RU2497508C2 - Acaricidal pharmaceutical composition of quaternary phosphonium salts, substituted dinitrobenzofuraxan and xymedon hydrochloride - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary science, and may be used in veterinary science in treating parasitic skin diseases in animals caused by itch mites. An agent for itch mite treatment in veterinary science contains a quaternary phosphonium salt, substituted dinitrobenzofuraxan, xymedon hydrochloride and dimethylsulphoxide in weight ratio 0.1:1:10:100. The treatment uses 1% emulsion of the given agent in dimethylsulphoxide.

EFFECT: agent is non-toxic and possesses the high acaricidal efficacy after two administrations every 7-10 days.

4 tbl, 7 ex

Description

The invention relates to the field of agriculture, in particular to veterinary medicine, and can be used in the treatment of parasitic diseases of the skin of animals caused by scabies mites (scabies) in animals.

Under the name "scabies mites" mites are usually combined - parasites of humans, domestic and wild animals that parasitize them inside or on the skin and cause a long-term illness - scabies. Scabies mites belong to the type of arthropods, to the class of arachnids and to the order of mites.

Sarcoptoidosis in most cases proceeds in a chronic form, which is the reason for the lack of treatment and preventive measures. However, these invasions cause significant economic damage, which consists of a decrease in animal productivity, deterioration of the quality of the skin, the cost of treatment and preventive measures, etc., as shown in [Tokarev, A.N. The study of the activity of "Insectoacaricide - D" / A.N. Tokarev // Mat. scientific -. practical conf. "The contribution of young scientists to industry science, taking into account current trends in the development of agribusiness." - M., 2008. - S.265-266.].

The range of clinical signs in diseases caused by parasitic ticks is wide: from itching and local skin lesions to intoxication and depression of the central nervous system.

In different years, for the treatment of animals with sarcoptoidosis, chemicals from the group of phenols, sulfur, hexachloran were used [K. Abuladze Workshop on the diagnosis of invasive diseases of farm animals. M.:, "Ear", 1984, 252 S.]. The first of them have a weak acaricidal effect, and the latter are highly toxic substances for animals [Akbaev M.Sh. et al. Parasitology and invasive animal diseases. M.:, "Kolos S", 2002, 743 pp.]. In recent years, organophosphorus preparations, pyrethroids and macrocyclic lactones have been used to combat sarcoptoidosis, which destroy ticks parasitizing on animals and are relatively rapidly destroyed in the environment, which reduces their danger to animals [Akhmadeev, R.N. Acaricidal and therapeutic effectiveness of sulfoxides and sulfone in rabbit psoroptosis / R.N. Akhmadeev // Mat. Republic scientific and technical. conferences. - Kazan. - 1978. - S.20-21.].

However, in most cases, parasitic insects and ticks quickly become resistant to the drugs used, which necessitates the development and testing of new insectoacaricidal agents to combat ectoparasites of animals [Akbaev M.Sh. et al. Parasitology and invasive animal diseases. M.:, "Kolos S", 2002, 743 pp.].

One of the ways to solve the problem is to create anti-scabbing agents that have a multifaceted effect: ovocidal, analgesic, anti-inflammatory, immunomodulating, and wound healing.

The objective of the invention is to develop an acaricidal composition for the treatment of parasitic diseases of the skin of animals and birds caused by scabies mites (scabies).

The essence of the invention lies in the fact that they use a pharmaceutical composition in the form of a spray consisting of a quaternary salt of phosphonium (1), substituted dinitrobenzofuroxan (2), xymedonhydrochloride (3) and dimethyl sulfoxide, as a solvent (Degelm KD).

The main active ingredients of the desired composition are the pharmaceutical composition of the Quaternary phosphonium salt (1) and substituted dinitrobenzofuroxan (2), penetrating the tick cuticle and destroying it. The prototype of this application is our patent of the Russian Federation No. 2413513, publ. 03/10/2011 Bull. Number 7.

A new therapeutic composition based on a mixture of the quaternary salt of phosphonium (1), substituted dinitrobenzofuroxan (2), xymedonhydrochloride (3) and dimethyl sulfoxide allows you to get a new acaricidal pharmaceutical composition, namely a composition with a higher acaricidal and therapeutic effect, superior to currently used funds [Ilyaschenko V.I. Testing new acaricidal drugs for carnivore otodectosis. Sat scientific tr Semipalatinsk ZVI, part 1. Semipalatinsk, 1995. P.67-70].

