RU2160536C1 - Anti-parasitic agent - Google Patents

Abstract

FIELD: veterinary. SUBSTANCE: agent effective against ecto- and endoparasites and missing embriotoxic and teratogenic effects contains derivatives of benzimidazolcarbamates (preferably albendazole, 4-20%), avermectin group compounds (preferably aversectin C, 0.2-1%), and forming components: powdered perlite or zeolite. EFFECT: reduced therapeutic dose of active components and extended their activity spectrum. 5 cl, 6 tbl, 7 ex

Description

 The invention relates to veterinary medicine and relates to the creation of a combined broad-spectrum antiparasitic agent effective against ecto- and endoparasites without embryotoxic and teratogenic effects.

 Parasitic diseases of farm animals caused by ecto- and endoparasites are widespread on farms and cause great economic damage.

 For the prevention and treatment of parasitic diseases caused by nematodes, cestodes, trematodes, ticks, insects, a number of drugs have been developed. Widely known are drugs based on benzimidazole carbamates (BMC), for example, albendazole.

 The disadvantage of these compounds is that they do not act on ectoparasites, and also have a pronounced embryotoxic and teratogenic effect on farm animals, especially sheep. The latter circumstance sharply limits their use in reproductive animals.

 There are a number of methods for removing embryotoxic and teratogenic effects of BMK. Thus, the addition of phenobarbital, adenine, amino acids or vitamins, or iron or manganese salts to BMC removes their embryotoxic effect (Ryabova V.A., Novik T.S. Veterinary, 1983, p. 59-61; auth. Certificate SU NN 1795575 , 1795876, 1795577, 1795579, 1795580).

 The disadvantage of all of the above compounds is that their anti-teratogenic activity is manifested in high doses (50-600 mg / kg), and the anthelmintic activity of BMK does not always increase.

 The present invention allows to expand the range of substances that remove the embryotropic and teratogenic effects of benzimidazoles, and to create on their basis a combined antiparasitic agent that does not have embryotoxic and teratogenic properties, effective both against ectoparasites and against endoparasites, including round, flat and tapeworms.

 This result is achieved by the fact that as a substance acting on flatworms (Fasciola), BMK group compounds, for example albendazole, are used, and to remove its embryotropic and teratogenic effects and to expand the spectrum of antiparasitic action, compounds of the avermectin group, which are a vital product of the Streptomyces avermitilis culture, are used .

Actinomycete Streptomyces avermitilis, when cultured in the presence of carbon, nitrogen, and phosphorus sources under continuous aeration, produces eight structurally similar substances called avermectins (GB 1573955, 1980). All avermectins in chemical structure are 16-membered macrolides and differ among themselves with substituent radicals at 5 and 26 carbon ring atoms. Individual avermectins are designated A _1a , A _1b , A _2a , A _2b , B _1a , B _1b , B _2a and B _2b .

 The specific values of the corresponding radicals and the type of bond between 22 and 23 carbon ring atoms for all individual representatives of avermectins are shown in table 1.

Depending on the method of isolation of avermectins, you can get a product containing mainly one or two of the listed components, for example, avermectin B ₁ , called abamectin.

 Avermectin complexes with different contents of individual components are also obtained.

So, the avermectin complex, called aversectin C, contains individual components in the following ratio,%:
A _1a - 6 - 12
A _1b - Traces
A _2a - 15 - 25
A _2b - 2 - 4
B _1a - 30 - 40
B _1b - 2 - 12
B _2a - 14 - 24
B _2b - 1 - 2
As part of the antiparasitic agent of the present invention, aversectin C or abamectin is used predominantly, but ivermectin and other compounds of the avermectin group can also be used, highly effective against roundworms and ectoparasites (ticks, gadfly larvae, etc.), but not effective against flatworms (fasciola) . Either tween 80 to obtain a liquid form, or solid carriers such as perlite or zeolite to obtain a powder form are used as forming components.

Information confirming the possibility of carrying out the invention
Example 1

 Albendazole at a dose of 10 mg / kg in the form of an aqueous suspension on Tween 80 was administered once through the mouth to white outbred rats weighing 200-250 g on the 9th day of pregnancy (the period of the highest sensitivity of embryos to the effects of benzimidazole carbamates). The results of administration were taken into account on the 20th day of pregnancy. Females were killed, the abdominal cavity and uterus were opened. By the ratio of the number of yellow bodies of pregnancy, implantation sites, live, dead, and resorbed fetuses, pre-, post-implantation, and total fetal mortality were determined. Embryos were carefully examined for the presence of external developmental abnormalities.

 Example 2

 The preparations of albendazole at a dose of 10 mg / kg and aversectin C at a dose of 0.5 mg / kg in the form of an aqueous suspension on Tween 80 were administered simultaneously through the mouth to white outbred rats weighing 200-250 g on the 9th day of pregnancy once.

