EA005132B1 - Medical preparation - Google Patents

Abstract

1. A medical preparation for the treatment and prophylaxis of infectious and inflammatory diseases, comprising benzyldimethyl[3-(myristoilamino)propyl] ammonium chloride and a pharmaceutical diluent, characterized in that contains comprising benzyldimethyl[3-(myristoilamino)propyl]ammonium chloride as monohydrate. 2. The medical preparation according to claim 1, characterized in that contains water and/or alcohol as a pharmaceutical diluent and monohydrate benzyldimethyl[3-(myristoilamino)propyl]ammonium chloride in 0.01-1.0%. 3. The medical preparation according to claim 1, characterized in that contains any base of vegetable, animal or synthetic origin as a pharmaceutical diluent with the following component ratio: vegetable, animal or synthetic baseá99.0-99.9 benzyldimethyl[3-(myristoilamino)propyl]ammonium chloride, monohydrate 1.0-0.01 4. Use a medical preparation according to claims 1-3 for the treatment and prophylaxis of infectious and suppurative inflammatory diseases of different aetiology and localization and a preparation having antiseptic, disinfecting, spermicidal, antiviral and immuno-modulating action.

Description

The present invention relates to medicine, and more specifically relates to a drug for the prevention and treatment of specific inflammatory and nonspecific inflammatory diseases of various etiologies and localizations, as well as its use as an agent for the treatment of human herpes viruses and human immunodeficiency, antiseptic, disinfectant, immunoadjuvant and spermicidal agents.

Surfactants have found application in medicine, mainly as antiseptic and disinfectants rocal, zephyrol, catamine AB, zerigel, dehmitsid, chlorhexidine bigluconate, etc. (Mashkovsky M.D., Medicines, M. Medicine, 1999). The limited use of surfactants in medicine is due to the fact that many of them, along with antimicrobial properties, have irritating effects on the skin and mucous membranes, as well as toxic effects on the body. In addition, the mechanism of their action on the micro- and macroorganisms has not been fully clarified, simple and informative methods have been developed that allow quick and accurate characterization of the harmlessness of the action, there is no information about mutagenic properties, the question of their carcinogenicity remains controversial (Krivoshein Yu.S. et al., Antibiotics, 1984, No. 7, pp. 519-526; A. Skuratovich et al., Bulletin of Dermatology and Venereology, 1983, No. 11, pp. 29-32).

Known means for the prevention of specific (venereal) diseases - potassium permanganate, furatsilin, chlorhexidine, silver preparations, mercuric chloride and others (Ovchinnikov N.M. et al., Bulletin of Dermatology and Venereology, 1978, No. 6, p. 49; Skuratovich A. A. Act.project of derm. And venus. Minsk, 1980, S. 172-175). For the treatment of diseases of the genitourinary system, antibiotics, boric acid, zinc sulfate, osarsol, imidazole and other compounds are widely used. However, none of the listed drugs is effective simultaneously against pathogens of specific and nonspecific diseases of the genitourinary system, most of them have an irritating effect on the skin and mucous membranes of the genitals, even microorganisms develop resistance to expensive drugs.

The use of antiseptics in the treatment of inflammatory diseases of the nasopharynx is known. For this, furatsilin, potassium permanganate, rivanol, chonosol, chlorhexidine bigluconate, octinisept and others are used. The main disadvantages of these agents are their suppression of the motor activity of the ciliary epithelium of the upper respiratory tract, local immune reactions, as well as a pronounced irritant effect (G. Piskunov s. et al., Russian Rhinology, 1996, No. 5, pp. 23-25; Piskunov SZ et al., Russian Rinology, 1995, No. 34, pp. 6-11).

Antiseptics are used in ophthalmology for the treatment of conjunctivitis and the prevention of post-traumatic and postoperative complications (furatsilin, boric acid, decamethoxin, zinc sulfate, etc.). The effectiveness of treatment with these drugs is not very high, besides this, their irritating effect and allergic reactions are often observed (Maychuk Yu.F. Allergic eye diseases, M. Medicine, 1983, 224 pp.). These drugs are not effective for chlamydial and herpetic eye lesions.

There are experimental studies on the antiviral effect of certain surfactants, contraceptives containing these compounds, as well as their use for the prevention of HIV infection in humans (Atatbegd M.A. e! A1. ΙηαοΙίναΙίοη οί Nitap 1tipobeps! Épsu Uiiz Toure 1 ίη T1zie Siebes E1gpb apb ίη Oesh1a1 8esgebopz bu! Be 8regtk1be Vepza1kopit Sb1opbe. 1. ίί Cl. met.Miokhupo1-9. Tbe Baise !, 1988, 1 N 8600, p. 1456, 1. Kg1zz e! a1. EGPsasu οί Νοηοχνηο1-9 СГИГасерЦуе Зрогше Езе ί ΡΐΌΐΌηΙίηβ Ne1egozehia1 Asstsyzyyup οί N1U ίη ΝηίΓο6ί RgozShgPez., 1AMA 1992, N 4, 477-482). The closest analogue to the claimed technical solution is a drug for the treatment of infectious and inflammatory diseases, including myristamidopropyl dimethylbenzylammonium chloride (miramistin) as an active component and a pharmaceutical diluent (AO 93/00892). At the same time, water for liquid forms or any plant, animal and synthetic base for other forms are proposed as a diluent. The disadvantages of this technical solution include the fact that only one liquid form of an aqueous solution is provided, the effectiveness of which, like other forms, is high enough only at miramistin concentrations above 1 wt.%, As well as a narrow range of applications - diseases of the genitourinary system.

The purpose of the invention is the development of a medicinal product (LP), expanding the range of drugs that have a detrimental effect on pathogens of infectious and inflammatory diseases (bacteria, viruses, fungi, protozoa), without causing side effects from the body during its use, as well as expanding the scope of its use .

The problem is solved in that the drug, including benzyldimethyl [3- (myristoylamino) propyl] ammonium chloride (AB) and a pharmaceutical diluent, contains the active substance in the form of monohydrate, chemical formula 1,

SNZO

I // [C ₆ H ₅ - CH ₂ - N - (CH ₂ ) s - ΝΗ - C p CE H ₂ O

I \

СНз С13Н27

Formula 1

Benzyl dimethyl [3- (myristoylamino) propyl] ammonium chloride monohydrate, which reduces its effective concentration, contains water and / or alcohol as a pharmaceutical diluent and is recommended as a means for the treatment and prevention of infectious and inflammatory diseases, including specific and non-specific diseases of both the genitourinary system and the nasopharynx, eyes, as well as agents for the prevention of herpes and HIV infection during sexual transmission, spermicidal, antiseptic and disinfection citing means.

