JP2001081034A - Antiprotozoal agent for animal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antiprotozoal agent that is additionally effective for dissolving several troubles in protozoal diseases, for example, there is never known any therapeutic agent that is sufficiently effective against several protozoal diseases among those known in aquaculture industry or domestic animal- breeding industry, the appearance of protozoans resistant to the conventional therapeutic agents, the safety (toxicity) on the therapeutic agent and the residual properties of the therapeutic agent in the meat. SOLUTION: Fosmidomycin or salts thereof are used as prophylactic and therapeutic agent against protozoal diseases in (domestic) land animals, for example, coccidiosis, toxoplasmosis, babesiosis, theileriosis and the like, or against protozoal diseases in aquaculture industry, for example, white spots in several kinds of fishes, Beko disease in eels (pleistophorosis), Kudoa diseases in yellowtail, red sea bream and tiger puffer (Fugu rubripes). The fosmidomycin is a known compound as 3-(N-formyl-N-hydroxyarninopropylphosphonic acid and has antimicrobial actions against a variety of pathogenic microorganisms.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the prevention or treatment of coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, white spot disease in fish, downy mildew in eel, yellowtail, red sea bream and tiger puffer. And a novel use of fosmidomycin or a salt thereof. Further, the present invention provides a method for administering fosmidycin or a salt thereof to a terrestrial animal or fish, which comprises coccidiosis, toxoplasmosis, babesiosis and tyreliosis in a land animal, white spot disease in fish, and downy mildew in eel. , Yellowtail, red sea bream, and tiger puffer are provided. Furthermore, the present invention relates to coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, white spot disease in fish, downy mildew in eel, qudidae in yellowtail, red sea bream and tiger pufferfish, comprising fosmidycin or a salt thereof. The present invention provides a preventive or therapeutic agent for the disease, and is useful in the field of veterinary medicine.

[0002]

BACKGROUND OF THE INVENTION Fosmidomycin used in the present invention comprises:
It is a known compound 3- (N-formyl-N-hydroxyamino) propylphosphonic acid, which is known to have antibacterial activity against various pathogenic bacteria (for example,
See JP-A-53-40720).

[0003]

The protozoal infections coccidiosis, babesiosis and theileriosis in livestock and poultry are important diseases facing the livestock industry. In addition, toxoplasmosis in livestock, dogs and cats not only affects meat productivity, but also causes human infection.
Protozoan infections in fish include white spot disease, downy mildew on eels, and kudosis on yellowtail, red sea bream, and tiger puffer fish, and are highly damaging to the aquaculture industry. Among these protozoal infections, there are no effective therapeutic agents, the emergence of resistant protozoa to the therapeutic agents, the safety of the therapeutic agents, persistence in meat, etc. There is a need for more effective drugs that solve these problems.

[0004]

SUMMARY OF THE INVENTION The present inventors have surprisingly found that fosmidomycin has been shown to cause coccidiosis, toxoplasmosis, babesiosis and theileriosis in terrestrial animals, white spot in fish, downy mildew in eel, The present invention has been found to be useful for the prevention or treatment of kuduosis in yellowtail, red sea bream and red puffer fish, and has reached the present invention.

In the present invention, as an active ingredient for the prevention or treatment of coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, white spot disease in fish, downy mildew in eel, yellowtail, red sea bream, and tiger pufferfish. The compound used is fosmidomycin or a salt thereof. As the salts,
For example, sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N.I. Salts with inorganic or organic bases such as N'-dibenzylethylenediamine salt and salts with basic amino acids such as arginine salt are pharmaceutically and pharmacologically acceptable salts.

