HK1158109A - Nifurtimox for treating diseases caused by trichomonadida - Google Patents

Description

Nifurtimox for the treatment of diseases caused by trichomonales

The present invention relates to the use of nifurtimox for the treatment of diseases caused by trichomonas (trichomonas) and trichomonas (diplomandida), such as for example histomoniasis, in particular turkey histomoniasis.

The efficacy of nitroheterocycles against protozoal diseases is known in principle (1).

Protozoa include mononuclear organisms whose basic structure is eukaryotic cells. However, more accurate taxonomy shows large differences in the habits, morphologies and biochemical metabolism of individual phyla (St ä mme), classes, genera and species. This is why chemicals that rely on their target and principle of action do not generally work equally well for all protozoa, but only for a specific group of protozoa (2, 3, 4).

To date, only protozoan species of the genus nifurtimox antitrypanosoma such as trypanosoma brucei (R) ((R))Trypanosoma brucei) And Trypanosoma cruzi: (Trypanosoma cruzi) Efficacy of (5, DE-AS-1170957). Trypanosomes have flagella, which are initially attached to a substrate ("hairy substrate",thus belonging to the order of the moving substrate (Kinetoplastida)) and develops into a fluctuating film with the substrate. Trypanosomes grow mainly in plasma and are transmitted by blood-sucking arthropods. These pathogens cause chagas disease ("trypanosomiasis") in humans. Nifurtimox is almost the only compound currently acting against these pathogens. This activity may be based on the inhibition of trypanosoma glutathione spermidine reductase (trypanothionine reductase), a trypanosoma specific enzyme. This enzyme is not present in other protozoan pathogens, in particular trichomonas and histomonas.

To date, the efficacy of nifurtimox within trichomonas and trichomonas has not been described. Trichomonas is all parasitic protozoa for which multiple (usually 4 to 6) flagella are typical. One notable morphological feature is the contractile rods (Kontraktiler Stab, = coral ribs) in organisms, which participate in locomotion. Unlike the order of kinetocomelia, the order trichomonas does not have mitochondria, which are important organelles for energy metabolism. Instead, energy metabolism occurs in the body of the enzyme known as catalase. In these organelles, pyruvate is oxidatively decarboxylated, with ATP synthesis and ferroredox protein-controlled electron transfer (6). These single-cell parasites multiply by division. No sexual stage or cysts were found. The order Trichomonas includes many genera (particularly Trichomonas and histomonas) and many others, but most of these are harmless and non-pathogenic. However, there are representatives that trigger serious diseases and cause significant economic damage to animal husbandry. These include the genus Trichomonas (in particular Trichomonas californicus (A.), (B.))T. gallinae) And trichomonas avicularis: (T. gallinarum) Trichomonas genus (in particular Trichomonas embryosus: (A), (B), (C), (T. foetus) And Trichomonas suis: (T. suis) And of the genus histomonads (in particular of the turkey histomonads: (H. meleagridis))。

Trichomoniasis (Trichomonas) of pigeons and poultry is a trichomonas carinii (Trichomonas)Trichomonas gallinae) And trichomonas avicularis: (T. gallinarum) Causing infectious diseases. Trichomonas gasseri (A. gasseri.), (B. gasseri.), (T. gallinae) It is mainly parasitic in the pharynx, esophagus and crop. However, the device is not suitable for use in a kitchenHowever, during the disease, other organs, mainly the liver, heart and lungs, are also infected. Infection of young pigeons occurs earliest during the first feeding of pigeon milk by a latently infected older animal. Other sources of infection are infected drinking water or feed. This disease is considered to be the most common disease in young pigeons, causing severe damage, especially in breeding herds. In addition to high mortality, symptoms observed were digestive disturbances, loss of appetite, reduced consumption of drinking water and food, and limited flight ability. Trichomonas avicularis (Trichomonas gallinarum) Parasitizing in the cecum of chickens and turkeys. The disease causes growth retardation, severe diarrhea and necrotic inflammation of the liver.