AB is obtained by itself known for the reaction of condensation of myristamidopropyl dimethylamine with benzyl chloride, followed by purification to the required qualification. Moreover, special conditions for the isolation and purification make it possible to obtain it in the form of a monohydrate.

The resulting substance is an odorless white fine crystalline powder, soluble in water, low molecular weight alcohols, acetone, chloroform.

As shown below, the results of laboratory and clinical studies, the monohydrate form allows you to achieve higher efficacy of drugs at lower concentrations of AB, which is an unexpected effect of this technical solution.

For the purposes of treatment and prevention, it is proposed to use the drug in a pharmaceutical diluent with a mass fraction of 0.01-1.0%, when the diluent can be water, an organic solvent, as well as any plant, animal or synthetic base in the following ratio of components (in%):

pharmaceutical diluent 99.0-99.9 LP 1.0-0.01

Such dosage forms provide protection against bacterial, viral, fungal and protozoal sexually transmitted infections, as well as a reliable therapeutic effect in urethrostatitis, sinusitis, conjunctivitis and other inflammatory diseases of various localization.

The proposed drug can be produced in the form of a 0.01-1.0% solution in distilled water in special bottles with a nozzle made of polyethylene, as well as in the form of ointments, gel, suppositories, tablets and in aerosol containers.

Preclinical trials of the drug Antimicrobial properties of drugs

Using the methods recommended by the World Health Organization (WHO), we studied the antimicrobial effect of drugs against 611 standard museum and wild strains of microorganisms (413 gram-negative, 135 gram-positive bacteria, 52 fungi, 8 viruses, 3 protozoa).

The data obtained showed that LP is most active against gram-positive bacteria, vegetative forms of bacilli and fungi, pathogens of dermatomycosis (0.00010.01%). The range of antimicrobial effects of drugs on gram-negative bacteria was in the range of 0.002-0.05% for most cultures. The growth of bacteria of the genera Prgo1sn5. Procrastinus and Musobacilli was inhibited at a concentration of 0.5-2.0%. The simplest - Tpsyoshoyak wadsheyk - turned out to be sensitive to a concentration of PL of 0.002-0.02%. LP showed high virucidal properties against complex viruses (herpes viruses, HIV-1, influenza, adenoviruses, etc.) (see tables 1 and 2).

It was revealed that LP was the most active anti-HIV-1 agent compared to other disinfectants tested to inactivate this virus. Our data completely coincide with the results obtained by other researchers (Table 3).

The antimicrobial properties of drugs are preserved for a long time at room temperature, in a refrigerator (observation period up to 5 years). The bactericidal activity of the drug does not depend on the drug resistance of microorganisms. PL suppresses the conjugation transfer of plasmids that determine the pathogenic properties of bacteria (H1y, Εηΐ, P and others).

The mechanism of antimicrobial and virucidal action of drugs, studied using electron microscopy, physico-chemical and biochemical methods, showed that it is due to the disintegration of surface glycoproteins of the cell wall, as well as a violation of the enzyme systems in the cell. These processes go in parallel and depend on the dose of the drug.

Immunomodulating properties of drugs

Using generally accepted methods for assessing the humoral and cellular immunity иη ν 11th and ίη νίνΌ, it was found that the drug LP has a dose-dependent effect on the immune system. In working concentrations, LP causes an immunoadjuvant effect, which manifests itself in an increase in the primary and secondary immune response; in higher concentrations - immunosuppressive, suppressing immune responses. The stimulating effect is manifested on the opsonophagocytic mechanism and such indicators as the phagocytic number, phagocytic index, HCT test. An increase in the level of EaPOK and Et-ROK was noted; RBTLs with PHA stimulate the functional activity of T-T and T-B-induced helpers, reducing the activity of T-T and T-B-induced suppressors. Thus, the dose-dependent stimulating effect of the drug on the absorption capacity of leukocytes and the level of oxygen-dependent microbicidal systems, the expression of receptors for the immunoglobulin Refragment and complement component C by monocytic cells was proved. Based on the data obtained, it can be concluded that LP has not only antiseptic, but also immunomodulating properties.

Toxicology

Acute toxicity was determined by BO ₅₀ on white mice and rats with a single intragastric and subcutaneous administration of the drug according to the generally accepted method. The data obtained showed that BO ₅₀ LP for intragastric administration to mice is 1000 mg / kg, and for rats - 1200 mg / kg. Subcutaneous injections of the drug caused the death of animals from lower doses - ΕΙΤ was 628 mg / kg for mice and 670 mg / kg in rats. BO ₅₀ for intravenous administration of LP was 38.5 mg / kg for mice and 42.5 mg / kg for rats.

Based on the data obtained, it can be concluded that the drug belongs to drugs with low toxicity - hazard class IV [GOST 12.1.007-76. Toxic effect of substances on the body (hazard classes)].

Chronic toxicity of drugs was studied in rabbits, which were applied 3 times a day daily for shaved areas of the skin for 0.01-0.1-1.0% solutions for 45 days. Five animals were taken for each dose. An ointment containing 0.5% LP was applied to rats (16 animals) in the form of a thin layer daily on a skin area equal to 0.1 body area for 1 month. LP aerosol concentrate was administered to rabbits in the vagina at a dose of 1 ml per animal daily (7 animals). Glue (0.5%) was applied to rats according to the method of applying ointment.

Assessment of the state of the animal organism in the experiments was carried out according to the following indicators: general condition, survival, body weight, peripheral blood, ECG, tests characterizing the functional state of the liver and kidneys, weight coefficient of internal organs and their morphological state. In rats, in addition to the indicators indicated above, reactions reflecting the state of the central nervous system were studied; in rabbits, pulmonary ventilation and blood pressure. In some animals, the activity of leukocyte peroxidase was studied using the Graham reaction, glycogen content by the method of ΗοΙοΙιΕίδδ and Shabadash, and temperature-perturbation differential spectrophotometry of serum albumin was performed.

