + 0.24 6.12 + 0.39 6.26 + 0.32 6.20 + 0.23 Neutrophils (%) 1. Control 2. The proposed tool 20.1 ± 0.32 20.4 + 0.33 28.2 ± 2.15 31.4 + 1.74 24.8 + 1.5 23.2 + 0.17 27.2 + 1.58 21.2 + 0.89 p _2. | <0.05 Lymphocytes (%) 1. Control 2. The proposed tool 64.6 + 2.6 65.3 + 1.56 65.8 + 3.43 69.4 + 3.0 70.6 + 2.15 70.8 + 4.51 69.2 + 2.58 66.0 + 3.86 Monocytes (%) 1. Control 2. The proposed tool 0.62 + 0.06 0.51 + 0.08 4.4 + 0.38 5.4 + 0.23 3.03 + 0.27 1.8 + 0.06 Ρ2-ι <0.05 1.6 + 0.08 0.41 + 0.03 ρ ₂ .ι <0.05 Eosinophils (%) 1. Control 2. The proposed tool 1.5 + 0.02 1.6 + 0.03 3.4 + 0.09 3.2 + 0.27 3.4 + 0.93 2.6 + 0.17 3.2 + 0.36 1.6 + 0.01 P2_1 <0.05 ESR, mm / hour 1. Control 2. The proposed tool 2.05 + 0.04 2.1 + 0.04 10.2 + 0.99 10.2 + 0.65 10.6 + 0.78 5.2 + 0.36 Ρ2-ι <0.05 3.2 = 0.19 2.0 + 0.08 Ρ2-Ι <0.05

Thus, according to hematological analysis, the proposed tool has an anti-inflammatory effect, providing a therapeutic effect in the development of bacterial prostatitis in rats.

Biochemical studies of total blood serum protein in rats without treatment and after 10 days of treatment with the proposed tool revealed an increase in total blood serum protein in the group treated with the drug (Table 32), which is probably associated with an increase in the number of immunoglobulins in chronic infectious disease.

Table 32

The effect of the proposed tool on the total protein content (g / l) in rat blood serum when modeling chronic bacterial prostatitis

Groups of animals Source data 3 days after surgery (start of treatment) 4th day of treatment niya (7th day of prostatitis) After 10 days of treatment (14th day of prostatitis) 1. Control 58.23 + 2.35 88.00 + 1.92 81.67 + 6.01 78.20 + 1.59 2. The drug 60.2 + 2.12 84.80 + 2.37 75.80 + 1.39 68.40 + 1.29 Ρ2-Ι <0.05

Data pathomorphological studies. The use of the proposed remedy leads to the elimination of signs of inflammation in the organ: a decrease in interstitial edema, restoration of the secretory function of the epithelium.

When studying the structure of the prostate of control animals on the 14th day of the development of bacterial prostatitis, pronounced interstitial edema, diffuse infiltrate from leukocytes and lymphoid cell elements in the interlayers of the connective tissue and the lumen of the terminal parts of the gland, plethora of the vascular bed were noted. The secretory function of the gland is impaired, which is expressed in atrophy of the secretory epithelium, the absence of secretion in the terminal sections.

Treatment of animals with the proposed agent led to the elimination of signs of inflammation in the organ. In the parenchyma of the prostate, there were marked areas of the gland with an increase in the height of the epithelial layer and its surface area, and areas with end sections filled with secretion and lined with prismatic and cubic epithelium. At the same time, isolated areas of edema were detected.

- 24 010427 stroma, as well as the presence of single leukocytes in the secretion of glands.

The specific pharmacological effect of the proposed tool was studied in modeling bacterial prostatitis in rats, as well as ίη νίΐτο.

In tests ίη νίΐτο, the proposed tool has a pronounced bactericidal effect.

Course rectal administration of the proposed agent for 10 days led to normalization of the function of the prostate gland, to a decrease in inflammatory phenomena, as evidenced by a decrease in blood phagocytic activity, a decrease in the total serum protein, a decrease in the percentage of neutrophils, monocytes, eosinophils, ESR, and elimination of signs of inflammation in organ: reduction of interstitial edema, restoration of the secretory function of the epithelium.

As shown by studies, the proposed tool in the form of a suppository has a high level of organotropic activity and a high level of antimicrobial activity.

Claims (5)

CLAIM 1. Agent for the treatment of diseases of the prostate gland, made in the form of a suppository, containing a complex of bioregulatory peptides of the prostate gland of cattle in powder form with a content of water-soluble peptides of at least 20% and a base, characterized in that it additionally contains an antimicrobial agent, which is an antibiotic , or an antiviral agent, or an antiprotozoal agent, or a mixture of an antibiotic and an antiprotozoal agent, taken in a 1: 1 ratio, or a mixture of antiviral and p otivoprotozoannogo means, taken in a 1: 1 ratio, with the following ratio of components, g per candle: complex of bioregulatory peptides of the prostate gland of cattle - 0.05-0.4, antimicrobial agent - not more than 0.7, base - sufficient to obtain a suppository weighing 2.15-2.35 g 2. The tool according to claim 1, characterized in that as an antibiotic it may contain an antibiotic from the group of fluoroquinolones, in particular lomefloxacin, ofloxacin, or from the group of penicillins, in particular amoxicillin, ampicillin, or from the group of cephalosporins, in particular cefaclor, cefixime , or from the group of tetracyclines, in particular doxycycline, tetracycline, or from the group of sulfonamides, in particular cotrimoxazole. 3. The tool according to claim 1, characterized in that as an antiviral agent it contains, in particular, ribavirin, lamivudine. 4. The tool according to claim 1, characterized in that as an antiprotozoal agent it contains an antiprotozoal drug from the group of nitroimidazoles, in particular metronidazole, ornidazole, tinidazole. 5. The tool according to claim 1, characterized in that the basis is any pharmaceutically acceptable basis for the preparation of a suppository, in particular Witepsol, tallow, cocoa butter.