Histomoniasis is an infectious disease caused by turkey Histomonas meleagris. Tissue infusorium is an intestinal parasite. Histomoniasis is particularly important in turkeys, which is also known as blackhead disease. In turkeys, the disease is caused in particular by the pathogen turkey Histomonas meleagris. In addition to turkeys, other animals that can be infected with the pathogen include chickens, guinea fowl, peacocks, pheasants, partridges and quails, which are also storage hosts.

Infection with turkey Histomonas meleagris causes severe inflammation of the cecum and liver, as the pathogen damages intestinal tissue and reaches the liver via the blood, where it causes necrosis formation. One concomitant symptom of the disease is usually circulatory failure, which can be identified by the dark blue head of the affected animal to which the disease name is assigned.

In infected herds, such as poultry production units, the disease spreads very quickly throughout the herd, resulting in severe economic losses due to its very high mortality rate (in some cases up to 100%).

Thanks to its structural flagella, turkey Histomonas meleagris (Histomonas meleagris) belongs to the sub-phylum flagellata (class of flagellates) and order of Trichomonas. This flagellate stage is propagated in the caecum by division. Starting from the infected cecum, the amoeboid phase permeates the liver via blood vessels, where it is destroyed via extensive necrosis (7).

Because outside the host, the tissue infusorian pathogens can only survive for a short time, and because most of them are killed when passing through the digestive tract, tissue infusorian transmission via direct routes, such as oral ingestion of fresh feces containing tissue infusorian, is minimal. Experiments conducted by us researchers have shown that infection of turkeys occurs more readily in animal trials via the cloaca than the oral route. Because the cloaca undergoes a slight inhalation after the feces have accumulated, infections via this route are likely to occur under normal conditions, such as via contaminated litter. The spread of pathogens via intermediate hosts has proven to be scientifically unquestionable. It is in particular a caecum worm heterodera gallinae, known as a carrier, in particular as a transport vector for turkey Histomonas meleagris (Heterakis gallinarum) (egg or larva). Tissue infusorian can remain infected in eggs of embryonated heterodera for up to 4 years. Other intermediate hosts may be earthworms and arthropods contaminated with eggs of the genus heterodera. In addition, chickens and other poultry species are potentially dangerous. They are less sensitive than turkeys, are often loaded with pathogens, but are not clinically susceptible; as such, they facilitate the transmission of pathogens.

Turkeys can be infected at any age; however, the disease most commonly occurs at 3 to 12 weeks of age. In most cases, the period between infection and manifestation of the disease is 7-12 days. Mortality rates can be as high as 100% and reach its maximum at day 17 post infection. Inflammation can be found in the cecum from day 8 and in the liver from day 10.

Infected animals were unresponsive, tired, had heads and wings drooping, and had refused to eat. It is typical to have a sulfur-colored stool, diarrhea, and then even blood in the stool. The circulatory disturbance associated with the disease causes a severe blackish-blue colour of the head, which gives the name of the disease. .

The course of the disease is mainly determined by the age of the turkey and the intestinal flora. Infection of Escherichia coli (E. coli) Clostridium perfringens (A), (B), (C)Clostridium perfringens) Or additional bacterial infection of coccidia (Coccidien) can exacerbate the process (8).

The diagnosis of histomoniasis can be carried out with the aid of saline solution using natural samples from the cecum and liver. Amoeba-like active periods were discernible under phase contrast microscopy. For histological studies, PAS staining was used.

Until 1950, arsenic compounds (e.g. phenylarsonic acid, cacarsine, roxarsine) were the only effective compounds against histomoniasis. However, it is well known that arsenic compounds are often not sufficiently effective to treat infections once established. A further disadvantage is that its safety index is very low: even a double dose of roxarsone resulted in a disturbed motor function of the turkey.

Since 1960, other nitroimidazoles or nitrofurans have been used, for example in the diet or drinking water, but since the mid 90 s EU and USA have gradually banned their use in livestock and as feed additives. In 1997, dimetridazole exited the USA market, and in 2001 it was banned for use as a feed additive in EU. Since 31/3/2003, even nifuratel, the only product still licensed in the EU is no longer used due to security concerns. Therefore, drugs for the treatment of histomoniasis and agents for the prophylactic control of histomoniasis are not currently and in the future available.

