BG1246U1 - Foods with paromomycine for poultry and other birds - Google Patents

Abstract

The model proposed concerns foods with paromomycine for poultry and other birds applied in veterinary medicine as a means for prevention against the histomosoma disease, for a decreased horizontal spreading of the illness among infected and contact birds, as well as for the achievement of better zootechnical characteristics in bird raising. The foods contain from 19 to 750 ppm paromomycine which is added in the form of sulphate or another pharmaceutically acceptable salt. The foods contain forages with paromomycine, which can also be granulated, as well as liquid foods, water or nutrient additives containing paromomycine appropriate for birds.

Description

The utility model relates to foods with paromomycin for poultry and other poultry that are used in veterinary medicine as a means of preventing histomonosis disease, reducing the horizontal spread of the disease between infected and contact birds, and achieving better zootechnical characteristics in breeding of birds.

BACKGROUND OF THE INVENTION

The use of paromomycin as a therapeutic agent in veterinary medicine for gastrointestinal and parasitic infections is known. As a medicine, it is given for a short period of time at a fixed dosage.

Histomonosis is a protozoal disease affecting various bird species. The disease causes the highest mortality in turkeys, often affecting the entire flock. In broiler chickens, high mortality and deterioration of zootechnical parameters can also be observed. Other types of birds are susceptible to the disease, including quail, pheasant, guinea fowl.

The treatment of histomonosis disease using chemotherapeutic agents, in particular nitroheterocyclic compounds, which has been used in the past, including enteptin, nithiazine and nitroimidazole derivatives, is known. For example, US 4,000,300 describes the use in treating the disease of aminobenzimidazole derivatives, US 4,046,908 describes the use of benzimedazole derivatives, and US 4,025,638 for carboalkoxyaminobenzimidazole.

The use of arsenic derivatives, such as Histostat®, or in particular nitarzone or 4-nitrophenyl arsenic acid, is known. Given that these compounds are carcinogenic, or their use leads to the accumulation of carcinogenic products in the tissues of treated animals, their use is significantly restricted and even banned in the United States, Europe and other important regions where turkeys are reared. No compound or product is currently authorized in the European Union for use in the treatment or prophylaxis of histomonosis in turkeys and other birds. As a result, there have been reports of re-migration of histomonosis to larger poultry farming areas.

Attempts have been made to administer coccidiostats (eg, monensin, salinomycin, diclazuril, etc.) throughout the poultry development cycle to prevent coccidiosis and histomonosis, but their use has been shown to be unsuccessful (6) with regard to histomonosis.

Attempts have been made to use paromomycin as a chemotherapeutic agent for the treatment of histomonosis. The disadvantage is the high dose required and the need for continued administration to achieve limited success (3). Continuous inclusion of 1000-2000 ppm of paromomycin in feed mixtures has been shown to reduce to some extent the mortality of already infected birds, but toxic effects associated with the use of paromomycin - the presence of lesions and liver hypertrophy - have been observed at this dose. . The infection of birds was performed by direct oral administration of infected eggs from the intermediate host nematode Heterakis gallinarum, without examining the effect of paromomycin on the horizontal spread of histomonosis infection. Attempts have been made to use paromomycin as a chemotherapeutic agent in broiler chickens. Its administration in vivo has proved ineffective when at concentrations of 200 and 400 ppm in broiler chickens feed (4).

The positive effect of some antibiotics on growth is known, but in practice, aminoglycosides are usually administered as therapeutic agents for a short period of time. Prolonged administration is not desirable due to side-effects, in particular liver toxicity.

The technical nature of the utility model

The essence of the utility model is food for poultry and other poultry to which steam is added. These foods provide prevention of histomonosis disease, limit the horizontal spread of the disease and lead to improved zootechnical parameters in intensive rearing of poultry and other birds.

The definition of paromomycin bird food is more general and includes both feed containing paromomycin, which may be in granular form, as well as liquid food, water or nutritional supplements that contain paromomycin and are intended for poultry.

The amount of paromomycin may vary depending on different conditions of food administration ranging from 10 to 750 ppm.

Paramomycin is an aminoglycoside antibiotic obtained by fermentation of microorganisms of the genus Streptomyces sp. It is structurally related to neomycin, streptomycin and kanamycin and has a broad spectrum of action, including against protozoa, bacteria and cestodes (tenenias).

