Application of fungicides for treatment of mycoses in fish

FIELD: medicine.

SUBSTANCE: invention relates to fish-breeding and veterinary. Application of fluoxastrobin as preparation for fighting mycoses in fish and invertebrates, as well as in all stages of their development, caused by fungi of genus Saprolegnia, Achlya, Aphanomyces.

EFFECT: invention ensures stop of development or cessation of vital activity of pathogenic fungi in breeding and maintenance of fish for prevention and treatment of fish diseases in aqua-culture, water bodies for breeding, reservoirs for breeding, aquariums, natural water bodies for sport fishing, ponds and sea reservoirs for fish.

1 ex

 

The invention concerns a method for the prevention and treatment of mycoses in fish and invertebrates and all their stages of development, caused by fungi of the genera Saprolegnia, Achlya, Aphanomyces, and other species of importance to aquaculture (hereinafter referred to as pathogenic fungi), by using at least one fungicide, presented by the substances from the following group: 2-[[[[1-[3-(1-fluoro-2-phenylethyl)oxy]phenyl]ethylidene]amino]oxy]methyl]-alpha-(methoxyimino)-N-methyl-alpha-E-benzeneacetate, amisulbrom, cyazofamid, anestrous, famoxadone, fenamidone, fluoxastrobin, orysastrobin, picoxystrobin and perience.

The invention also relates to products containing at least one fungicide presented in the following group: 2-[[[[1-[3-(1-fluoro-2-phenylethyl)oxy]phenyl]ethylidene]amino]oxy]methyl]-alpha-(methoxyimino)-N-methyl-alpha-E-benzeneacetate, amisulbrom, cyazofamid, anestrous, famoxadone, fenamidone, fluoxastrobin, orysastrobin, picoxystrobin and perimekar, for the prevention and treatment of mycoses in fish and invertebrates and all their stages development, caused by fungi of the genera Saprolegnia, Achlya, Aphanomyces, and other species of importance to aquaculture (hereinafter referred to as pathogenic fungi). It can be applied in breeding and maintenance of fish at all stages of its development, especially for profilakticheskogo therapeutic use in patients and subjected to stressful effects of fish.

In addition, the invention concerns the use of funds for proteoliticheskoi processing caviar fish.

Due to the growing worldwide demand in fish, it is increasingly diluted using aquaculture. As examples for aquaculture, which is not, however, restrict, should mention the following important species: catfish, trout, salmon, pangasius and perch. Because of the close proximity of fish with each other, these being cultivated in water, are highly susceptible towards the effects of pathogens, in particular pathogenic fungi. Pathogenic fungi that affect both fish and eggs, as well as other stages of development, include the following genera: Saprolegnia hypogyna, S.ferax, S.australis, S.declina, S.longicaulis, S.mixta, S.parasitica, S.sporangium, S.variabilis, Aphanomyces invadans and Achlyaflagellata spp.

Because of fungal infections in breeding and maintenance commercial and ornamental fish, crustaceans and other invertebrates, there are large economic losses (Bruno, D.W., Wood, V.R., 1999: Saprolegnia and other Oomycetes. In: Woo, P.T.K., Bruno, D.W. (Hrsg.): Fisch Diseases and Disorder. Vol.3 Viral Bacterial and fungal infections. CAB International, Wallingford).

However, so far only known to a small number of substances, which are suitable for combating fungal infections in fish.

In the past, as active substances for the prevention and treatment of fungal infections often used krassi the spruce malachite green. However, because of its carcinogenic, mutagenic and teratogenic properties of this substance in Germany is permitted only for caviar processing fish, but not officially allowed to treat fish (Meyer, P.P.; Jorgenson, T.A., 1983: Teratological and other effects of malachite green on development of rainbow trout and rabbits. Trans. Am. Fish. Soc. 112, 818-824 (Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin, 2002). Since malachite green is a dye, it may change the color of the water and processed fish. In addition, malachite green has a long half-life, so that it can later be in the form of residues in consumed fish (D.J.Alderman in the Journal of Fish Diseases 8. (1985) 289-298).