The only currently available strategies to avoid infection with the disease include sanitation, optimization of feed density and nutrient supply, and avoidance of pathogen carriage. These measures are insufficient and alone are not able to prevent the infection from becoming diseased.

No vaccine against histomoniasis was provided. For example, vaccination against turkey Histomonas meleagris (Histomonas meleagris) is biologically impossible because natural immunity is not obtained even after infection. Once infected, the animal may become ill again. Attempts to confer immunity via live attenuated vaccines failed.

Therefore, there is a need for active substances for the treatment of diseases caused by the order trichomonas, such as, for example, histomoniasis, wherein the active substances have good activity and good toxicological properties.

Surprisingly, we have now found that nifurtimox is effective against trichomonas and that nifurtimox also has good toxicological properties. To date, this activity has not been described, nor has its good toxicological properties been expected.

The invention relates to

Use of nifurtimox for the preparation of a medicament for the treatment of a disease caused by trichomonales.

Nifurtimox is a compound of formula (I):

optionally, the use of conventional pharmaceutically acceptable salts thereof is contemplated. Furthermore, optionally, hydrates or other solvates of the active substance or, optionally, salts of hydrates or other solvates may be considered.

The use may be both prophylactic and therapeutic. Trichomonas includes the genera Histomonas (Histomonas), Trichomonas (Trichomonas). As the genus Trichomonas, mention may be made in particular of Trichomonas gasseri ((I))T. gallinae) And trichomonas avicularis: (T. gallinarum). For the genus Trichomonas, mention may be made in particular of embryonic Trichomonas (III)T. foetus) Three-bristle trichomonas suis (A. and B. suis) ((B))T. suis) And Trichomonas equi: (T. equii). As the genus Histomonas, mention may in particular be made of turkey Histomonas meleagris (Histomonas meleagris).

The order of Trichomonas includes six penisTrichinella (Hexamita). As the genus Hexaflagellate, mention may be made in particular of Pigeon Hexaflagellate (H. columbae) Six flagellates of turkey (A)H. meleagridis) And Hexaflagellate of Salmon: (H. salmonis)。

Preferably against histomoniasis. It is caused by the Histomonas spp. Very particularly preferably, according to the invention, the histomoniasis caused by turkey Histomonas meleagris (Histomonas meleagris) is controlled. The activity of nifurtimox in controlling histomoniasis is not only directed against the intestinal phase of the pathogen, but also against the hepatic phase of the pathogen.

Animals are treated according to the invention. Examples which may be mentioned are mammals, such as, for example, cows, horses, pigs, dogs, cats. Poultry, such as, for example, chickens, guinea fowl, partridges, quails, ducks, geese, peacocks, pheasants, pigeons, in particular turkeys (Puten), are preferably treated (used synonymously herein with turkeys (Truth ä hn).

Examples of diseases that may be emphasized are the following:

trichomoniasis of pigeon, turkey or poultry is caused by trichomonas avicularis (T. gallinarum) And/or Trichomonas gasseri (a)T. gallinae) And (4) causing.

Histomoniasis occurs in chickens, guinea fowl, peacocks, pheasants, partridges, quails, and particularly turkeys. The histomoniasis (blackhead disease) of turkeys is caused in particular by turkey histomoniasis (h.

The active substances are administered directly or in suitable formulations via the enteral, parenteral or dermal route.

Enteral administration of active substances is carried out, for example, orally in the form of powders, suppositories, tablets, capsules, pastes, drinkable preparations (Tr ä nken), granules, drenches, boluses, medicated feeds or drinking water. Dermal administration is carried out, for example, in the form of dipping, spraying, bathing, washing, pouring (Aufgie. beta. en) and dusting. Parenteral administration is carried out, for example, in the form of injections (intramuscular, subcutaneous, intravenous, intraperitoneal) or implants.

The proper preparation is

Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;

emulsions and suspensions for oral or dermal administration and for injection; a semi-solid formulation;

formulations wherein the active substance is added to an ointment base or an oil-in-water emulsion base or a water-in-oil emulsion base;

solid formulations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; aerosols and inhalants, shaped articles comprising active substances.