For a better understanding of the invention, examples are given below.

Example 1. Obtaining acaricidal pharmaceutical composition Degelm KD.

In a porcelain mortar, 0.1 g: 0.1 g of the phosphonium quaternary salt of n-hexadecyltriphenylphosphonium bromide of the formula (1), 1 g of 5,7-bis- (m-nitroanilino) -4 is mixed and triturated; 6-dinitrobenzofuraxan (2) and 10 g of xymedone hydrochloride (3) to obtain a uniform red powder. Then, in portions with thorough stirring, add 100 ml of dimexide (solvent) and stir until a homogeneous liquid is obtained. The liquid is the dosage form of the Degelm KD pharmaceutical composition for the treatment of animals infected with scabies mites, which is used as a spray.

The synthesis of salt (1) and furoxan (2) is described in our patent of the Russian Federation No. 2413513, publ. 03/10/2011 Bull. Number 7. A method of producing xymedone hydrochloride (3) is described in RF patent No. 2044730, publ. 1995.9.27, RF patent 2219910, publ. 2003.12.27, RF patent 2086240, publ. 1997.08.10.

Example 2. The study of the acaricidal activity of "Degelm CD" against ticks P.cuniculi in vitro.

The studies were carried out in vitro on isolated P.cuniculi ticks taken from spontaneously infested rabbits according to the method of V. Ilyashchenko. [Ilyaschenko V.I. Sarcoptoid mites, the improvement of diagnostic methods and their control .: Abstract. dis. Doct. biologist, sciences. S. - P., 1993. - 36 p.]. On live filter paper, in a Petri dish moistened with 1-2 ml of Degelm KD of different concentrations from 0.025 to 1%, 20 live ticks were placed and covered with a second sheet of paper soaked in the compositions. Closed cups were placed in a thermostat at a temperature of 30 °, while providing oxygen access. Tick monitoring was carried out after exposure to the drugs and after 10, 20, 30 minutes, 1, 2, 4, 24, and 72 hours after application of the drugs for an hour. The control was 20 ticks placed on filter paper moistened with distilled water. The research data are summarized in table 1.

Table 1 Acaricidal efficacy of the composition A drug Concentra-
composition ratio,% The number of ticks in the experience Tick condition after 30 minutes Tick condition after 24 hours Tick condition after 72 hours Living The dead Living The dead Living The dead 0,025 twenty twenty - 2 eighteen - twenty 0.05 twenty eighteen 2 one 19 - twenty 0.1 twenty 17 3 one 19 - twenty 0.4 twenty 9 eleven - twenty - twenty Degelm KD 0.8 twenty 3 17 - twenty - twenty 1,0 twenty - twenty - twenty - twenty Water The control twenty twenty - twenty - twenty -

From table 1 it can be seen that 30 ticks were found dead in 1% concentrations at 30 minutes after applying the Degelm KD composition, at 17 and 11% at 0.8% and 0.4% concentrations, respectively. A further decrease in concentration had a less detrimental effect on ticks. When applying 0.1 and 0.05% concentration, 3 and 2 ticks died, respectively. Degelm KD in 0.025% concentration did not have an acaricidal effect.

When examining the samples after 24 hours, it was found that applying the Degelm KD composition in 0.4-1% concentrations had a 100% acaricidal effect. When using the composition in 0.1-0.05% concentrations, 19 ticks out of 20 turned out to be dead, and in 0.025% - 18 ticks.

72 hours after application of the composition in 0.025-1% concentrations, Degelm KD showed a 100% acaricidal effect.

In the control, when water was applied to ticks for 24 hours, all ticks remained alive.

Thus, the effect of the composition Degelm KD increases with increasing concentration during the first 24 hours. After 72 hours, all test concentrations from 0.025 to 1% were effective.

Example 3. The study of the effectiveness of acaricidal composition in rat notoedrosis.