In addition, to date formalin, which although has some fungicidal effect against pathogenic fungi, however, in practical use is not satisfactory and, in addition, represents a security problem, especially in closed systems.

In the German patent DE 10237740 describes the use of natural and synthetic humic substances in fish farming.

Still, from German patent DE 2037610 it is known that certain benzimidazole possess activity against Saprolegnia parasitica in laboratory conditions (in vitro). However, the potential use in breeding fish is not mentioned.

Chinese patent CN 1472448 describing the tsya herbal compounds with fungicidal effect for use as anti-Saprolegniasis on fish shrimp and crabs. These formulations contain Galla Chinensis 40-70, Cortex Phellodendri (Phellodendron Chinese and/or Phellodendron amurense) 10-30, Paeonia suffructicosa bark 10-30, Houttuynia cordata 10-30% of the mass.

Can also apply tea extracts contain a variety of polyphenols (Japanese patent JP 3698745).

In the international application WO 04002574 describes a mixture of enzymes containing glucanase, for the prevention and treatment of mycoses in fish and in the stages of its development (caviar).

In the international application WO 9805311 to struggle with various diseases living in aquatic organisms, in particular, salmon and caviar, used bronopol (bromo-2-nitropropane-1,3-diol).

In addition, it is known the use of chlorine dioxide (international application WO 9518534), 3-phenoxycarbonylamino-1,1,2-triiodothyronine-1-propene (Japanese patent JP 57116012), and 2-pyridinethiol-1-oxide (Japanese patent JP 47019191) for use against diseases caused by Saprolegnia.

From international application WO 97006690 known use for combating mycoses in fish of kresoximmethyl.

However, firstly, the effectiveness of this substance when using only small doses is often unsatisfactory. Secondly, it may lead to a restriction of transferability of treatment due to toxicity to fish, so that the effective dose cannot be used sufficiently. In addition, accurate dosing, special is about to vegetable or tea extracts or enzyme mixtures is difficult because of the unstable level of content of active substances. In addition, the use of these drugs is only suitable for certain types of fish and their diseases. In addition to all the above, the use of drugs is often limited for a period of time long before the fish ("harvesting") because of their toxic properties, because we needed a large time between the use of drugs and consumption of fish.

Since the ecological and economic requirements of modern antifungal drugs continuously rising, for example in terms of spectrum of activity, toxicity, selectivity, norms of consumption, sediment and facilities of industrial production, it remains a constant challenge for the development of new antifungal drugs, which, at least in a partial range of advantages in comparison with the already known.

Moreover, these substances have toxic side effects. The use of, for example, formalin, chloramine T and Malachite green oxalate is often associated with side effects and risks, for example, they possess carcinogenic, mutagenic, harmful to the chromosomes, teratogenic potential, act as poison gas, additionally, there are consequences in the form of cellular abnormalities and damage to many organs, as well as significant changes biohimicheskaya blood (Sanchez and others 1998; Srivastava and others 2004; thesis St. Heidrich, 2005).

Along with clean disinfectants are used and also other substances. These include acetic acid (for immersion processing), the chlorides of sodium and calcium (for processing for regulation of osmotic pressure), sodium carbonate and carbon dioxide (to stun fish)and sodium sulfite (to improve liluplanet) and povidone iodine (for surface disinfecting eggs fish).

The causes of the shortcomings of traditional prevention and treatment are the result of many years of widespread and somewhat reckless use, for example, in the case of antibiotics, chemotherapeutic agents, as well as triphenylmethane dyes and other active substances for the destruction of bacterial, parasitic and due to the influence of environmental diseases, as well as to improve the yield. Partly because of such use has evolved undesirable types of resistance in the treatment of diseases in animals and humans. In addition, the use of traditional tools often associated with severe side effects, risks and hazards to the environment.