Solutions for injection are for example administered intravenously, intramuscularly and subcutaneously.

Oral solutions are administered directly. The concentrate is administered orally after pre-dilution to the use concentration.

The solution applied to the skin is dropped, painted, rubbed, sprayed on or applied to the skin by dipping, bathing or washing.

The gel is applied to or smeared on the skin or introduced into a body cavity.

Pour-on formulations are poured or spot-on a limited area of the skin, the active substance penetrating the skin to act systemically or to be distributed on the body surface.

Emulsions are water-in-oil or oil-in-water and can be administered orally, transdermally or as an injection.

The suspensions may be administered orally, transdermally or as injections.

The semisolid formulations can be administered orally or transdermally. They differ from the above-mentioned suspensions and emulsions only by their higher viscosity.

To prepare a solid formulation, the active substance is mixed with suitable excipients, optionally additives are added, and brought into the desired shape.

Particularly preferred according to the invention is the use in poultry. This is preferably done by oral administration, in particular via medicated feed or drinking water.

All the abovementioned pharmaceutical forms, the additives and auxiliaries used and the preparation of these pharmaceutical forms are known in principle to the skilled worker.

The active may be present in combination with a synergist or other active. Other active substances which may be mentioned are:

anticoccidial agents, such as robenidine or apremium, in some cases in combination with folic acid antagonists (e.g., ethopabate, pyrimethamine, epiprilin);

polyether antibiotics, such as monensin, salinomycin, lasalocid, narasin, and maduramicin;

triazinones such as toltrazuril, ponazuril or diclazuril;

sulfonamides (sulfaquindoxine, sulfadimidine, sulfadiazine).

For long-term therapeutic effect, it is recommended to disinfect the animal stalls before housing or after the end of the fattening period.

Helminths, in particular heterodera species (larvae) (9), act as transport vectors in the transmission of tissue infusorian. Thus, in the treatment of histomoniasis, it may be of interest to perform a combination therapy with an anthelmintic. Accordingly, anthelmintics such as, for example, the benzimidazoles albendazole or fenbendazole are known to have prophylactic activity in vivo when treated from the time of infection. A common anthelmintic treatment is 14 days from the time point of infection. Thus, by combination therapy with nifurtimox and an anthelmintic, improved treatment of trichomonas-induced diseases is obtained.

Anthelmintics which may be mentioned are benzimidazoles such as albendazole, fenbendazole, or Probenzimidazole such as febantel. These substances have, for example, activity against species of the genus Heterodera, in particular against Heterakis gallinarum (Heterakis gallinarum), which is known to act as a transport vector (10) for the Histomonas melegridis (Histomonas meleagris).

Other drugs that may be mentioned are imidazothiazoles (levamisole, tetraimidazole), tetrahydropyrimidines (pyrantel, morantel, octopine), amidine derivatives such as amistar, triphendimidine and deacylaamistar derivatives Bay d 9216 and aminoacetonitrile derivatives (see, for example, Kaminsky et al,Nature452,176-.

Among the anthelmintics, preferred substances that may be mentioned are depsipeptide anthelmintics. Depsipeptides such as PF1022A and Emodepsid have broad spectrum anthelmintic activity against nematodes of various animal species such as the orders galliformes, rodents, reptiles, dogs, cats, sheep, cattle, goats, horses (11, 12, 13, 14). Here, PF1022A and Emodepsid have been shown to be active against nematodes of the Heterakoidea superfamily. These include, for example, heterodera species from the heterodera family, and heterodera gallinae in chickens: (Heterakis gallinarum) (ii) Heterodera spongii, Ostertagia nematoda of the family murineHeterakis spumosa). For example, PF1022A at an oral dose of 50mg/kg has activity against the latter, and Emodepsid at a dose ranging, for example, from 1 to 10mg/kg also has activity against the latter (13, 15). Furthermore, PF1022A has been demonstrated, for example, to have activity against other representatives of the Heterakoidea superfamily, chicken roundworm (Ascaridia galli), which belongs to the general family of roundworms. Here, the compound acts at a dose of 2mg/kg (16). Thus, these substances from the class of cyclic depsipeptide compounds are particularly suitable for the prophylactic control of histomoniasis.