The therapeutic efficacy of the acaricidal composition was tested in 25 rats infected with knothedrosis and divided into 5 groups. The rats of group 1 were used the new Degelm KD composition, the animals of group 2 used the quaternary phosphonium salt (1) and substituted dinitrobenzofuroxan (2) dissolved in dimethyl sulfoxide Group 3 - the phosphonium quaternary salt (1) and substituted dinitrobenzofuroxan (2) dissolved in oil, only solvent - dimexide was tested in group 4, and group 5 was the control and rat rats were not treated with knothedrosis. All drugs were applied externally to the affected area twice with an interval of 6 days. The research results are presented in table.2.

table 2 The efficacy of drugs in rat notoedrosis No. gr. AI before treatment Infection Intensity (AI) by Day Ticks Eggs 7 10 fifteen twenty Ticks Eggs Ticks Eggs Ticks Eggs Ticks Eggs one. +++ +++ + + - - - - - - 2. +++ +++ + + - + - - - - 3. +++ +++ + + + + - - - - four. +++ +++ + + - + - + + + 5. +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

From table No. 2 it can be seen that in the first group of animals the drug Degelm KD gives a positive result already 10 days after the start of the course of treatment. It acts fatally on both the pathogen eggs and ticks. It should be noted that when using the new Degelm KD preparation, the healing of damaged areas of the ear and the back of the nose of rats is already noted on the 10-15th day of the study.

In the second group of animals, a complete positive result is achieved only on the 15th day of treatment. To this period, after processing, both eggs and adult mites died. A similar result was obtained in rats of the third group.

When treating animals of the fourth group, eggs and adults were installed in scrapings during the entire study period.

Throughout the experimental period, in acarological studies of scrapings of skin from the ears in group 5 rats, we found in the microscope field of view both the mite eggs and their adult individuals, moreover, on the 10th day the imago became somewhat smaller, and by the 15th the day their number increased again.

During the experiment, N.notoedres eggs and ticks were found in scrapings of the control group at different stages of development.

Thus, for the treatment of rats infected with notoedrosis, the drug Degelm KD we proposed was the most effective.

Example 4. The study of the effectiveness of acaricidal composition in psoroptosis of rabbits.

The experiments were carried out on rabbits sick with psoroptosis (pathogen Psoroptes cuniculi) with a moderate and severe degree of damage. The animals were divided into 6 groups (3 animals each). Rabbits of group 1 were treated with Degelm KD, animals of group 2 were treated with phosphonium salt (1) and furoxan (2) in a solvent - dimethyl sulfoxide, rabbits of group 3 were studied the effect of the previous composition of ingredients (1 and 2) dissolved in unrefined sunflower oil, in animals of group 4, the effect of only xymedone hydrochloride (3) in dimethyl sulfoxide was studied. The effect of a pure solvent, dimethyl sulfoxide, was studied in group 5 rabbits, and group 6 was the control, in which treatment was not performed. Animals were treated twice with drug suspensions with an interval of 7 days.

The results of the experiments were taken into account by examining the auricle with the subsequent examination of scrapings taken from the inner surface of the auricles for the presence of live ticks. Accounting was carried out 1, 3, 5 and 7 days after the first treatment and 7, 14 and 30 days after the secondary application of drugs. The research results are given in table.3.

Table 3 Drug efficacy in rabbit psoroptosis No.
column AI before treatment Intensity of the day by day Ticks in different. stages of development Eggs 7 10 fifteen twenty thirty Ticks Eggs Ticks Eggs Ticks Eggs Ticks Eggs Ticks Eggs one. +++ +++ - + - - - - - - - - 2. +++ +++ - + + + - - - - - - 3. +++ +++ - + + + - - - - - - four. +++ +++ + + + + + + + + + + 5. +++ +++ - - + + + + + + + + 6. +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++

The table shows that before treatment in scrapings of the skin of sick rabbits, both Psoroptes cuniculi ticks and eggs were found.

After treatment in group 1 animals, tick scrapes were found on the 7th day of the study in skin scrapings. When taking scrapings from animals, 2 groups of ticks were found on the 10th day of the study; in the following days, eggs and ticks were not found in scrapings.

In group 3 rabbits, on day 7, tick mites were found in skin scrapings, and on day 10, Psoroptes cuniculi ticks were found. In the following days, eggs and ticks were not found in scrapings. In animals of the 4th group, eggs and ticks were found in scrapings at all stages of the study.

In rabbits that were treated with dimethyl sulfoxide (group 5) on day 7, live mites were not found in scrapings. In the following days, eggs and ticks were found in the material at different stages of development. Rabbits in the control group were infected with psoroptosis at all stages of the study.