Therefore, in aquaculture there is an increased need for effective tools that control pathogens, reducing produktivnost for commercial fish farming. Upon detection of diseases in fish always plays a big role early adoption of measures primarily preventive in nature, as well as prevention and mitigation of factors that cause the disease. For this reason, looking in the direction of alternative treatment options deserve exceptional attention. The means employed to monitor a wide range of pathogens and to meet existing safety provisions. The present invention fulfils these criteria and provides other benefits.

Unexpectedly, it was found that at least one fungicide, presented by the substances from the following group: 2-[[[[1-[3-(1-fluoro-2-phenylethyl)oxy]phenyl]ethylidene]amino]oxy]methyl]-alpha-(methoxyimino)-N-methyl-alpha-E-benzeneacetate, amisulbrom, cyazofamid, anestrous, famoxadone, fenamidone, fluoxastrobin, orysastrobin, picoxystrobin and perimekar is well suited for how to prevent and cure fungal infections in fish shrimps, crabs, and other invertebrates and all their stages of development, caused by fungi of the genera Saprolegnia, Achlya, Aphanomyces, in particular fungal diseases caused by Saprolegnia spp. The means according to the invention are suitable for combating fungal infections, which are caused by Saprolegnia species and/or Achlya, and/or Aphanomyces.

The use of wiseness is the R fungicides when processing is compared with the known from the prior art substances, or, respectively, processing methods, the following advantages: they show good performance and do not accumulate in undesirable amount in the body of the fish, they have a favorable environmental and other Toxicological characteristics, and exhibit no unacceptable impacts on the ecosystem.

Consequently, the invention concerns the use of at least one fungicide, presented by the substances from the following group: 2-[[[[1-[3-(1-fluoro-2-phenylethyl)oxy]phenyl]ethylidene]amino]oxy]methyl]-alpha-(methoxyimino)-N-methyl-alpha-E-benzeneacetate, amisulbrom, cyazofamid, anestrous, famoxadone, fenamidone, fluoxastrobin, orysastrobin, picoxystrobin and perimekar to fight fungal infections in fish for all fish populations and at all stages of their development, especially those that are caused by a pathogen Saprolegnia.

Fungicides used in the method according to the invention are already known as substances agrochemical activity (cf., for example, Pesticide Manual, 13thedition).

Diseases of fishes play a role in the breeding of fish and aquaculture, the aquarium, and fish populations living in natural conditions. We should distinguish between different types of diseases, such as hereditary diseases, infectious and caused by parasites, diseases, injuries,damages, due to water and damage caused by stress factors in the conditions. Between the immune system, disease and conditions of life is the complex interaction effects, which ultimately determines the beginning of an infectious disease. A large number of common diseases in fish is called with the defeat of parasites. Parasites are responsible for about 50 percent of deaths in young animals in the aquarium. Defeat parasites may, depending on the type of pathogen, be slow or vzryvoobrazno and creates preconditions to ensure that most or all animals in the pond suffered from diseases. Fungi, bacteria and viruses can also be the causes of diseases in fish.

Diseases caused by fungi are called mycoses. This may also be a secondary infection, that is, that prior to the occurrence of mycosis fish or water have already been infected with other diseases. Fungi can exist as a primary parasites. Because mushrooms are also limiting membrane, penetrated into the skin mycoses can be cured only with great difficulty.

Saprolegnia belongs to the class of the oomycetes. Affected fish show these symptoms: they are outside white with a grayish tint fungal, it is either kind of scraps of wool. Moreover, these fungi can repeatedly to stay on the fish, if protecting the mucous layer or epidermis is injured. Growth of the fungi of this type may be consequences stab or bite wounds caused by other organisms or from mechanical damage, and also be caused by temperature or wastewater. However, danger and also the eggs of fish. Naturally, the fungus is found in all fresh water and operates on a weakened fish. It often turns out that strongly affected, especially older male trout. Saprolegnia is a parasite that kills the weakened individuals, which is a secondary and a primary parasite, which can directly affect fish and eggs. In addition, it can affect all species of fish.

The purpose of this invention is the identification of areas of application in the prevention and treatment of injuries of fish that occur during catching, transport and maintenance, improving the yield of fish breeding, as well as during processing of caviar and ensuring the smooth functioning of the equipment when breeding in aquaculture and the aquarium.