Preferred depsipeptide-anthelmintics for use are the 24-membered cyclic depsipeptides. The following may be mentioned:

a compound of formula (IIa)

Wherein

Z represents hydrogen, N-morpholinyl, NH₂Mono-or dimethylamino.

Furthermore, there may be mentioned compounds of the following formula (IIb):

wherein

R¹、R²、R³、R⁴Independently of one another, represents hydrogen, C₁-C₁₀Alkyl or aryl, in particular phenyl, optionally substituted by hydroxy, C₁-₁₀Alkoxy or halogen.

Compounds of the formulｃA (IIb) are known and can be obtained by the processes described in EP-A-382173, DE-A4317432, DE-A4317457, DE-A4317458, EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787141, EP-A-865498, EP-A-903347.

Cyclic depsipeptides having 24 ring atoms also include compounds of the general formula (IIc)

Wherein

R^1a、R^2a、R^11aAnd R^12aIndependently of one another represent C_1-8Alkyl radical, C_1-8-haloalkyl group, C_3-6-cycloalkyl, aralkyl, aryl,

R^3a、R^5a、R^7a、R^9aindependently of one another, represents hydrogen or straight-chain or branched C_1-8-alkyl, which may optionally be substituted by hydroxy, C_1-4-alkoxy, carboxyl,Formamide,Imidazolyl, indolyl, guanidino, -SH or C_1-4-alkylthio substitution; furthermore, it represents aryl or aralkyl, where the radicals may be substituted by halogen, hydroxy, C_1-4Alkyl radical, C_1-4-an alkoxy group substitution,

R^4a、R^6a,、R^8a、R^10aindependently of one another, hydrogen, straight chain C_1-5Alkyl radical, C_2-6-alkenyl, C_3-7-cycloalkyl, which groups may be optionally substituted by: hydroxy, C_1-4Alkoxy, carboxyl, carboxamide, imidazolyl, indolyl, guanidino, SH or C_1-4-alkylthio substitution; and represents aryl or aralkyl, said radicals being optionally substituted by halogen, hydroxy, C_1-4Alkyl radical, C_1-4-an alkoxy group substitution,

and optical isomers and racemates thereof.

Preferred compounds of formula (IIc) are those of the following: wherein R is^1a、R^2a、R^11aAnd R^12aIndependently of one another, represents methyl, ethyl, propyl, isopropyl, n-, sec-, tert-butyl or phenyl, which are optionally substituted by halogen, C_1-4Alkyl, OH, C_1-4-alkoxy substituted, and represents benzyl or phenylethyl, which groups may be optionally substituted by the groups mentioned for phenyl;

R^3ato R^10aHave the above-mentioned meanings.

Particularly preferred compounds of the formula (IIc) are those in which R^1a、R^2a、R^11aAnd R^12aIndependently of one another, represent methyl, ethyl, isopropyl or n-, sec-, tert-butyl.

R^3a、R^5a、R^7a、R^9aRepresents hydrogen, straight or branched C_1-8-alkyl, in particular methyl, ethyl, propyl, isopropyl, n-, sec-, tert-butyl, which groups may optionally be substituted by: c_1-4Alkoxy, especially methoxy, ethoxy, imidazolyl, indolyl, or C_1-4Alkylthio, in particular methylthio, ethylthio; further represents phenyl, benzyl or phenethyl, which radicals may optionally be substituted by halogen, in particular chlorine,

R^4a、R^6a、R^8a、R^10aindependently of one another, represents hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, which may optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, and represents isopropyl, sec-butyl, and further represents optionally halogen-substituted phenyl, benzyl or phenylethyl.

The compounds of the formulｃA (IIc) can also be obtained by the processes described in EP-A-382173, DE-A4317432, DE-A4317457, DE-A4317458, EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787141, EP-A-865498, EP-A-903347.