Based on the analysis of the numerous data obtained, it was concluded that the drug in concentrations up to 1.0% with prolonged entry into the body (chronic experiment) through the skin and mucous membranes does not adversely affect the vital organs and systems of animals, i.e. not toxic to the body.

The local irritant effect of PL on the skin and mucous membranes of the eyes and vagina was studied in guinea pigs and rabbits, and on the mucous membranes of the urethra and bladder in dogs.

The data obtained showed that the application of PL solutions on the skin in concentrations of 0.01-0.5% for 40 days did not cause any visual or histological changes. An increase in the concentration of the drug to 1.0% led to a 30 day application of slight dry skin and slight atrophy of the epidermis. Large concentrations of LP (3-5%), starting from 10-15 days, caused more significant changes in the skin.

Instillation of the drug solution in the eyes of rabbits and guinea pigs for 10 days at concentrations of 0.01-0.05% of the irritating effect on the mucous membranes did not cause (Dryse score - 0, according to the Ogur classification - group A). Higher concentrations of the drug caused irritation of the mucous membranes of the eye (on the Dreis scale - 8-10 points, according to the Ogur classification group B).

After the installation of a 0.01-0.05% solution of the drug in the urethra of male dogs of 20 ml for 10 days 4 times a day, no changes in the behavior of animals were observed. Analysis of urine, blood and histological studies of the mucous membrane of the urethra, bladder and other organs of dogs did not reveal abnormalities.

There were also no morphological and histological changes in the vaginal mucosa of female animals when installing solutions, 0.5% ointment and aerosol.

The allergenic effect of drugs was studied on sexually mature male guinea pigs weighing 300-400 g. The data showed that on the primary-contact and secondary-contact areas of the skin, the irritation reaction was never observed during the observation period. On histological sections of the skin and other organs of animals scored on the day of the experiment, no inflammatory micro-reactions or other changes were revealed. Therefore, LP does not have an allergenic effect.

Thus, toxicological studies have concluded that LP refers to substances with low toxicity (class IV harmful substances). In working concentrations (0.01-1.0%), the drug does not have an irritating effect on the skin, mucous membranes of the eyes, urethra, bladder and allergenic properties. Some side effects are manifested only when using drugs in doses far exceeding its working concentration. Long-term intake of drugs in the body does not cause any noticeable deviations in the functioning of vital organs and systems in experimental animals.

The study of the mutagenic, embryotoxic effect and carcinogenic properties of drugs was carried out according to WHO recommendations. Mutagenic properties were studied on microbial test systems according to B. Atek, as well as by detecting the frequency of chromosome aberration and dominant lethal mutations in mouse bone marrow cells. Based on the data obtained, it was concluded that LP does not have a direct mutagenic effect, and also does not form compounds having mutagenic properties during metabolic activation of ίη νίίτο and ίη νΐνο.

Studies of the embryotoxic effect of LP and its effect on reproductive function were performed in rats. In the first group, female rats were given an intragastric solution of LP in the period from the 6th to the 18th day of pregnancy. In total, each animal received up to 1000 mg / kg of the drug. In the second group, drugs were administered from the first day until the end of pregnancy 1 time per day. In the third group, the drug was installed to males for 60 days, to females - 30 days, then mating was performed.

Based on the studies, it can be concluded that LP does not have a teratogenic, embryotoxic effect, does not reduce reproductive function and does not violate the development of offspring in the postnatal period of life.

The carcinogenic properties of the drug were investigated by introducing it into the bladder in dogs mixed with non-acryl 65 quick-hardening plastic, as well as in mice and rats, which were applied 3-5 times a week to the shaved areas of the skin in the interscapular region for a year. Experimental and control mice and rats were kept under standard conditions until natural death, dogs were killed after 2.5 years, their pathological, anatomical and histological studies were performed.

Summarizing the obtained data, it can be concluded that LP does not cause the formation of tumors or changes characteristic of this pathology in the bladder, skin, and other internal organs of animals, i.e., does not have carcinogenic activity.

The study of spermicidal action was carried out according to the method recommended by WHO. For this, human sperm were mixed with various concentrations of LP and their motility was monitored under a microscope, as well as other parameters were studied (pH, reduction of methylene blue, test of contact with cervical mucus, level of fructose, etc.). In total, 27 sperm of men aged 18-23 years were examined. The results of the experiments showed that the optimal concentration of the drug stopping sperm motility within 30 s is 0.02%. Higher concentrations of the drug lead not only to instantaneous immobilization of spermatozoa, but also to their lysis.

The effect of drugs on the function of mucociliary transport. It is proved that mucociliary clearance plays a leading role in the protective function of the nose and paranasal sinuses. Many drugs suppress the transport function of the ciliated epithelium of the nasal mucosa, therefore, are not used in otolaryngological practice.

The effect of the drug on the function of mucociliary transport was studied in an experiment on the mucosa of the frog’s esophagus, as well as in a human clinic using a saccharin test, a polymer film with methylene blue and saccharin, and using a radionuclide tag. It has been proven that in concentrations of 0.01 and 0.05%, LP does not affect the transport function of the ciliated epithelium, and in patients with sinusitis normalizes mucociliary clearance.

The study of the preventive and therapeutic effects of drugs in animals

The prophylactic effect of drugs in sexually transmitted diseases was studied on a model of experimental syphilis in rabbits. The experiments were carried out on 156 chinchilla rabbits, which were infected with a freshly prepared suspension of pale treponema (Nichols and TsKVI-8 strains) by the cutaneous method. After 30, 60, 120, 180 and 240 min after infection, the skin of the infected area was treated with a 0.01-1.0% solution of LP. The control rabbits were treated with distilled water. All animals were under clinical and serological control for 6-12 months. For control, we used the Wassermann reaction (RV), RIBT and RIF, which were set from 1.5 months after infection every 2-3 months. We also used methods of passaging the lymph nodes and re-infection into the skin of the scrotum by suspension of treponem of a similar strain. The results of the experiments showed that the treatment of experimental rabbits with a 0.01-1.0% solution of LP in the period from 30 minutes to 2.5 hours from the moment of infection leads to 100% protection of animals from syphilis.

The therapeutic effect on the models of purulent wounds and peritonitis in experimental animals (rats, rabbits, guinea pigs, dogs of more than 500 animals) was carried out according to generally accepted methods using bacteriological, morphological, histological and immunological research methods.