Paramomycin; like other aminoglycosides, it is most commonly in the form of sulfate. There are opportunities for other types of pharmaceutical forms. The amount of paromomycin as a base is always used as a basis for comparing the concentrations used. Thus, the dosage is independent of the form in which the active substance is paromomycin.

The subject of the utility model is all possible pharmaceutical salts and other derivatives, including crude and technical intermediates containing paromomycin as a composition of food for poultry and other poultry.

Histomonosis, also known as blackhead, causes the highest mortality in turkeys, often affecting the entire flock. Serious outbreaks have been reported in turkey farms, leading to a decrease in the growth and reproduction of infected birds. The disease can spread rapidly and reach a mortality rate of up to 100% within weeks. The occurrence of the disease in chickens, broilers, and laying hens is also a common occurrence and the mortality rate is as high as 10-20%. As with other protozoal infections, some zootechnical parameters are significantly impaired. In general, in chickens the disease runs as severely as coccidiosis, which is now considered a disease state, which determines the economic and zootechnical parameters of industrial poultry production.

Histomonosis is caused by the protozoan Histomonas meleagridis. The life cycle of the parasite is complex and often involves an intermediate host. With regard to the epidemiology of this disease and its spread in different species of birds, two factors must be considered:

1) Transfer of histomonosis between birds, or from flock to flock, via an intermediate targeting host - the parasite Heterakis gallinarum and

2) Horizontal or lateral transmission of histomonosis directly from bird to bird, enabling rapid spread of the disease in the flock to places where turkeys or other affected species are raised, even without the presence of an intermediate host (1).

Until recently, there was a perception that transmission of the disease through an intermediate host, the Heterakis gallinarum nematode, was the predominant and predominant way of spreading the disease in poultry. The epidemic spread of the disease, especially in turkeys, cannot be explained by this mechanism alone. The horizontal spread of histomonosis in this species can be observed in an environment where Heterakis sp is not present. or other nematodes to serve as an intermediate host.

Recently (2), it has been shown that in turkey flocks, the disease can spread horizontally through the phenomenon of "absorption of fluid through the cloaca". In these cases, fluid or suspended solids pass toward the end of the enlargement or cecum. The passage is facilitated by the reverse movement of urine from the cloaca caused by reverse peristalsis.

In controlled trials, it has been demonstrated that through this mechanism:

(i) turkeys can be infected with live culture and (ii) the disease can be effectively transmitted horizontally to healthy birds through the faeces of infected birds.

This combination of different ways of infecting and spreading the disease actually makes it impossible to predict and control the kinetics of the disease in a given population. Histomonosis can be manifested by different clinical course of the disease: changing from very mild, slow passing through a herd, to very acute and severe epidemic outbreaks, to epidemics affecting only one part of the room while the other part; separated in a very primitive way from the afflicted may remain unaffected by the disease.

The phenomenon of fluid ingestion through the cloaca is determined by the physiology of the bird species and is observed not only in turkeys but also in other bird species. Although the horizontal spread of histomonosis by ingestion of fluid through the cloaca has been proven only for turkeys at present, there are all prerequisites for the realization of this mechanism in other types of poultry.

In a series of experiments evaluating compounds as a preventative for the prevention of histomonosis in turkeys, it has been found that the continuous administration of paromomycin in feed at doses in the range of 10 to 750 ppm has a significant effect in terms of:

(i) reducing the mortality of infected birds;

(ii) significantly reduce the horizontal spread of disease from infected healthy birds and (iii) improve the growth and utilization of feed in both infected and healthy birds.

The antibiotic was continuously added to the feed from zero day continuously for several weeks during the risk period.

The criteria for evaluating the effectiveness of different products against histomonosis are the two main indicators - the mortality rate and the number of lesions caused. Mortality should be related to the disease and not caused by other factors. This is evidenced on the basis of the observed clinical signs and pathological anatomical findings characteristic of the disease. Pathologically, lesions of the liver and caecum are a typical picture of histomonosis infection. The number of lesions is used to evaluate the degree of disease / infection.

Significant effects on reducing mortality, reducing the horizontal spread of disease and increasing growth have been shown to be achieved by including amounts of 250 to 750 ppm. These results were achieved under severe conditions of infection with the highly pathogenic strain Histomonas meligridis. When there is no risk of an outbreak, or where there are less pathogenic strains of Histomonas in the environment, the dose required to provide protection against the spread of the disease may be reduced from 10 to 750 ppm.