 Example 3

 Albendazole at a dose of 10 mg / kg and aversectin C at a dose of 0.25 mg / kg (both drugs in the form of an aqueous suspension on Tween 80) were administered simultaneously through the mouth to white outbred rats weighing 200-250 g on the 9th day of pregnancy once.

 Example 4

 Albendazole at a dose of 10 mg / kg and ivermectin at a dose of 0.5 mg / kg (both preparations in the form of an aqueous suspension on Tween 80) were administered once to outbred white rats weighing 200-250 g on the 9th day of pregnancy.

 Example 5

 Albendazole at a dose of 10 mg / kg and abamectin at a dose of 0.5 mg / kg (both drugs in the form of an aqueous suspension on Tween 80) were administered simultaneously through the mouth to white outbred rats weighing 200-250 g on the 9th day of pregnancy once.

 Example 6

 A weighed portion of albendazole 4 g was placed in a mixer, 0.2 g of aversectin C dissolved in 10 g of polyethylene oxide-400 and 85.8 g of zeolite were added there. The mixture was thoroughly mixed.

 A combined form was obtained containing 4% albendazole and 0.2% aversectin C (the ratio of albendazole and aversectin C was 20: 1).

 The combined form was administered by mouth to white outbred rats weighing 200-250 g on the 9th day of pregnancy once at a dose of 10 mg / kg for albendazole and 0.5 mg / kg for aversectin C.

 Example 7

 A weighed portion of albendazole 20 g is placed in a mixer, 1 g of aversectin C dissolved in 30 ml of polyethylene oxide-400 and 49 g of perlite are added thereto. The mixture is thoroughly mixed. A combined form is obtained containing 20% albendazole and 1% aversectin C (the ratio of albendazole and aversectin C is 20: 1).

 In all examples, the methodology for assessing the effect of compositions on the embryonic development of rats is similar to that described in example 1.

 Table 2 shows the results of the use of albendazole alone and in combination with aversectin C, ivermectin and abamectin. As follows from the data of table 2, the introduction of one albendazole on the 9th day of embryogenesis led to a significant increase in post-implantation and total fetal death of the fetus, in particular, the latter indicator was 47.0% versus 12.7% in the control (P ≤ 0.05) . The weight and size of the fruit were significantly reduced.

 With the combined administration of albendazole with aversectin C, abamectin and ivermectin at a dose of 0.5 mg / kg, the post-implantation and total fetal death of the fetuses significantly decreased, while these indicators did not significantly differ from the control values, i.e. in intact animals. At the same time, the weight and size of the fruit were completely normalized (or were higher) only in rats treated with albendazole together with aversectin C, the latter at a dose of 0.5 mg / kg. With the simultaneous administration of albendazole (10 mg / kg) and aversectin C at a dose of 0.25 mg / kg, despite the obvious positive effect of the latter on fetal development of fetuses compared with the administration of albendazole alone, the parameters significantly differed from the control values (postimplantation and total embryonic death, reduced weight and size of the embryos).

 Table 3 shows data on the effect of the powdered combination form based on albendazole with aversectin C at doses of 10 and 0.5 mg / kg, respectively, on the embryonic development of rats when administered on the 9th day of pregnancy.

 Unlike albendazole itself, the combined dosage form does not have an embryotoxic effect. The total embryonic mortality with the introduction of the combined form was 10% compared with 47% of deaths with the introduction of albendazole alone and was at the level of mortality in the control group.

 Tables 4, 5 and 6 show the data on the action of the powdered combined form on various parasites, pathogens in laboratory and farm animals.

Industrial applicability
The decision to use avermectins (aversectin C, ivermectin, abamectin, etc.) to relieve the embryotoxicity and teratogenic effects of benzimidazole carbamates (albendazole) allows us to create new dosage forms of highly effective antiparasitic drugs that lack side embryotropic action with a decrease in therapeutic doses and an expansion of the spectrum of activity.

 The tool obtained according to the invention can be recommended for use on reproductive livestock. When using the combined form of albendazole with aversectin C, a healing effect in the postnatal development of the offspring is observed.

Claims (5)

 1. An antiparasitic agent containing benzimidazole carbamate derivatives and excipients, characterized in that it further comprises compounds of the avermectin group.  2. The antiparasitic agent according to claim 1, characterized in that it contains albendazole as benzimidazole carbamate derivatives.  3. The antiparasitic agent according to claim 1, characterized in that as a representative of the compounds of the group of avermectins contains aversectin C.  4. The antiparasitic agent according to claim 1, characterized in that it contains powdered perlite or zeolite as forming agents.  5. Antiparasitic agent according to claims 2 and 3, characterized in that it contains albendazole in an amount of 4 - 20%, and aversectin - in an amount of 0.2 - 1.0%.

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