The fosmidomycin or a salt thereof of the present invention can be administered to terrestrial animals or fish as it is, or as a mixture, preferably a pharmaceutically and pharmacologically acceptable excipient or carrier. Can be administered as a mixture with The veterinary pharmaceutical composition of the present invention can be used, for example, in the form of a solid, semi-solid or liquid preparation, which is suitable for oral or external use, parenteral application such as intravenous, intramuscular, and the like. It contains fostomycin or a salt thereof as an active ingredient in a mixture with an organic or inorganic carrier or excipient. Examples of the active ingredient include oral preparations such as tablets, pills, powders, granules, fine granules, premixes, capsules, solutions, emulsions, and suspensions, injections, drops, suppositories, and ointments. , Plasters,
It can be used as a parenteral preparation such as a patch or aerosol, and can be formulated together with a usual non-toxic, pharmaceutically and pharmacologically acceptable carrier.

Carriers which can be used include water, glucose, lactose, gum acacia, gelatin, mannitol, starch, cellulose, methylcellulose, magnesium trisilicate, magnesium stearate, talc, keratin, colloidal silica, urea, alginic acid and other , A solid suitable for use in manufacturing the formulation,
There are semi-solid or liquid carriers, and in addition, auxiliary, stabilizing, thickening, coloring and flavoring agents can be used.

When administered in the form of a mixture with a feed, corn flour, wheat flour, soybean meal, fish meal, a compound feed mainly containing vitamins and the like, raw minced fish (eg, minced mackerel, sardine, cuttlefish, etc.) To a feed (moist pellets, dry pellets) obtained by mixing a feed or a compound feed and a fish mince, fosmidomycin or a salt thereof is added directly or in the form of the above various dosage forms.

[0009] The fosmidomycin or a salt thereof of the present invention is contained in the veterinary pharmaceutical composition in an effective amount sufficient to obtain the desired effect on the progress or disease state of the disease.
In addition, the composition can be used alone or in combination with other drugs, such as other antibiotics.

To apply this composition to terrestrial animals or fish, it is used by oral administration or parenteral administration such as intravenous administration, intramuscular administration, subcutaneous / intradermal administration, topical administration, transmucosal administration, and rectal administration. However, it is preferable to add feed or drinking water to terrestrial animals, and to fish to be added to a raw feed or a mixed feed or a mixture thereof, or to be immersed in breeding water containing the composition. The dosage of therapeutically effective fosmidomycin or a salt thereof depends on the type of disease, the mode of administration,
The dose is usually 1 to 100 mg / kg, depending on the animal species to be treated, the individual body weight and the condition. In addition, when added to feed or drinking water for administration, the added concentration is usually 1 to 1000 ppm. When immersed in fish for administration, the concentration in the breeding water is usually 0.00
1 to 1000 ppm.

The fosmidomycin of the present invention or a salt thereof and a composition thereof are provided by Eimeria tene (Eimeria tene).
lla) etc., coccidiosis in chickens, cows, sheep, pigs, dogs and cats; Toxoplasma gondi
dii) toxoplasmosis in sheep, pigs, dogs and cats;
Babesia disease in cattle, horses, dogs, etc. caused by Babesia ovata etc .; Theileria sargenti (Th
ileeria sergenti) and other cattle and buffalo theileriosis; heterosporis anguillarum (Heterosporis a)
Equine downy mildew caused by E. nguillarum); Kudosis of yellowtail, red sea bream and tiger pufferfish caused by Kudoa amamiensis, etc .; Seawater caused by Cryptocaryon irritans and Ichthyophthirius multifiliis It is useful for treating or preventing white spot disease of fish and freshwater fish.

Representative evaluation methods and effects for showing the usefulness of the present invention are shown below. 1. Evaluation method for coccidiosis Chicks (8-day-old chicks of chunky broiler males) are divided into a non-infection-free group, an infection-free group, and an infection-administered group, with 10 birds per group. In the treatment group, a powdered feed (pre-broiler feed) containing a predetermined concentration of the test compound was given and administered from 2 days before infection to the end of the test, and spore formation of Eimeria tenella was completed for the chickens in the infected group. About 20,000 fresh oocysts / wing are orally inoculated (infected). Eight days after infection, survival rate, weight gain, intestinal lesion value (Kakuta's method) and fecal oocyst value (the number of oocysts in feces on the 7th and 8th day after infection was measured, and The ACI value (relative gain rate + survival rate-oocyst value-lesion value) is calculated from the calculated value, and the infection protective effect is evaluated. The standard of evaluation by the ACI value is less than 120, no effect, 120 or more and less than 150, weak effect, 150 or more and less than 180, moderate effect, and 180 or more, strong effect.