There are three basic options for controlling the disease: through vaccination, treatment of infected birds with chemotherapeutic agents, and prophylaxis or metafilactics.

The use of vaccines is based on the immune system response of the treated birds to the disease agent. Histomonosis causative histomonas meleagridis has not been detected so far. There are vaccines developed for some similar diseases, such as coccidiosis caused by some species of Eimeria sp. Given the very high susceptibility of certain bird species, in particular turkeys, to infection with Histomonas meleagridis, there is serious doubt that vaccination could be a successful approach.

Treatment of the disease using chemotherapeutic agents requires the administration of diseased / infected birds. Since it is difficult and practically almost impossible to separate diseased birds from farmed birds on farms, a chemotherapeutic agent should be applied to the whole herd. Successfully, the chemotherapeutic agent must effectively destroy or stop the development of the disease-causing microorganism or parasite. Chemotherapeutic agents are administered at a predetermined dose for a short period of time sufficient to destroy the agent - microorganism or parasite.

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Prophylaxis means the application of a prophylactic agent to healthy birds or a whole flock of healthy species before infection is detected, in order to prevent infection or spread the disease. When prophylactic treatment is applied only during a period when the population is more sensitive or more likely and at risk for developing the disease, it is called metaphilactic. The administration of a prophylactic agent usually begins as early as possible, often at the very beginning of the bird's life cycle, to prevent infection.

As explained above, a decrease in the mortality of histomonosis-infected birds resulting from the administration of paromomycin has been observed earlier, but the required dosage is higher than 1000 ppm, which is economically disadvantageous and the use of paromomycin in such a high concentration leads to the toxic effects that are usually observed when high doses of aminoglycosides are administered.

It has been found that a significant effect can be achieved to reduce the mortality of infected birds when paromomycin is continuously administered as a feed additive at concentrations ranging from 10 to 750 ppm. This can be attributed in particular to the use of an inoculation method that more accurately presents the field conditions, as well as the experimental design for the study - testing a wider dose range and a larger number of trial units.

The second effect of the administration of the foods subject to this utility model application is to reduce the horizontal spread of the disease, i. transmission of the infection from infected to healthy birds. Studies on the mechanism of disease spread to date have focused on disease models based on the use of Heterakis gallinarum as an intermediate vector because it was thought to be the predominant mechanism for the spread of infection. It has been shown that in the intensive rearing of turkeys, the horizontal spread of histomonosis directly between infected and healthy birds may also occur without the presence of an intermediate host, which may also explain the explosive spread of the disease. Previous studies have shown that there is no clear correlation between the number of already infected birds and the number of newly infected birds (5). This fact confirms the mechanism of the spread of the disease by "ingesting fluid through the cloaca" - infected feces of one bird can "inoculate" with the parasite a large number of birds from the same flock.

Bird food containing paromomycin at concentrations within the specified limits in the utility model has been found to significantly reduce and even eliminate the horizontal spread of disease from infected to healthy birds. The observed dose-related effect indicates the presence of an antibiotic action mechanism on the mode of transmission of histomonosis from infected to healthy birds, which is of particular importance in intensive breeding of nails.

Improvement of zootechnical characteristics has been observed with the use of bird feed containing paromomycin within the specified limits, which is determined by two main indicators: growth and feed absorption efficiency. The gain is an increase in the weight of the birds raised. It can be improved if the bird quickly reaches a predetermined (regulated) weight, or if at the end of a predetermined period the birds reach a larger theta. Feed absorption efficiency is the ratio between the feed consumed and the growth achieved over a given period. The higher this ratio, the lower the efficiency of the farm, since more feed is needed to achieve the same weight.

Continuous addition of paromomycin to turkey feeds at concentrations within the specified limits has been shown to improve the weight index and feed utilization of both infected and non-infected birds.

Examples of implementation of the utility model

The following examples illustrate the effect of the invention but do not limit it in any way.

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Example 1.

The purpose of the present experiment is to investigate the sensitivity of the strain Histomonas meleagridis strain HNA.C0. A.L1 isolated from histomonosis-infected turkeys in an epidemic in France to different concentrations of paromomycin added to feed. The feed contains concentrations of 500 ppm and 1000 ppm paromomycin (as a base). The study included one hundred and sixty (160) one day old turkeys and were randomly distributed into 4 groups of 40 birds in one room.