Fungicides can be represented in the form of individual substances as well as mixtures of different possible isomeric forms, in particular, stereoisomer is s, such as E - and Z-, threo - and Erythro, and also optical isomers, such as R - and S-isomers or atropisomers, and if necessary also the tautomers. This invention includes both the pure isomers and mixtures thereof.

Depending on the type of the substituents described above, these fungicides have acidic or basic properties and can form salts, and if necessary also internal salts. If fungicides contain hydroxy-, carboxy - or other groups which induce acidic properties, these compounds can interact with bases to form salts. Suitable bases are, for example, hydroxides, carbonates and acid carbonates of alkali and alkaline earth metals, in particular such compounds of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary or tertiary amines with alkyl residues containing from 1 to 4 carbon atoms, mono-, di - and trialkanolamines of alcohols containing from 1 to 4 carbon atoms, choline, and harolyn. If fungicides contain amino, acylamino or other groups which induce basic properties, these compounds can interact with acids to form salts. Suitable acids are, for example, mineral acids such as hydrochloric, sulfuric and phosphoric acid, organic acids such the AK acetic acid or oxalic acid, and acid salts such as NaHSO4and KHSO4. The salt thus obtained, have fungicidal properties.

The fungicides to be applied according to the invention, above.

Preferred fungicides are representing substances from the following group: amisulbrom, cyazofamid, anestrous, famoxadone, fenamidone, fluoxastrobin, orysastrobin, picoxystrobin and perience.

Especially preferred are fungicides, which are substances from the following group: anestrous, famoxadone, fenamidone, fluoxastrobin, orysastrobin and picoxystrobin.

Most preferred are fungicides, which are substances from the following group: fenamidone and famoxadone.

In addition, the most preferred are fungicides, which are substances from the following group: anestrous, orysastrobin and fluoxastrobin.

Highly preferred are fungicides, which are substances fenamidone and fluoxastrobin.

In the method according to the invention, the methods of application and tools themselves can be selected separately and as a combination of several fungicides.

According to the invention fungicide is added to the water in the structures for aquaculture, for example, in the apparatus for the incubation of eggs, Vogue the Ah for cultivation, tanks for breeding, swimming pools, containers for food, aquariums, natural ponds for sport fishing and breeding marine fish and their impact causes growth inhibition, or inhibition of activity of pathogenic fungi. Under the structures for aquaculture involves equipment that is used for cultivation of fish or invertebrates in fresh water, sea water mixed with fresh water or in salt water. Fungicides added to the water. The dose is determined depending on the characteristics of water (organic load) in the construction for aquaculture, the activity of the fungicide and the stage of development of fish that can be processed. The level of activity is supported through continuous or periodic additions that suppresses existing fungal infections and prevent new infections.

Consumption rates, depending on the type and stage of development of the fish and the type of fungicide, in terms of the active substance is from 0.1 ág/l to 1 g/l, preferably from 1 mg/l to 100 mg/l, most preferably from 5 μg/l to 1 mg/L. generally, in higher concentrations, there is no need, however, depending on the connection type or method of application, especially in the case of artificial systems, such as, for example, tanks for breeding fish or aquariums, when processing on one hundred is the second of eggs, larvae and fry they may be needed.

In addition, the effect against fungal infections is achieved by the fact that fungicides are used not only in free form in the aquatic environment in the construction for aquaculture, but also in the form associated with the surface (mucosa) of the organisms that you want to protect, or their eggs. This method should be preferred in the case when there is a high risk of infection necessitates a higher content of fungicide or if at high water consumption in the building for aquaculture impossible continuous addition of a mixture of fungicides. Such linking is achieved using a time-limited pre-incubation for handling animals or their eggs with elevated concentration of fungicide, and, along with a mixture of fungicides, are preferably used substances that enhance the binding of fungicide.