The data obtained showed a high therapeutic activity of the drug used in the form of an aqueous solution, ointment and aerosol for purulent-inflammatory diseases and peritonitis in experimental animals. LP turned out to be a more effective drug in the treatment of purulent wounds compared with the widely used antiseptic chlorhexidine bigluconate (Table 4).

It has been statistically reliably proved that the observed positive effect in experimental animals is due to the stimulating effect of the drug on resistance factors - the phagocytic index and neutrophil bactericidal activity. The antiseptic chlorhexidine bigluconate does not have a similar effect (Table 5).

Analyzing the data obtained when using a 0.5% LP ointment for the treatment of purulent experimental wounds in rabbits, it can be concluded that the ointment has a pronounced therapeutic effect, which is associated with a bactericidal effect, a decrease in microbial load, enhancing regeneration and stimulating local immune responses. The study of the antifungal effect of the ointment LP.

In models of candidiasis in guinea pigs, reproduced by intradermal administration of SapbLa AlSapc, followed by scarification and trichophytosis caused by rubbing of the cells of Tps1yur11u1optit (strain 796) into a previously depilated and scarified skin area on the lateral surface, the therapeutic effect of 0.5% ointment was studied. For comparison, the official antifungal ointments undecin, clotrimazole and cicundan were used.

Summarizing the results obtained, we can conclude that the therapeutic effectiveness of the ointment containing 0.5% of the drug is quite high and exceeds the effectiveness of the comparison ointments. So, by the 4th day of applying the ointment, the area of lesions caused by candida albicans and trichophyton decreased by 2 times, the center of the focus was cleared of ulcers, crust erosion, tissue contamination by pathogenic fungi decreased by 1-2 orders of magnitude, and by the 8th day there was a clinical recovery. Summing up the research results, we can conclude that the ointment LP is an effective antifungal agent that has advantages over analogues.

The therapeutic effect of drugs on mouse burn models.

In mice on a depilated dorsal surface of the back, a thermal contact burn was caused using a standard device. Treatment was started 24 hours after the burn with ointment and aerosol with 0.5% of the drug. For comparison, the official ointment levosin was used. The results are presented in table. 6.

As can be seen from the data table. 6, a significant decrease in the area of wounds during treatment with ointment and aerosol with LP begins after 8 days, which is 4 days earlier than in the control. It can be argued that this reduction occurs due to the accelerated transition from the inflammatory phase to the repair phase and is associated with the anti-inflammatory and immunoadjuvant properties of the drug.

The effect of LP in purulent-inflammatory lesions of the cornea of the eyes.

The experiments were performed on 14 chinchilla rabbits weighing 2-2.5 kg. Purulent inflammatory lesions of the cornea were caused by introducing into the cornea of the eye a daily culture suspension of 81 aryu1ossossik aiteik strain 209 R. On day 2-4, 13 rabbits on the cornea of the eye formed ulcers 3x6 mm in size with purulent discharge at the bottom, and inflammatory reactions were observed: conjunctivitis , blepharospasm, etc.

Test rabbits were divided into three groups. The animals of the first group were treated with a solution of LP (eye drops based on LP LPGK), the second with official decamethoxin eye drops (DHA), and the animals of the third, control group, were injected with isotonic sodium chloride solution in the affected eyes. Preparations were instilled daily three times throughout the experiment.

All animals were monitored daily, monitoring the dynamics of changes in the cornea of the eyes of experimental and control animals according to the previously described method. In addition, we carried out inoculations of flushes from the cornea of rabbits' eyes for meat-peptone broth to determine the presence of 8. aiteic 209 R. The results of the experiments are presented in table. 7.

The data presented indicate that purulent discharge and detection of 8. aiteic completely stopped on the 4th and 6th day in all animals treated with LPGK and DHA, respectively. At the same time, among untreated animals purulent discharge was observed throughout the entire period of the experiment.

Resorption of purulent infiltrate faster began and ended in all animals treated with LPGK on the 3rd day, and DHA on the 5th day from the start of treatment. In animals treated with LPGK and DHA, the time of onset and completion of resorption of purulent infiltrate was 4 and 10 days, respectively, from the start of treatment. Epithelization of the cornea of the eyes occurred in all animals by the 10th and 16th day from the start of treatment with LPGK and DHA, respectively.

Thus, from the above data it can be concluded that LPGCs are a highly effective agent in the treatment of purulent-inflammatory lesions of the cornea, and the therapeutic effect of LPGCs is higher than that of DHA (decamethoxin eye drops), which are produced by industry.

Clinical researches

A clinical study of drugs as a means of individual prevention of sexually transmitted diseases was carried out in 7 leading skin and venereological institutions, and as an antiseptic for the treatment and prevention of purulent-inflammatory processes in 20 clinics of the surgical, obstetric, gynecological, ophthalmological, otorhinolaryngological, and combiological profiles.

The analysis of reports received from medical institutions showed that the drug in various dosage forms did not have a harmful side effect on the human body, did not cause skin or mucous membrane irritation, as well as allergic reactions.

Venereology.

The use of a 0.01% solution of PL for the prevention of sexually transmitted diseases by treating the urethra, vagina and external genital organs protects patients in 100% of cases if the drug was used no later than 2.5 hours after intercourse. In total, more than 1000 patients at risk were under observation.

Urology.

The use of drugs in the treatment of acute and chronic urethroprostatitis of specific and nonspecific etiology revealed its high efficiency, which was confirmed by a complete clinical cure, as well as a decrease in the duration of treatment (Table 8). Methods for the use of drugs in the treatment of chlamydial urethroprostatitis have been developed.

Surgery.

The use of various dosage forms of drugs (aqueous and alcoholic solutions, ointments, gels, aerosols, glue) for the treatment and prevention of purulent-inflammatory processes of various etiologies and localizations revealed their high efficiency and the absence of adverse reactions.

The drugs were used with a positive effect in the purulent wounds of traumatic and postoperative wounds, hands and fingers, pleuropulmonary and burn, post-amputation wounds for obliterating vascular diseases of the extremities (Table 9), fistulas, bedsores, and trophic ulcers, as well as peritonitis (Table 10). Aqueous and alcoholic solutions of drugs have been tested as antiseptics for treating the surgeon's hands and the surgical field. Glue LP proved to be highly effective for the prevention of purulent complications of microtraumas and non-dressing management of postoperative wounds.

Obstetrics and gynecology.