Throughout the study (day 1 to day 55), group 1 received standard turkey feed without additive (negative control), group 2 received histostat® feed at 187.5 ppm nitrazone and used as positive control. Test groups 3 and 4 received feed with the addition of paromomycin, respectively 500 g per ton (ie 500 ppm) and 1000 g / ton feed (ie 1000 ppm). On day 40, groups 1,2,3 and 4 were infected through the cloaca with the HNA.CO.A.L1 strain isolated from a histomonosis epidemic in turkeys in France in July 2006. From that day onwards, the birds were observed daily for clinical signs. On day 55, all living / remaining birds were sacrificed and examined for damage to the caecum and liver.

Table 1 shows the mortality rates due to histomonosis disease. It is clearly observed that even a low dose of paromomycin provides significant protection compared to the infected, untreated group.

The same conclusion can be drawn from the results of the lesion assessment presented in Table 2.

The results of this experiment clearly demonstrate that paromomycin can have a protective effect against histomonosis, when used in feed at concentrations below 1000 ppm, for example 500 ppm.

Example 2.

The aim of the study was to investigate the susceptibility of the European strain Histomonas meleagridis to various doses of turkey steam, its use as a prophylactic agent and its effect on the horizontal spread of histomonosis between infected (inoculated) birds and uninfected (contact) birds.

In addition, the effect of paromomycin on growth was examined in all groups.

Initially, 750 day-old turkeys of 750 were randomly assigned to one of the five treatment groups (eg, 25 birds per room); male birds are housed in half of the premises and female birds in the remaining half:

• Treatment 1 = non-infected untreated control group (UUC);

• Treatment 2 = Contaminated untreated control group (SC);

• Treatment 3 = Contaminated, 250 ppm paramomycin in feed (P25G);

• Treatment 4 - Contaminated, 500 ppm steam in my feed (P50G);

• Treatment 4 = Contaminated, 750 ppm paramomycin in feed (P75G).

Note: The dosage of paromomycin is calculated as sulfate. The inputs used as a base correspond to 187,375 and 562 ppm respectively.

Forage treatment at treatments 3, 4 and 5 starts from the 1st and lasts until the 45th (last) day of the study. Birds in groups 2, 3, 4 and 5 were infected with Histomonas meleagridis on the 29th day of the study. Birds from all groups were examined for clinical signs daily from that day (29th) to the end of the study (day 45). On day 29, birds from treatments 2, 3, 4 and 5 were infected through the cloaca, with a culture of Histomonas meleagridis strain HNA.CO.A.L1. This strain was isolated from histomonosis-infected turkeys in an epidemic in France in the summer of 2006.

7 turkeys per room were infected to mimic the field conditions and to study the effect of steam on my horizontal disease spread. Previous studies (McDougald, 2005) have shown that the disease is effectively spread in the room by being transmitted from infected to healthy animals. The inoculation was performed with a syringe with a plastic tubing inserted into the cloaca. The single dose for inoculation is 400,000 Histomonas. This procedure was repeated at 15 min intervals to reduce the risk of failure of infection due to rapid defecation. The infected birds received a total of 800,000 Histomonas.

Table 4 shows experience mortality data. Data on mortality of infected birds are also presented graphically in Figure 1. Obviously, even the lowest dose of paromomycin provides a reduction in the effect of infection. There is a clear correlation between the impact of the disease on birds and the amount of paromomycin involved. This tendency is confirmed by the established lesions in infected birds, as shown in Table 5. The lower rate of damage is the reduction of lesions in the gastrointestinal tract and liver in the presence of infection.

It is important to consider contact bird mortality due to histomonosis. Data on overall mortality are shown in Table 4. In the infected untreated group (GC), there is a 30% mortality rate as a result of the horizontal spread of the disease from contact birds.

In all treated groups, contact birds did not have histomonosis mortality, which was detected at necropsy by identifying the absence of typical lesions. This shows clearly that the horizontal spreadsheet is eliminated:

the spread of disease from infected to healthy birds, which is the predominant mechanism for outbreaks in farms.

Table 6 shows the total zootechnical data for the groups of experience. The increase at the end of the experimental period was significant for all paromomycin-treated groups compared to untreated and uninfected control groups (UUC). The increase was between 15.3% 3arpynaP25Gn31.2% for the P75G group.