An effective amount of a fungicide includes, for example, the amount dosed per fish, approximately equal to the value of from 1 μg to 10 mg/kg/day, which can be administered in a single dose or divided into individual doses, for example, from 1 to 4, in the course of the day. Preferably the compounds are administered dose less than 10 mg/kg/day as a single dose or divided into a number from 2 to 4 doses.

The active substance may be used which change directly or to be mixed with conventional inert carriers. In principle, as inert carriers suitable such substances that facilitate or provide an even distribution of the active substance in water or on the surface (mucosa) of organisms that must be protected or their eggs.

Active substances depending on their physical and/or chemical properties, in each case, can be converted to conventional compositions, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, fine capsules in polymeric materials and coating masses for seed, as well as compositions for cold produced by using ultra low volume (ULV) and hot mist.

These songs get known methods, for example, by mixing the active substances with solvents, or also with liquid solvents, gases liquefied under pressure, and/or with substances-carriers, optionally with the use of surface active agents and emulsifiers and/or dispersants and/or foam-forming means. In the case of using water as a diluent can be used, for example, organic solvents as auxiliary solvents. As liquid solvents are mainly taken into account the following: aromatics, such as xylene,toluene or alkylnaphthalenes, chlorinated aromatics or chlorinated aliphatic hydrocarbons, such as chlorobenzene, chlorethylene or methylene chloride, aliphatic hydrocarbons, such as cyclohexane or paraffins, for example petroleum fractions, alcohols, such as butanol or glycol and also their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents, such as dimethylformamide and dimethylsulfoxide, and water. Under liquefied gaseous diluents or carriers are meant such liquids at normal temperature and normal pressure are gaseous, for example, aerosols with the working gases, such as kalogeropoulou, as well as butane, propane, nitrogen and carbon dioxide. As solid carriers consider, for example, natural mineral powders such as kaolin, alumina, talc, chalk, quartz, attapulgite, montmorillonite or hard-shelled land, and synthetic mineral powders such as highly dispersed silicic acid, alumina and silicates. As solid carriers for granules are considered, for example, crushed and fractionated natural rocks such as calcite, pumice, marble, thick, dolomite, and also synthetic granule the s of inorganic and organic powders, and granules of organic materials such as wood flour, coconut shell, corn cobs and stalks of the tobacco plants. As emulsifying and/or foam-forming means are considered, for example, nonionic and anionic emulsifiers, such as esters of polyoxyethylene and fatty acids, ethers of polyoxyethylene and fatty alcohols, for example, a simple alkilammonia broadcast polyglycol, alkyl sulphonates, alkyl sulphates, arylsulfonate, and protein hydrolysate. As dispersing funds are considered, for example, sulphite lye with lignin and methylcellulose.

The compositions can be applied means improving adhesion, such as carboxymethylcellulose, natural and synthetic powdered, granular or latexotica polymers, such as gum Arabic, polyvinyl alcohol, polyvinyl acetate, and also natural phospholipids, such as Catalina and lecithins, and synthetic phospholipids. Other additives can be mineral and vegetable oils.

It is possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide, Prussian blue, and organic dyestuffs, such as alizarin, azo and metallophthalocyanine dyes, as well as micronutrients such as iron salts, manganese,boron, copper, cobalt, molybdenum and zinc.

Generally, the compositions contain from 0.1 to 95 mass% of the active substance, preferably from 0.5 to 90%.

The subject of the invention is a method of processing an effective fungicide fish affected by mycosis, as well as all stages of its development.

It is obvious that the specific dose and frequency of dosing may vary for certain types of fish, and depending on the development stage and will depend on a number of factors, including the effectiveness of specific compounds, the metabolic stability and length of action of that compound, the species, age, weight, General health, sex and diet of fish, method and time of administration, rate of excretion and the severity of the particular condition.

This invention is also a drug for veterinary use, which includes at least one fungicide that can cure diseases caused by Saprolegnia and other diseases of fish, the amount effective for these purposes, but is also compatible with pharmaceutical use media or compatible with pharmaceutical purpose solvent. Compositions according to the invention may contain other therapeutic agents, such as described below, and can make songs,for example, with conventional solid or liquid carriers or means of dilution, such as pharmaceutical additives of a type suitable for the intended administration of the drug (for example, excipients, thickeners, preservatives, stabilizers, flavoring agents, etc.), according to techniques that are well known from the field of pharmaceutical technology or are required in the accepted pharmaceutical practice.