In addition, it was found that wound healing at the site of localization of ticks in animals of group 1 occurred faster (by day 15) than in other groups.

Example 5. The study of the effectiveness of acaricidal composition in otodectosis of cats.

Patients with otodectosis of cats caused by the pathogen Otodectos cynotis, parasitizing on the inner surface of the skin of the auricle and in the external auditory canal, were treated with the Degelm CD acaricidal composition. Before use, the acaricidal composition was heated to 30-35 ° C and shaken thoroughly. The treatment was carried out by aerosol spraying into the auricles and the external auditory canal, where pathogens are localized. Group 1 animals were applied with a 1% emulsion in Degelm KD dimethyl sulfoxide at a dose of 0.5 ml in each auricle in the form of a spray. Multiplicity of processing 2 times, with an interval of 6 days. As a reference, a commercially available Ivermek Spray drug was used (animals of the 2nd group). Animals of group 3 were not treated. The results of the experiments were taken into account by examining the surface of the auricle and ear canal and examining scrapings for the presence of live ticks.

Table 4 The effectiveness of drugs for otodectosis in cats No. gr. AI before treatment Intensity by day (AI) Ticks in different. stages of development Eggs 7 fifteen thirty Eggs Ticks Eggs Ticks Eggs Ticks one. +++ +++ - - - - - - 2. +++ +++ + - - - - - 3. +++ +++ +++ +++ +++ +++ +++ +++

The table shows that before treatment, scrapes of the skin of sick animals found both Otodectes cynotis ticks and eggs.

After treatment in group 1 animals, on the 7th day of the study, tick mites were not found in scrapings. In cats of the 2nd group during this period, only tick eggs were found. In the following days, no scraps or eggs were found in scrapings from animals of groups 1 and 2 of the group. Animals of the control group were infected with otodectosis at all stages of the study.

Example 6. The study of the effectiveness of acaricidal composition in demodicosis of dogs.

The experiment used 10 dogs aged 7 months to 3 years, patients with a cup-shaped form of demodicosis and divided into 2 groups (experimental and control). Dogs of the experimental group of patients with demodecosis caused by the pathogen Demodex canis were treated (1% emulsion) with the Degelm KD acaricidal composition. In sick dogs on the scalp (the area of the superciliary arches, lips), lesions were found in the form of separate round spots covered with bran-shaped scales of the keratinized epidermis. The skin on the affected areas with a reddish-bluish tint. Microscopic examination of deep scrapings revealed Demodex canis ticks.

The acoricidal composition was applied to the skin of dogs that had previously been cleaned of impurities and crusts. Degelm KD was applied by spraying the affected skin with a 1% emulsion twice with an interval of 7-10 days.

A week after treatment, the skin acquired a light gray color. No new foci were observed. When examining scrapings during this period, Demodex canis ticks were found. 15 days after treatment, ticks were not found in the scraping. A recovery has occurred. In dogs of the control group, ticks were found in scrapings and the disease progressed.

Example 7. Determination of acute toxicity of the claimed pharmaceutical composition Degelm KD.

The level of acute toxicity of the claimed composition was determined by standard methods in the vivarium department of parasitology of the Kazan State Academy of Veterinary Medicine. It was found that with intragastric administration of the composition to mice, LD ₅₀ equals 9750 mg / kg. According to GOST 12.1.007-76, the acaricidal composition refers to substances of the 4th toxicity class - non-toxic [N. Metrov. Parameters of toxicometry of industrial poisons with a single injection / N.F. Izmerov I.V. Sanotsky, K.K. Sidorov // Medicine, m. - 1977. - S.196-197.].

Thus, the pharmaceutical composition, including the quaternary salt of phosphonium (1), substituted dinitrobenzofuroxan (2), xymedonhydrochloride (3) and dimethyl sulfoxide as a solvent, has 100% acaricidal effect and is not toxic.

Claims (1)

An agent for the treatment of scabies mites in veterinary medicine, including the Quaternary phosphonium salt, substituted dinitrobenzofuroxan, xymedone hydrochloride and dimetisulfoxide at a weight ratio of 0.1: 1: 10: 100, for the treatment 1% emulsion of this agent in dimethyl sulfoxide is used.