Very particularly preferred depsipeptides which may be mentioned are the compound PF1022 which is known from EP-OS 382173; which is a compound of formula (IIa) wherein two substituents Z represent hydrogen. Thus, PF1022 has the following formula (IId):

。

further preferred depsipeptides are the compounds disclosed in PCT application WO 93/19053, which are compounds of the formula (IIa)

Wherein

Z represents N-morpholinyl, NH₂Mono-or dimethylamino.

Very particular preference among these compounds is given to the depsipeptide Emodepsid (PF 1022-. Which are compounds of formula (IIa) wherein two radicals Z represent morpholinyl. The INN Emodepsid represents a compound having the following system name: cyclo [ (R) -lactyl-N-methyl-L-leucyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucyl- (R) -lactyl-N-methyl-L-leucyl-3- (p-morpholinophenyl) lactyl-N-methyl-L-leucyl ]. Emodepsid is described in WO 93/19053, having the formula:

。

depending on their structure, the active substances mentioned above, which are suitable for combination, can be present in stereoisomeric form or stereoisomeric mixtures, for example as enantiomers or racemates. According to the invention, both stereoisomeric mixtures and pure stereoisomers can be used.

Further, the following may optionally be used: salts of the active substance with pharmaceutically acceptable acids or bases, and solvates, in particular hydrates, of the active substance or of its salts.

The combined use means that nifurtimox and the second active substance, in particular the cyclic carboxylic acid peptide, can be used separately or in temporally staged manner. In this case, nifurtimox and the second active substance are formulated separately as separate medicaments.

Simultaneous use is also contemplated. According to an embodiment suitable for this case, the active substances of the combination are formulated together in one reagent.

Ready-to-use (Anwendingsfertig) formulations generally comprise the active substance in a concentration of from 10 ppm to 20% by weight, preferably from 0.1 to 10% by weight.

The formulations diluted before use contain the active substance in a concentration of from 0.5 to 90% by weight, preferably from 5 to 50% by weight. In the concentrated solutions metered into drinking water, the active substances are present in a concentration of, for example, 0.5 to 20% by weight, preferably 1 to 15% by weight, particularly preferably 2 to 10% by weight.

In general, it has proven advantageous, in order to achieve effective results, to administer amounts of from about 0.05 to about 200mg, preferably from 0.1 to 100mg, of active substance per kg of body weight.

In mixtures with other anticoccidial or polyether antibiotics, the active substances according to the invention are generally mixed in a ratio of 1: 0.01-50 to 1: 1-50 by weight.

The active substance can also be administered with animal feed or drinking water.

Feed and food contain 0.005 to 1000ppm, preferably 0.05 to 500ppm of active substance in combination with a suitable edible substance.

Such feeds and foods are useful for therapeutic and prophylactic purposes.

Such feeds or foods are prepared by mixing conventional feeds with concentrates or premixes comprising 0.5 to 30% by weight, preferably 1 to 20% by weight, of active substance in admixture with an edible organic or inorganic carrier. Edible carriers are, for example, corn flour or corn and soybean flour or mineral salts, which preferably include a small amount of an edible anti-dusting oil, such as corn oil or soybean oil. The premix thus obtained can then be added to a complete feed before it is provided to the animals.

The use in histomoniasis can be described by way of example:

for the treatment and prevention of histomoniasis in poultry, in particular in chickens, ducks, geese or turkeys, 0.005 to 1000ppm, preferably 0.05 to 500ppm, of active substance is mixed with a suitable edible substance, for example a nutritional feed. These amounts can be increased, if desired, particularly when the recipient is well tolerated by the active substance. Accordingly, administration via drinking water may be performed.

However, it may sometimes be necessary to deviate from the amounts mentioned, in particular with regard to the body weight of the experimental animal or the type of route of administration, and also depending on the animal species and individual reflection for the active substance, or the type of formulation and the time or interval of administration. Thus, in some cases it may be sufficient to use less than the minimum amount described above, whereas in other cases the upper limit described above must be exceeded. When larger amounts are administered, it may be desirable to divide them into several individual doses during the course of the day.

The activity of the compounds according to the invention can be demonstrated, for example, in a cage test using the test design described below, in which the animals are treated with the corresponding active substances.