The above active fungicides can be applied in any suitable way, for example, orally in the form of tablets, capsules, granules or powder, sublingual, cheek, parenteral, for example, by subcutaneous, intravenous, intramuscular or nutritionally injection or infusion (e.g., in the form of sterile, suitable for injection, aqueous or non-aqueous solutions or suspensions), superficially, for example, in the form of a cream or ointment or as a composition for controlled admission that contain non-toxic, compatible with pharmaceutical use carrier or diluent. Fungicides may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by use of suitable drugs, which is held above the active fungicides or in particular, in the case of prolonged release when using devices such as subcutaneous implants or osmotic pumps. The compounds may also be administered liposomal. For example, the active substance may be applied in the form of a composition such as tablet, capsule, solution or suspension that contains from about 5 to about 500 mg per unit dosage of a compound or mixture of compounds from the list above fungicides or applied externally (from 0.01 to 5% by mass. fungicide, from one to five treatments per day). They can also the traditional way to be mixed with physiologically compatible carrier, auxiliary substance, binder, preservative, stabilizer, flavor, etc. or with a carrier for external application. Connections can also be of such composition as sterile solutions or suspensions for parenteral administration. From about 0.1 to 500 mg of fungicide may be mixed with physiologically compatible carrier, auxiliary substance, binder, preservative, stabilizer, etc. in the form for a single application, such as required by accepted pharmaceutical practice. The amount of active substance in these compositions or dosage forms preferably is such that, where is Asa dosage is saved in the specified field.

For example, compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting mass, alginic acid or sodium alginate as suspendida funds, methylcellulose as an amplifier viscosity and sweetener or flavouring, such as known in the art, as well as tablets with immediate-release, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, fillers, acid, solvents and lubricants, such as those known in the technique. Examples of forms that can be used are molded tablets, compressed tablets or liofilizovannye tablets. Compositions include, for example, such forms in which the mixed fungicidal active substances with instant dissolving agents such as mannitol, lactose, sucrose and/or cyclodextrins. Such compositions can also contain auxiliary substances with high molecular weight, such as cellulose (Avicel) or polyethylene glycol (PEG). Such compositions may also contain auxiliary substances, in order to promote adhesion to the mucosa, such as hydroxypropy the cellulose (GOC), the hypromellose (HPMC), sodium carboxymethyl cellulose (NCMC), copolymer of maleic anhydride (e.g., Gantrez), and means for regulating the release, such as a copolymer of acrylic polymer (e.g., Carbopol 934). For simple cooking and applications can be added to lubricating agent, a substance which imparts lubricity, flavor, coloring agent and stabilizers.

The above-mentioned fungicides can be entered either as individuals or in combination with other fungicides. Particularly advantageous is a combination of fungicides, which also have activity against fungal infections in fish, in order respectively to insure the action and effectively prevent the emergence of resistance to a fungal pathogen in relation to the active substance.

Confirmation of the effectiveness of the means for processing can be proven using a laboratory experiment or experiment with animals. Laboratory experiment allows us to accurately characterize the efficacy of compounds for their acting abilities. For this purpose the active substance is added to the culture medium, and after a certain incubation period is determined by the growth of fungi. In experiments with animals are treated, for example, IR the Incas farmed fish. For this purpose a tank of water, which contains caviar fish, is added to the tool for processing in a suitable concentration. This is done, for example, water that continuously flows in the incubation tank for breeding fish. After the introduction preparations for the treatment of circulation water block for some time, to the means for processing can be affected. This processing may be performed once or continuously for several days or daily intervals or after a few days, during the period of time ranging from minutes to a small number of hours. Then the means for processing is removed from the incubation tank with water changes. The efficacy and tolerability of treatment is determined on the basis of the number of living and not affected mushrooms eggs. The efficacy and tolerability for hatched, developing fish or adult is defined in the water tank in which the cultured fish. For this purpose, the means for processing is supplied to the tank for the fish. After the introduction preparations for the treatment of circulation water block for some time, for that. to the means for processing can be affected. This processing may be performed once or continuously for several days or is also with daily intervals or after a few days, during the period of time ranging from minutes to a small number of hours. The efficacy and tolerability of treatment is determined on the basis of the amount of live fish and the degree of fungal attack.