Drugs have shown high efficiency in the treatment and prevention of purulent-inflammatory processes that occur after ruptures of the perineum and vagina during childbirth, after cesarean section, vaginal hysterectomy, conservative plastic vaginal operations, prevention of puerperal infection in women with OPH-gestosis (Table 11), and also in the treatment of inflammatory diseases of the vagina of a non-specific and specific (chlamydia, herpes, etc.) etiology - vulvovaginitis, colpitis, cervicitis, etc.

Otorhinolaryngology.

Large-scale trials of drugs in ENT practice revealed its high efficiency in the treatment of inflammatory diseases of the paranasal sinuses - acute and chronic sinusitis, rhinosinusitis, as well as tonsillitis, laryngopharyngitis, etc. (Table 12). The observed effect is due to the antiseptic and immunoadjuvant properties of the drug, as well as the fact that it does not suppress mucociliary clearance of the mucous membrane.

Ophthalmology.

Drugs in the form of eye drops (0.01% drug solution in 0.9% sodium chloride solution) were tested for the treatment of conjunctivitis of a nonspecific and specific (chlamydial, gonococcal) etiology. The high clinical (90.4%) and etiological (63.7%) efficacy of the etiopathogenetic treatment of ophthalmic chlamydia with topical application in the form of installations in the conjunctival cavity of 0.01% LSA was established.

LPHCs were also effective in preparing patients for intraocular operations and their postoperative management for the prevention of purulent-inflammatory complications.

The observed effect, in our opinion, is due to the antiseptic, anti-inflammatory, antichlamydial, immunomodulating effect and the ability of the drug to normalize the local fibrinolytic potential of the conjunctiva of the eye.

Dermatology.

Various dosage forms of LP have been tested in dermatology for mono- and complex therapy of bacterial and fungal skin diseases. Drugs in the form of ointments and gel are highly effective in the treatment of strepto- and staphyloderma, candidiasis of the skin and mucous membranes, foot mycoses and large folds, including dyshidrotic forms and forms complicated by pyoderma, smooth skin dermatoses, onychomycosis and keratomycosis, pityriasis versicolor. In patients with various clinical forms of pyodermatitis, a positive effect was achieved in 98.3% of cases, which reduces the average treatment time by 2-3 days compared with traditional methods of therapy. A positive therapeutic effect was noted for acne and herpetic lesions of the skin and mucous membranes (Table 13).

Immunoadjuvant properties of drugs in the treatment of purulent-inflammatory diseases in humans

It is well known that patients with purulent inflammatory processes, as a rule, develop immunological deficiency in the form of a violation of local and general immune reactions (Kuzin MI, Kostyuchenok BM Wounds and wound infection. A guide for doctors. -M.: Medicine. 1990, 591 pp .; Theory and practice of local treatment of purulent wounds, under the editorship of B. Datsenko, Kiev, Zdorovya, 1995, 383 pp.).

Numerous laboratory and general clinical research methods have reliably shown that the positive therapeutic effect of drugs in purulent-inflammatory processes is due not only to its antimicrobial properties, but also to a stimulating effect on the body's immune responses.

In the treatment of 68 patients with chronic urethroprostatitis with the use of drugs, they observed significantly significant stimulation of the absorption capacity of urethral neutrophilic granulocytes (Table 14). The positive therapeutic effect upon the inclusion of LP in the therapy was 92.8% and exceeded the effect obtained with thymalin immunomodulator (86.9%). In the group of patients who received basic therapy without immunoadjuvants, a positive effect was noted only in 52.9% of cases.

In the treatment of 235 patients with various clinical forms of pyoderma, the inclusion of 0.5% ointment in the complex therapy of the ointment made it possible to obtain a positive clinical effect in 98.3% of cases, while in the compared group this effect was achieved in 89.2% of cases.

In patients with pyoderma, indicators of the immunological reactivity of the body are changed. LP has a stimulating effect on the opsonophagocytic mechanism and other indicators of immunity (see table. 15). Based on the presented data, it can be concluded that the immunomodulatory effect of 0.5% ointment in the treatment of patients with pyoderma occurs due to the effect of the drug on the activity of oxygen-dependent microbicidal systems with a parallel increase in their reserves in phagocytic cells, changes in the antigenic irritation of the receptor apparatus of monocytes and lymphocytes, and stimulation of fibronectinsynthetic leukocyte function, etc.

A similar effect on the immune factors of the body of various forms of LP was obtained in the treatment of patients with purulent-inflammatory diseases of various etiologies and localization in surgical, obstetric, gynecological, ophthalmological, otorhinolaryngological and other clinics.

In the results of numerous experimental and clinical studies, it was noted that LP is superior in effectiveness to the widely used antiseptics of chlorhexidine bigluconate, furatsilin, iodvidon, etc. and can be recommended for widespread use in clinical practice.

The disinfecting activity of drugs

The use of drugs for surgical antiseptics

Experimental justification for the use of 0.1% aqueous and 0.1% alcohol solutions of drugs for surgical antiseptics.

The experiments were carried out under conditions consistent with the practical use of antiseptics. We used the method of M. Ko Ne g (Koyeg M. NuDhes Naib E51nGes11op // 1nGes1. Soi. 1984. No. 1. P. 18-22) on human volunteers with the calculation of the reduction coefficient after contamination of the skin with standard test strain E. soi . As a control, we used methods for treating hands with first-aid and 0.5% alcohol solution of chlorhexidine bigluconate (gibitane) in accordance with applicable standards (Order of the Ministry of Health of the USSR No. 720-78; Instruction of the Ministry of Health of the USSR No. 06-14 / 10 of 3.08.84).

The remanent aftereffect of the LP was established in the model of K. Muib et al. (Muayib K., Ms. Sga111 M., Soo5 Arreisayop OG a Dauebba pb tobe Gog tiiryagatei teakigeshei OG 8kt-be1egttd asbuyu // 1. K1t. Mugo. 1976. No. 3. N. 406-413).