At the same time, the rate of feed uptake, which is the ratio of feed consumed per unit of growth, is significantly reduced in the paromomycin-treated groups. This decrease is between 7.2% for the P25G group and 10.4% for the P75G group.

The improvement in zootechnical performance achieved is statistically significant and surprisingly high in size, given that it is typical for antibiotics to be used as growth promoters to achieve a 5% increase in growth and a 5% decrease in feed conversion.

Table!. Example !: Mortality caused by hspiioviasis

Days after infection Infected Untreated Group 1 (¢ = 28) Infected Treated with Histostat * Group2 (n = 38) Affected, treated with paromomycin 500 ppm, Group 3 (¢ = 35) Affected, treated with paramomycin 1000 ppm, Group 4 (n = 35) 1 0 0 0 0 2 0 0 0 0 3 0 0 0 0 4 0 0 0 0 5 0 0 0 0 6 0 0 0 0 7 7 0 0 0 8 9 0 0 0 9 3 0 0 0 10 3 0 0 0 11 2 0 1 0 12 1 1 2 0 13 - 0 0 0 14 - 0 4 2 15 - 1 1 0 Total 25 2 8 2 Mortality (%) 96.15% 5D6% 22,86% 5.71%

Table 2. Example 1: Assessment of lesions after necropsy

EXPERIENCE GROUP Average lesion score Tecum Liver Infected, untreated Group 1 3.89 3.86 Infected, treated with Histostat * Group2 1,26 1.13 Affected, treated with paromomycin 500 ppm, Group 3 2.11 1.77 Affected, treated with paromomycin 1000 ppm, Group 4 1.51 1.43

Table 3. Example 1: Zootechnical parameters

Infected Untreated Group 1 Infected Treated with Histostat * Group 2 Affected, treated with paromomycin 500 ppm, Group 3 Affected, treated with paromomycin 1000 ppm, Group 4 Average weight before infection (kg) (40 days of age) 1.78 1.92 2.07 2.28 Average weight at Hexponcm (kg) (55 days old) 1.44 3.20 3.09 3.60

Table 4. Example 2; Total mortality

A glowing burrow UUC Group IUC Group P25GGroup P50G Group P75Group Infected pvdv Contact Ethics Contacts of birds Contaminated for the first time Xshakpya vptsi They sewed on Kshpmchi sewed Frozen birds Kopakshi birds ethyl 1 there is 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 5 0 0 0 0 0 0 0 0 0 b b 0 0 0 1 0 0 0 0 7 0 1 0 1 0 0 0 0 0 S 0 4 1 2 0 0 0 0 0 9 0 6 0 4 0 0 0 0 0 10 - - - - - - - - - 11 1 8 5 2 0 0 0 0 0 12 1 3 1 2 1 1 0 1 0 13 1 2 Ί 4 0 3 0 4  0 14 2 4 7 3 0 « 2 1 0 15 2 2 1 0 0 0 0 1 0 16 3 0 « 2 0 0 0 1 0 Total 10 30 34 20 2 10 2 8 0 Percentage (%) 6.99 81.08 32.69 47.62 2.15 23,81 2.00 19,51 0.00

Table 5: Example 2: Assessment of lesions in necropsy of infected birds.

The group Tecum Black drop UUC GOS 3.27 3.22 P25G 2.05 2.00 P50G 0.95 0.95 P75G 0.80 0.78

Figure !. Example 2: Mortality of infected birds in the days after infection (D-PI)

Mortality among infected birds

Days after infection (D-PI)

UUC IUC OP25G QP50G P75G

Table 6: Example 2, Zootechnical parameters

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Claims (5)

1. Foods for paromomycin for poultry and other poultry, characterized in that they contain from 10 to 750 ppm paromomycin. Foods of paramomycin for poultry and other poultry according to claim 1, characterized in that they are in granular form. Foods for paromomycin for poultry and other poultry according to claim 1, characterized in that the paromomycin is in the form of paromomycin sulfate or other pharmaceutically acceptable salt of paromomycin. Foods for paromomycin for poultry and other poultry according to claim 1, characterized in that the paromomycin is in the form of technical paromomycin obtained by direct drying of a fermentation broth from a microorganism synthesizing steam. Foods for paromomycin for poultry and other poultry according to claim 4, characterized in that the technical paromomycin is in powder or granular form and contains one or more compatible excipients.