The invention is explained in more detail by the following example.

An example of execution of the invention

Example 1: to determine the efficacy of substances in relation to fungi, parasitic on fish, for example, Saprolegnia spp.

Isolate Saprolegnia parasitica (CBS 540.67, Centraalbureau voor Schimmel-cultures, Baarn, the Netherlands) is applied and propagated at 20°C in the dark on PD agar (39 g/l final concentration). To determine the magnitude of the effective dose ED50plate PD agar mixed with fungicide, the efficiency of which it is necessary to determine the following range of concentrations: 0-0,03-0,1-0,3-1-3-10-30 ppm For each case on Wednesday, in Petri dishes with different concentrations of the fungicide, placed the seed Saprolegnia parasitica.

The plate is subjected to incubation for three days at 20°C in the dark, and then measure the growth of fungi on a plate of agar and counting the value of the ED50from the comparison with the untreated control sample.

In this experiment, fungicides such as, for example, fluoxastrobin, fenamidone, cyazofamid, famoxadone and perimekar demonstrate the indicator ED50equal to or less than 5 m is.

Application fluoxastrobin as a means to fight against mycoses in fish and invertebrates and all their stages of development, caused by fungi of the genera Saprolegnia, Achlya, Aphanomyces.



 

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1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for local application in the form of cream or ointment contains as effective amount of voriconazole or its pharmaceutically acceptable salt, or a pharmaceutical carrier. Said dosage form of voriconazole contains max. 3 wt % of water. What is also described is a method for preparing the dosage form of voriconazole for treating local and non-systemic mycotic infections in an individual.

EFFECT: dosage form for local application under the invention maintains storage stability at temperature approximately 40°C and relative humidity approximately 75% for at least three months and has total storage impurity content is no more than 9 wt % as related to total weight of the dosage form.

12 cl, 1 dwg, 30 ex

FIELD: chemistry.

SUBSTANCE: polypeptide compounds contain cyclohexyl methyl amino groups or piperidyl methyl amino groups in the structure.

EFFECT: excellent activity against deep fungal infection.

16 cl, 66 tbl, 45 ex

Ear hygiene drug // 2431486

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and veterinary science, and represents a drug for treating ear diseases in humans or animals, containing (a) an anti-infectious agent representing fluoroquinolone, (b) in an oily base encapsulated in a primary package for introduction of one single dose.

EFFECT: invention provides unexpectedly good adhesion to a surface of an acoustic meatus thereby it is actually impossible to shake it off from the acoustic meatus.

18 cl, 13 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to amidines of formula (I) and to their derivatives, methods for making thereof and pharmaceutical compositions containing amidines of formula (I). According to said invention, amidines are applicable for inhibition of IL-8 induced chemotactic factor, and can be applied to produce medicine agents for treating psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and for preventing and treating injuries caused by ischemia and reperfusion.

EFFECT: higher clinical effectiveness.

7 cl, 6 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using compounds of general formulas (I) (II) or (III) for preparing pharmaceutical drugs use din treatment and/or prophylaxis of vessels diseases, and to compounds of formulas (I), (II) or (III), and a pharmaceutical composition used in vessels treatment. Invention provides enhancing effectiveness of treatment.

EFFECT: valuable medicinal properties of compounds and drugs, enhanced effectiveness of treatment.