An analysis of the data shows that during contamination of the hands with E. test strains, soy in 1 ml of washout contains an average of 1.4x10 ⁵ microbial bodies (5.15 log). Hand treatment with 70% alcohol, first-time, 0.5% alcohol solution of chlorhexidine bigluconate, as well as alcohol and water solutions of the drug led to a decrease in their seeding, but to varying degrees. 70% alcohol turned out to be the least effective of the studied solutions (reduction coefficient 3.47 1d ₁₀ ). The antimicrobial effect that meets the requirements for antiseptics used for surgical treatment, regulatory documents, was obtained when testing 0.1% aqueous and 0.1% alcohol solutions of drugs. Exposure of contaminated hands in a 0.1% antiseptic aqueous solution for 3 and 5 minutes yielded the same results: reduction coefficients were 5.11 1§ι ₀ . The highest reduction coefficient (5.15 1d ₁₀ ) was obtained using a 0.1% alcohol solution of the drug.

When treating contaminated hands with first-aid, the reduction coefficient was 4.94 1d ₁₀ , and with a 0.5% alcohol solution of chlorhexidine bigluconate - 5.04 1d ₁₀ .

The high efficiency of a 0.1% aqueous solution of LP was also confirmed in experiments on 20 volunteers without artificial contamination with a standard test culture of their hands, as well as in testing solutions of LP in clinical practice. Crop washings from the skin of the hands of all 20 volunteers treated with 0.1% aqueous and alcoholic solutions of the drug gave reduction coefficients from 2.5 1 §10 to 3.3 1 d _{1 ()} .

The remanent aftereffect of the drug solutions was checked on 10 volunteers, whose hands, after contamination of E. soy and treatment with the appropriate preparation, were put on with sterile surgical gloves, and then immediately and after 1, 2 and 3 hours they were sown from the skin of the hands, the number of grown E. soy and the reduction coefficient was determined.

The data obtained show that the reduction coefficients when using both drugs were high (5.22-5.25 1d ₁₀ ) and remained at these levels for 3 hours.

An analysis of the results of experiments on the effectiveness of processing the skin of the surgical field and elbow bends in 84 volunteers showed that the desired disinfecting effect is achieved using a 0.1% alcohol solution of the drug, as well as a 0.5% alcohol solution of chlorhexidine bigluconate (reduction factors 2.5-3 , 4 1d ₁₀ ), which corresponds to generally accepted standards.

Summarizing the results of the studies, we can conclude that 0.1% aqueous and 0.1% alcohol solutions of drugs in their properties meet the requirements for antiseptics used in surgical practice, they provide a quick disinfecting effect. The reduction coefficients of the drug solutions, as well as the remanent aftereffect, are superior to those of Pervomura and chlorhexidine bigluconate, preparations currently used for surgical antiseptics (Table 16).

A high disinfecting activity of a 0.1% alcohol solution of the drug during treatment of the surgical field and skin of the elbow bends was also revealed.

In no case of using 0.1% aqueous and 0.1% alcohol solutions of medicinal product, no adverse local or general reactions were noted. A positive point is the resistance of working solutions of drugs to the action of external factors and their long shelf life (observation period 3 years).

The prophylactic effect of drugs in infected wounds.

In the experiment, studies were performed on rats in which wounds were modeled according to the generally accepted method, infecting them with 8. aigeik. After 30 minutes, the wounds were treated with PL solutions, after which the development of the wound process was monitored using generally accepted indicators (see Table 17). Analysis of the obtained data shows that the best preventive effect was achieved when using aqueous and alcoholic solutions of drugs for treating infected wounds as compared with solutions of chlorhexidine bigluconate and iodine.

Clinical trials of aqueous and alcoholic drugs solutions for the prevention of purulent complications with microtraumas were carried out in the factory in workshops of increased injury for 3 years. Of 107 people with microtraumas and abrasions that came to the plant’s first-aid post, after treatment with drugs with solutions, secondary infection was observed in only 5 people (4.5%). In the control group (128 people), where microtrauma treatment was carried out with dyes (brilliant green, fucorcin, methylene blue), as well as iodine, accession of a secondary infection was observed in 49 people (34.6%). It was noted that the healing of microtraumas in individuals who underwent treatment with drug solutions occurred in the period from 3 to 6 days (on average 3.5 ± 0.6 days), while in the group where dyes were used, these terms ranged from 5 up to 8 days (average 5.5 ± 0.3 days).

The observed effect of drug solutions in the prevention of purulent complications of microtraumas is due to the pronounced antimicrobial effects of the drug and its ability to stimulate local immune and regenerative processes.

Table 1 Antimicrobial activity of drugs in relation to various taxonomic groups of microorganisms

Name of microorganisms Minimum concentration (mcg / ml) overwhelming drug 1. Gram-positive organisms: staphylococci, streptococci, 0.1 - 10.0 bacilli, mushrooms 2. Gram-negative organisms: 2.1. gonococci, aegierichia, shigella, salmonella, vibrios, chlamydia 2.0-20.0 2.2. Proteus, pseudomonads 50,0 - 200.0 3. Dctinomycetes: mycobacteria, corynebacteria 50,0 - 200.0 4. The simplest: Trichomonas 2.0 - 20.0 5. Viruses: herpes, HIV, flu, adeno 0.1 - 10.0

Table 2 Antiviral activity of the drug ίη νίίτο

Table 3

Minimum concentrations of various disinfectants that inactivate HIV

Drug name Ethanol Minimum | virus inactivating concentration (in%) 50.00 Link Sodium Hypochloride (No.aOS!) 0.10 one Paraformaldehyde 0.50 one Hydrogen peroxide 0.30 one Nonide R-40 1.00 one Twin 20 2,50 - does not inactivate one Chlorhexidine bigluconate 0.02 0.05 2 Nonoxynol-9 0.05 3 LP (medicinal 0.005 - 0.01 a drug) ....... .. -. ... - _____________________one

1. Maysh L.8., Ms Oonda 1 B.8., Luck! B. ΌοδίηίοοΙίοη apb shasbuabop οί Н1У // B. ! pGes (. ϋΪ8.-1985.-νο1.152.-Ρ. 400-403.

2. Natkop M.A., Natteg 8.M. 1 passbuabop ίί Ηΐ у (((аб аб аб аб аб аб (((иск иск иск // // // // // // // // // Б ГО ГО § §----.

3. Rokku V., Vagop R.R., Co1b IV., 8tbb I., Beppsep K.N., Agtzbopd Ό. 1n Uygo Shasbuabop OG -ν-1 у со со Ш ас ас ас ас ас де соп! А шеб шеб шеб шеб -9 -9 -9 1-9 // Lapse1.-1988.