2. Effect on coccidiosis by addition to feed The test was performed according to the method described in the above evaluation method.
m was added.

[Table 1] As shown in the table, the effect of fosmidomycin on coccidiosis was observed.

3. Evaluation method for toxoplasmosis Toxoplasma gondii (Toxo)
Inoculate 100 plasma gondii) tachyzoites / animal. Thereafter, once a day for 30 consecutive days, an aqueous solution of the test compound at a predetermined concentration is orally administered by gavage, and the protective effect against infection is evaluated by the survival and death of mice.

4. Evaluation method for white spot disease Goldfish are bred in an experimental aquarium, and goldfish naturally infected with white spot disease are bred in the same aquarium for infection. Infected fish are grouped in separate aquariums, fed daily with a predetermined concentration of the test compound added, and bred for 30 days to produce white spots,
Evaluate the protective effect by controlling the survival of infected fish.

The present invention will be described in more detail with reference to the following examples.

Example 1 Preparation of Injection 250 mg of a monoammonium salt of fosmidomycin is filled in a sterile ampule and sealed. At the time of use, 2 ml of distilled water for injection is added and dissolved to prepare an injection.

[0017]

Example 2 Preparation of Tablet Monosodium salt of fosmidomycin 200 mg Mannitol 400 mg Starch 50 mg Magnesium stearate 10 mg The above ingredients were mixed and compressed into tablets by a conventional method, and then, if necessary, sugar-coated tablets by a conventional method And

[0018]

Example 3 Preparation of Capsules Monopotassium salt of fosmidomycin 300 mg Magnesium stearate 15 mg The above components were mixed, and the mixture was filled into a normal hard gelatin capsule to prepare a capsule.

[0019]

Example 4 Addition to feed 1% by weight of fosmidomycin monosodium salt and lactose 9
Mix 9% by weight to obtain a 100-fold powder. 10 obtained
1 g of 0 times powder is mixed with 999 g of powdered feed for poultry or pigs to obtain 1 kg of an additional feed having a compound concentration of 10 ppm.

Claims (6)

[Claims] 1. A method for the treatment of coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, white spot disease in fish, downy mildew in eel, and kudosis in yellowtail, red sea bream and tiger pufferfish, comprising fosmidomycin or a salt thereof. Prophylactic or therapeutic agent. 2. Prevention of fosmidycin or a salt thereof against coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, white spot disease in fish, downy mildew in eel, and kudosis in yellowtail, red sea bream and tiger pufferfish. Or use for treatment. 3. A method comprising administering fosmidycin or a salt thereof to a terrestrial animal or a fish, wherein the disease comprises coccidiosis, toxoplasmosis, babesiosis and theileriosis in a terrestrial animal, white spot disease in a fish, downy mildew in an eel, A method for preventing or treating Kudu's disease in yellowtail, red sea bream and tiger puffer. 4. Prevention of focidomycin or a salt thereof against coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, white spot disease in fish, downy mildew in eel, and kudosis in yellowtail, red sea bream and tiger pufferfish. Use for the manufacture of drugs or therapeutics. 5. Coccidiosis, toxoplasmosis, babesiosis and tyreliosis in terrestrial animals, consisting of a mixture of fosmidomycin or a salt thereof with a carrier or excipient, white spot disease in fish, downy mildew in eel Veterinary pharmaceutical composition for the prevention or treatment of kuduosis in yellowtail, red sea bream, red sea bream and red puffer fish. 6. The method for preparing a veterinary pharmaceutical composition according to claim 5, wherein fosmidomycin or a salt thereof is mixed with a carrier or excipient.