The feed containing the active substance is prepared by: the required amount of active substance is mixed well with a nutritionally balanced animal feed, for example with a chicken feed as specified below.

If it is desired to prepare a concentrate or premix which is ultimately diluted to the above-mentioned values in the feed in the experiment, the general method is to mix about 1 to 30%, preferably about 10 to 20% by weight of the active substance with an edible organic or inorganic carrier, such as corn flour and soybean meal or mineral salts, which contains small amounts of edible anti-dusting oil, corn oil or soybean oil. The premix thus obtained can then be added to the complete poultry feed before its administration.

Suitable examples of substances according to the invention for use in poultry feed are the following compositions:

。

such feed comprises 18% crude protein, 5% crude fiber, 1% Ca, 0.7% P and per kg 1200 i.e. vitamin a, 1200 i.e. vitamin D3, 10mg vitamin E, 20mg bacitracin zinc.

Reference documents:

1. Raether W., Hänel H. (2003): Nitroheterocyclic drugs with broad spectrum activity Parasitol Res. 90:19-39。

2. Harder A., Greif G., Haberkorn A. (2001a): Chemotherapeutic approaches to protozoa: Haemosporina – current level of knowledge and outlook。

3. Harder A., Greif G., Haberkorn A. (2001b): Chemotherapeutic approaches to protozoa: Giardia, Trichomonas and Entamoeba – current level of knowledge and outlook。

4. Greif G., Harder A., Haberkorn A. (2001): Chemotherapeutic approaches to protozoa: Coccidia – current level of knowledge and outlook。

5. Harder A., Greif G., Haberkorn A. (2001c): Chemotherapeutic approaches to protozoa: Kinetoplastida – current level of knowledge and outlook. Parasitol Res 87:778-780。

6. Kulda J. (1999): Trichomonas, hydrogenosomes and drug resistance. International Journal for Parasitology 29:199-212。

7. McDougald L.R. (2005): Blackhead Disease (Histomoniasis) in Poultry: A critical Review. Avian Diseases 49(4):462-476。

8. McDougald, L.R., Hu, J. (2001): Blackhead Disease (Histomonas meleagridis) aggravated in broiler chickens by concurrent infection with cecal coccidiosis (Eimeria tenella). Avian Diseases 45:307-312。

9. Hegngi F.N., Doerr J., Cummings T.S., Schwartz R.D., Saunders G., Zajac A., Larsen C.T., Piierson F.W. (1999): The effectiveness of benzimidazole derivatives for the treatment and prevention of histomonosis (blackhead) in turkeys. Veterinary Parasitology 81:29-37。

10. Hegngi, F.N., Doeerr, J., Cummings, T.S., Schwartz, R.D., Saunders, G., Zajac, A., Larsen, C.T., Pierson, F.W. (1999): The effectiveness of benzimidazole derivatives for the treatment and prevention of histomonosis (blackhead) in turkeys. Veterinary Parasitology 81:29-37。

11. von Samson-Himmelstjerna G., Harder A., Schnieder T., Kalbe J., Mencke N. (2000): In vivo activities of the new anthelmintic depsipeptide PF1022A. Parasitol. Res. 86:194-199。

12. Mehlhorn H., Nicolay F., Harder A., von Samson-Himmelstjerna A. (2000): Synergistic action of Bay 44-4400 and piperazine on nematodes of the mouse in vitro and in vivo : a light and transmission electron microscopic study. Parasitol. Res. 86:982-992。

13. Harder A., Schmitt-Wrede H.-P., Krücken J., Marinovski P., Wunderlich F., Willson J., Amliwala K., Holden-Dye L., Walker R. (2003): Cyclooctadepsipeptides – an anthelmintically active class of compounds exhibiting a novel mode of action. Int. J. Antimicrobial Agents 22:318-331。

14. Mehlhorn H., Schmahl G., Frese M., Mevissen I., Harder A., Krieger K. (2005): Effects of a combination Emodepsid and praziquantel on parasites of reptiles and rodents. Parasitol. Res. 97 Suppl 1:65-69。