Table 4 The results of the action of drugs on the healing of purulent wounds in experimental animals (rats, guinea pigs, rabbits) compared with the antiseptic chlorhexidine bigluconate (in days)

Groups of animals Registration Start Complete healing Control (treatment of wounds with distilled water) 7.2 + 1.1 20.0 ± 3.5 Healing 0.02% chlorhexitin bigluconate 4.5 +0.7 14.7 + 1.3 Treatment 0.01% LP 2.7 ± 0.3 10.3 + 0.9

Table 5

Dynamics of the neutrophil phagocytosis index (numerator) and the peripheral blood neutrophil bactericidal index (denominator) in the treatment of LP wounds in experimental animals

Group number Qty LIVING X Method of treatment Terms of treatment one the control 25 1 day 3 days 5 days 4.0 + 0.2 47.6 + 0.4 7 days 4.2+ 0.2 43.1 + 0.1 10 days 4.0+ 0.6 42.2 + 0.3 Isotonic solution of sodium chloride 3.2 + 0.6 3.6 + 0.32 54.5 + 0.3 56.3 + 0.8 2 the control 25 0.02% solution of chlorhexidine bigluconate 3.4 + 0.4 3.6 +0.4 56.3 + 0.4 3 ^ 8 + 0 ^ 2 54.2 + 0.4 3.6 + 0.4 52.3 + 0.2 3.2 +0.3 50.3 + 0.3 57.1 +0.4 3 experience 25 0.01% r-rLP 4.2 + 0.4 5.6+ 0.4 60.3 + 0.5 5.2 + 0.3 57.3 + 0.4 3.9 + 0.9 53.1 +0.2 3.6 0 +0.3 55.1 +0.8 64.3 + 0.4

Table 6

The results of the planetometry of burn wounds treated with ointment and aerosol LP

Day Area of burn wounds, see sq. The control Levosin 0.5%> ointment 0.5% LP aerosol g 0.72 + 0.05 0.88 + 0.05 0.80 + 0.06 0.99 + 0.08 4 0.77 + 0.66 0.80 + 0.09 0.85 ± 0.07 0.81 + 0.09 6 0.80 ± 0.05 0.76 + 0.08 0.85 + 0.09 0.62 + 0.06 8 0.78 + 0.10 0.74 ± 0.06 0.83 + 0.10 0.76 ± 0.07 12 0.81 + 0.05 0.75 ± 0.05 0.70 + 0.06 0.24 ± 0.04 fifteen 0.36 + 0.05 0.20 + 0.02 0.18 + 0.03 0.14 + 0.03 eighteen 0.14 ± 0.04 0.10 + 0.03 0.08 ± 0.02 0.03 + 0.017 twenty 0.03 + 0.017 0.013 ± 0.001 0.012 ± 0.002 0.01 + 0.001

The results of the treatment of purulent-inflammatory lesions of the cornea of the eyes in rabbits with LP and decamethoxin eye drops

Table 7

Signs of therapeutic effect Animal Group Number The frequency of detection of signs of a therapeutic effect in the cornea (in%) according to the observation period (days): ** 2 3 4 5 6 7 8 10 12 14 sixteen eighteen twenty Lack of purulent one fifty 90 one hundred also also also also also also also also also also detachable eye 2 (YU) (YU) (YU) 88 (9) one hundred also also also also also also also also 3 12 (9) 0 (6) 12 (9) 0 (6) 55 (9) 0 (6) 0 (6) (9) 0 (6) 16 (6) 50 (6) 66 (6) 66 (6) 83 (6) 83 (6) 83 (6) 100 (6 Lack 8. aigeez one 0 (U) 90 one hundred also also also also also also also also also then in detachable eye 2 0 (9) (YU) (10) 88 (9) one hundred also also also also also also also same 3 0 (6) 44 (9) 0 (6) 66 (9) 0 (6) 0 (6) (nine) 0 (6) 16 (6) 50 (6) 66 (6) 66 (6) 83 (6) 83 (6) 83 (6) same 100 (6 Resorption one 0 (U) 40 70 one hundred also also also also also also also also also purulent 2 0 (9) (YU) (YU) (10) 55 (9) 66 (9) 88 (9) one hundred also also also also also infiltrate 3 0 (6) 0 (9) 0 (6) And (9) 0 (6) 44 (9) 0 (6) 0 (6) 0 (6) 16 (6) (9) 16 (6) 33 (6) 33 (6) 33 (6) 66 (6) 66 (6) one twenty thirty thirty fifty 80 80 (10) 80 one hundred also also also also also Epithelization 2 (YU) (10) (10) (YU) (YU) 22 (9) (10) (10 33 (9) 77 (9) one hundred also also 3 0 (9) 0 (6) o (9) 0 (6) o (9) | 0 (b) P (9) 0 (6) H (9) 0 (6) 22 (9) 33 (9) 0 (6) 16 (6) 16 (6) (9) 33 (6) 33 (6) _ fifty (6)

Note:

(*) 1 group of animals receiving LP eye drops;

a group of animals that received decamethoxin eye drops;

control group of animals.

(**) In parentheses is the number of eyes examined.

Table 8

Table 12

The effectiveness of treatment of patients with trichomonas urethritis

G ” Signs of the disease The time to normalize the signs of the disease in patients with urethritis (in -one Group of patients. receiving drugs (n = 33) A group of patients receiving basic drugs (n = 20) Credibility I Subjective sensations 2.24 ί 0.19 4.15 0.44 0.001. _________________________________ | Urethral discharge 2.64 ¹ 0.21 G '3.73 - 0.81 3.9 0.41 0.01 Nore urethral malization 5.50 0.45 0.ΟΙ Treatment duration sick 11.91> 0.32 18.3 0.56 0.01

The results of treatment of patients with purulent sinusitis using LP

Observation Parameters

The number of patients in groups

- conservative and operative in the nasal cavity

Table 9

The terms of postoperative treatment (in days) for various methods of post-amputation wound management in patients with obliterating diseases of the extremities

- operative on SNP followed by conservative treatment

Clinical Group | 1 group (0,0]% r-rLP) 2 group (0.02% chlorhexidine solution) 3 group (traditional treatment) Diabetic | 12.6 ί 1.6 (n = 19) 23.4 ± 1.2 (n = 28) 31.9 ί 14.7 (n = 30): gangrene Atherosclerotic 11.2 1 1.2 (n = 26) 22.1 + 1.3 (n = 43) 24.9 ζ 0.8 (11 = 461 gangrene ί Gangrene on the soil 15.0: 1.0 (n = 3) 16.0 ί 0.9 (n = 3) 49.6! 2.5 (11 = 51 obliterating zoonoarteritis Total (n = 203) 12.1 ± 1.3 (n = 48) 22.3 ί 1.2 (n = 74) 29.1 + 1.2 (n + 81)

| Allergic reactions to the applied 1 drug_

Duration of conservative treatment (in days)

11 treated patients in groups

Methods of treatment:

- conservative

Treatment Outcome:

- recovery

- improvement

- no change

- conservative and operational in ONP

Note: ONP - paranasal sinuses; LP - a drug; CG - chlorhexidine bigluconate.