8 cl, 3 tbl, 20 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

The invention relates to a new scriptfilename the compound of formula 1, in which AG is methyl, or phenyl, or any simple unsubstituted or substituted aromatic or heteroaromatic group; R1represents halogen; R2is HE or R1and R2may be combined together with the formation of the epoxy ring, aziridine ring; R1and R2may be combined together with the formation of a double bond between C18and C19; R3represents a lower alkyl group; R4and R5represent H; or R4and R5may be combined together with the formation of a double bond between the C13and C14; R6represents benzyl, hydroxybenzyl (oxybenzyl), alkoxybenzyl, halodukebeing, diplodactylinae, kaleidoscopically or dihaloalkanes group; R7, R8, R9and R10each independently represent H or a lower alkyl group; and X and Y each independently represent O, NH

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to diarylthiohydantoic compounds of formula wherein R1 and R2 together with carbon atom whereto attached are a cycloalkyl consisting of 4-5 carbon atoms, wherein R3 is specified in a group consisting of dimethylcarbamoylalkyl and cyanoalkyl and wherein R4 represents hydrogen or fluorine. Also, an invention refers to a pharmaceutical composition on the basis of the declared compounds, to a method of synthesis and application thereof.

EFFECT: there are produced new diarylthiohydantoic derivatives effective in treating hormone-resistant prostate cancer.

29 cl, 25 dwg, 11 tbl, 5 ex

Diarylhydantoins // 2448096

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylhydantoin derivatives and specifically to compounds of formulae The invention also relates to a pharmaceutical composition based on said compounds, a method of treating a hyperproliferative disease, based on use of said compounds.

EFFECT: obtaining novel diarylthiohydantoin derivatives, having useful biological activity.

24 cl, 29 dwg, 11 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of compounds of formula I where R1 denotes a hydrogen atom, a tritium atom, hydroxy, lower alkyl, lower alkoxy, a halogen atom, nitro, aminor or lower alkyl substituted with a halogen atom; R2 denotes a hydrogen atom, hydroxy or lower alkyl; X denotes N and Y denotes CH or CH2 or CH-lower alkyl, or X denotes CH and Y denotes N; Q denotes CH2,O, NH, N-alkyl, N-SO2-alkyl or N-SO2-tolul-4-yl; W denotes CH2 or a bond; m and n are independently equal to 1, 2 or 3; when m equals 2 or 3, R2 can be identical or different, when n equals 2 or 3, R1 can be identical or different; each dotted line, independently from another dotted line, may or may not denote a bond; and their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomeric forms of compounds of formula I in preparing medicines for treating bipolar disorder, schizophrenia, Parkinson's disease, Alzheimer's disease, epilepsy, eating disorders, diabetic complications, dyslipidaemia, energy assimilation and consumption disorders, temperature homeostasis disorders, sleep and circadian rhythm disorders. The invention also relates to use of a compound of formula IA, compound of formula I and medicine based on the compound of formula I.

EFFECT: obtaining novel 2-midazole derivatives having useful biological properties.

63 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), as well as pharmaceutically acceptable salts or stereoisomers thereof, having activity on the β2 adrenergic receptor. In formula R1 denotes a group selected from -CH2OH, -NHC(O)H, and R2 denotes a hydrogen atom; or R1 together with R2 form a -NH-C(O)-CH=CH- group, where the nitrogen atom is bonded with a carbon atom of the phenyl ring containing R1, and the carbon atom is bonded with a carbon atom of the phenyl ring containing R2; R3 is selected from a group containing hydrogen and halogen atoms, or denotes a group selected from -NH-CO-NH2, a hydantoic group, C1-C4alkyl and C1-C4alkoxy group; R4 is selected from a group comprising hydrogen atoms, halogen atoms and C1-C4alkyl groups; n, p and q are independently equal to 0, 1, 2, 3 or 4; m and s are independently equal to 0, 1, 2 or 3; r equals 0, 1 or 2; under the condition that at least one of m and r is not equal to, the sum n+m+p+q+r+s equals 7, 8, 9, 10, 11, 12 or 13, the sum q+r+s equals 2, 3, 4, 5 or 6. The invention also relates to a pharmaceutical composition and treatment and modulation methods.

EFFECT: high efficiency of the composition.

20 cl, 18 ex

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