15. Bernt U., Junkersdorf B., Londershausen M., Harder A., Schierenberg E. (1998): Effects of anthelmintics with different modes of action on the behaviour and development of Caenorhabditis elegans. Fundam. Appl. Nematol. 21:251-263。

16. Sasaki T, Takagi M, Yaguchi T, Miyadoh S, Okada T, Koyama S (1992): A new anthelmintic cyclodepsipeptide, PF1022A. Journal of Antibiotics 45:692-697。

examples

Medicated feed

Medicated feed can be prepared by mixing powdered nifurtimox at concentrations of 50, 100, 200 and 400ppm into the feed mixture detailed below.

Tablet formulation

Nifurtimox tablets are known and are available as pharmaceuticals, for example under the trade name Lampit @.

A. Biological examples cage assay; tissue trichomonas activity in turkeys

From day-4 (= 4 days before infection) to day 14, 10-day-old male turkeys without histomonas campestris received nifurtimox or a control compound in combination with feed at a concentration given in "ppm". Infection was performed on day 0. 10 animals were housed in each group of cages. 1 to 3 such groups were used per dose.

The infection was performed with a wild strain of histomonad (Histomonaden feldstmm) passaged in the laboratory and stored in liquid nitrogen. On day 0, 5 animals (except uninfected controls) in one cage were cloacally infected with 250000 histomonas (= direct infection) in 1ml of debaryon medium in each case. After a few days, these infected animals excrete new tissue trichomonas, thus transfecting the pathogen into the remaining 5 animals in the cage (= indirect infection).

To evaluate activity, consider the criteria of Mc Dougald and Hu 2001 (7):

mortality due to infection

Weight gain from beginning to end of experiment

Feed consumption

-feed conversion

Macroscopic evaluation of infection-related lesions in the cecum (blind ä rm) (Caecum) and liver. In this evaluation, a score of 0 = no lesions and a score of 4= severe lesions.

TABLE 1 study design 210 animals

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TABLE 2 study design 210 animals

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TABLE 3 mortality due to histomoniasis

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TABLE 4 mean weight gain (g) between day 0 and death time

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TABLE 5 average feed consumption between day 0 and day 14

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TABLE 6 average feed conversion between day 0 and day 14

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TABLE 7 mean lesions in the cecum

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TABLE 8 infection-related lesions in the liver

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B. Biological examples: anthelmintic properties of cyclic octreotide

Male mice (strain Bor CFW, 25 to 30g in weight) were housed in Makrolon cages (3 animals/cage) with an unlimited supply of drinking water and snaff rat chow (10 mm pellets). Mice were infected with heterodera spongiensis (Heterakis spomosa) by oral administration of 90 embryonated eggs. The eggs were obtained from female nematodes that had been isolated from the colon of mice 40 days post-infection. The eggs were incubated at 37 ℃ for a further 3 weeks. Mice were treated with each dose of PF1022A or Emodepsid for 4 consecutive days 35 days post infection. PF1022A was suspended in Cremophor EL. On day 7 post-treatment, mice were sacrificed and small intestine/cecum/colon sites were excised and worms were counted macroscopically. The ratio of the number of helminths repelled as a percentage of the total number of helminths in untreated infected control animals was defined as a measure of anthelmintic activity.

Experiments on chickens are described in (14) and the references.

TABLE 9 anthelmintic Activity of PF1022A and Emodepsid against nematodes from the Heterakoidea superfamily

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Claims (8)

1. Use of nifurtimox for the preparation of a medicament for the treatment of a disease caused by trichomonales.

2. Use according to claim 1 for the treatment of diseases caused by tissue infusorian.

3. Use according to claim 2 for the treatment of diseases caused by turkey histomonas mellonis.

4. Use according to claim 1 for the treatment of a disease caused by trichomonas.

5. Use according to claim 1 for the treatment of diseases caused by trichomonas.

6. Nifurtimox for use in the treatment of a disease caused by trichomonales.

7. An agent comprising nifurtimox and an anthelmintic.

8. An agent comprising nifurtimox and an anthelmintic depsipeptide.