Table 13

The results of treatment of patients with various forms of herpes 0.5% ointment LP

Table 10

The results of treatment of patients with diffuse peritonitis with the inclusion in the treatment complex of 0.01% solution of LP

Indicators Control group Main group abs. % abs. % Treatment duration 28.5 + 2.5 eighteen 5 + 1,5 (bed days) Suppuration of the wound sixteen 53.3 7 23.3 Eventration 2 6.6 one 3.3 Abdominal abscess 2 6.6 Intestinal fistula one 3.3 Mortality 7 (3) 23.3 one 3 (0) 10.0

Diagnosis Patient count Treatment results Up to 7 days (cf. 4.3) Up to 10 days (cf. 7.2) Over 10 days (cf. 12.3) Herpes simplex 37 31 5 one Tinea herpes twenty 6 thirteen one Anogenital herpes eighteen 12 4 one TOTAL 75 49 (65.7%) 22 (29.3) 3 (5%)

Table 14 Change in the phagocytic activity of urethral neutrophilic granulocytes in patients with chronic urethroprostatitis under the influence of LP

Table 11 The dynamics of the clinical course of postpartum injuries of the perineum and vagina under the preventive use of drugs (day)

Prevention method The beginning of wound cleansing The appearance of marginal nodulation 0.01% solution LP (n = 45) 2.7 ± 0.41 2.8 ± 0.42 0.02% solution of chlorhexidine bigluconate (n = 31) 4.1 + 1.27 4.1 + 1.27

The appearance of granulations

Seam divergence (qty)

3.7 ± 1.63 ί 2

Treatment duration

Note:

* statistically significant differences with control;

** Statistically significant differences in experience.

Table 15

The effect of treatment of patients with pustular skin diseases 0.5% ointment LP on the immune system

Learning Tests

Control

Main group

Chronic superficial staphylodermine

Acute deep streptoderma

Acute superficial streptoderma

1. HCT- (norm 15.2 + 1.4)

2. EA-ROM% (23.1 + 1.5)

3. PF (μg / ml) (382.9 + 9.2)

Acute deep staphylodermine

I Groups

I sick__

Acute superficial staphylodermine

3. NF (μg / ml)

3. PF (μg / ml)

3. PF (μg / ml)

3.11F (μg / ml) surface mixed pyoderma

Chronic deep mixed pyoderma deep staphylodermine

2. EA-ROM%

3. PF (μg / ml)

Note: HCT test is a nitrosine tetrazolium reduction test; EA-ROM% - a test characterizing the EC receptors of peripheral blood monocytes in the presence of autologous microbial antigens; PF - plasma fibronectin; RBTL with PHA - the reaction of blast transformation of lymphocytes with phytohemagglutinin; E-ROCK - E rosette-forming cells.

* Significant differences before and after treatment in one group.

Table 16

Comparative analysis of the treatment of the surgeon's hands with various drugs

Processing method Number of cases CFU / ml Reduction ratio CFU / ml | after operation Reduction ratio ί Unwashed hands After processing 0.1% water LP solution 40 1175 ± 112 0.65 ± 0.2 3.25 2.10 2.74 0.1% alcoholic 40 1380 ± 132 0.72 ± 0.3 3.28 1.95 ί 2.85 LP solution | Solution 21 1097 ± 98 0.96 + 0.4 3.05 2.28 2.68 1 first-born | 0.5% alcohol ! commodity solution 23 1137 ± 125 0.82 + 0.3 3.14 2.26 2.70 I chlorhexidipa ΐ bigluconate ..........one

Table 17 The dynamics of the development of signs of the wound process in rats, depending on the drug used to treat the wound 30 minutes after its application and infection 8. aigeik

No. pp Cool x The method of treatment of wounds Signs of a wound process (per day): no soldered the beginning of gra Sue Average her purification zero wide speed signs cancer zpshpeliza- healing 1 suppuration __ (% put up) [ one. thirty 0.025% water solution 28 3,810,3 4,810.31 10.3 * 3.21 10,310,22 LP 1 ² - thirty 0.01% alcohol solution 28 3,710,3 5.21 0.42 10.6 ± 3.3 10.9 + 0.31; LP 3. thirty 0.05% aqueous solution of chlorhexindine bigluconate 23 4,810,43 6,210.52 12,914,2 ⁷ , 2 ± 0.32 4. 25 Isotonic solution sodium chloride eighteen 14,310,9 15,210,29 25.2 + 4.5 3.41 + 0.18 5. twenty 5% alcohol 12 10,210,3 12.4 + 0.45 21.3 + 5.3 4.91 0.21 iodine solution ______

CLAIM

Claims (4)

1. A medicine for the treatment and prevention of infectious and inflammatory diseases, including benzyldimethyl [3 (myristoylamino) propyl] ammonium chloride and a pharmaceutical diluent, characterized in that it contains benzyldimethyl [3 (myristoylamino) propyl] ammonium chloride as a monohydrate. 2. The drug according to claim 1, characterized in that it contains water and / or alcohol and benzyldimethyl [3- (myristoylamino) propyl] ammonium chloride monohydrate in amounts of 0.01-1.0% as a pharmaceutical diluent. 3. The drug according to claim 1, characterized in that as a pharmaceutical diluent it contains any plant, animal and synthetic base in the following ratio of components (in%): Plant, animal or synthetic base 99.0-99.9 Benzyldimethyl [3 - (myristoylamino) propyl] ammonium chloride monohydrate 1.0-0.01 4. The use of the drug according to claims 1-3 for the treatment and prevention of infectious and purulent-inflammatory diseases of various etiologies and localizations, as well as an agent with antiseptic, disinfectant, spermicidal, antiviral and immunomodulatory effects.