DD202504A5 - PREPARATION OF A COMPOSITION FOR THE TREATMENT OF PIG EDYSENTERY - Google Patents

Abstract

The invention relates to compounds of the formula in which R & exp1! for = 0 or <& indOH! stands and R & exp2! and R & exp3! each represents hydrogen or an acyl derived from a carboxylic acid. The compounds are effective for the prophylaxis or treatment of swine dysentery or for the enhancement of porcine productivity. formula

Description

^ - / - Berlin, 18. 6. 1982

2 3 5 1 5 ^ ^ AP A 01 K / 235 154/6

60 133 11

Preparation of a composition for the treatment of swine dysentery

Field of application of the invention

The invention relates to a process for the preparation of a composition for the prophylaxis or treatment of swine dysentery.

The composition of the invention is used in livestock, especially in pig farming, and causes an increase in efficiency in pig breeding.

Characteristic of the known technical solutions

Swine dysentery is an epidemic intestinal disease in pigs caused by Treponema hyodysenteriae, the main symptom of which is a bloody-slimy diarrhea. The high incidence of this disease has been observed in almost all countries where pig farming is practiced. When this disease breaks out in one place, it gets around and is extremely difficult to control; In large flocks feed conversion is reduced so much that serious economic losses occur.

To date, various drugs have been used for the prophylaxis and treatment of swine dysentery, none of which has been found to be satisfactory, as some are not sufficiently effective, while others show serious weaving effects or are hazardous to health, particularly carcinogenic.

hu m η r, * £ \ 4 ^ ft

60 133 11

23515 4 6 -2-

From U.S. Patent 3,626,055 and by the publication of S. Havada et al., J. Antibiotics, 2Λ, 13 (1971) antibiotics such as T-2636 A, T-2636 D and T-2636 P are known also known as Lankacidin A, Lankacidin C, Lankacidanol A and Lankacidanol, respectively, which are included in the compound (I) of this invention. Furthermore, manufacturing methods for these compounds and their antimicrobial effect are disclosed.

(K. Ootsu et al., Cancer Chemother., Report Part 1, 59, 919 (1975) describes the anti-tumor and immunity-suppressing effects of the lankaeidino group and their use as antibiotics.

RH Rainier et al., American J. of Veterinary Research. 41 , 1349 (1980), describes the clinical and microbiological effects of carboxox and linkomycin on Treponema hyodysenteriae and porcine clock. Further details can be found in Merck Index.

Object of the invention

The aim of the invention is to provide a novel composition which is suitable for the treatment or prophylaxis of swine dysentery and does not produce any undesirable side effects.

Explanation of the essence of the invention

The invention has for its object to find a compound which is effective against swine dysentery, shows no undesirable lifting effects and is suitable as an active ingredient for compositions for the treatment of swine dysentery.

60 133 11

According to the invention, as the active ingredient in compositions for the prophylaxis and treatment of swine dysentery, one or more compound (s) of the general formula

(D

üthcoc

GH,

I JU! *

is administered, wherein R for = 0 or

• Η OH

and R and R 1 are either hydrogen or acyl derived carboxylic acid.

In the course of extensive investigations, it has surprisingly been found that the compound of the formula (I) has a pronounced prophylactic and therapeutic action against swine dysentery which could not be achieved with the medicaments known hitherto and that the compounds

235 154 6

(i) further promoting the growth of pigs and improving their feed conversion so as to increase pig breeding productivity. The compound of formula (i) can be used safely in pig farming and is therefore very useful for livestock farming.

The compound of formula (i) comprises antibiotic substances which form the T-2636 group of antibiotics from cultures of Streptomyces rocheivar. Volubilis obtained and referred to by the collective term "Lankacidine", and their derivatives. The lankacidines A (R: = O, R ² : H, R ³ : COCH), lankacidin C (r ¹ : = 0, R ² : H, R ³ : H),

Lankacidinol-A (R ¹ : <d? _W , R ² : H, R ³ : GOCH ,,) and lankacidinol

1 H 2 * 5 "(R:" N ₀ TT * R! H, R: H), as well as others and the organisms from which they can be obtained, the processes for their preparation and their physicochemical and biological properties are, for example, in Journal of Antibiotics, 2h, 1-41 (1971). Lankacidin A 8-propionate (R: = O, R ² : COCH ₂ CH, R ³ : COCH), lankacidin C 8-acetate (R ¹ .: = 0,

R ² : COCH ", R ³ : H), lankacidin C 8-propionate (R ¹ : = 0,

2T 1

R: COCH_CH ", R ^J : H), lankacidin C i4-propionate (R: = 0,

ρ - ^ '1

R: H, r3; COCH ₂ CH ₃ ), lankacidin C 8, i4-diacetate (R: = O, R ² , R ³ : COCH), lankacidin C 8,14-dipropionate (R ¹ I = O, R ² , R ³ : COCH ₂ CH ₃ ), lankacidin C 8-benzoate (R ¹ : = O, R ² : GOPh,

R ³ : H), lankacidin C i4-benzoate (R ¹ : = O, R ² JH, R ³ : COPh),

1 2 * ^ Lankacidin C i4-phenylpropionate (R: = O, R: H, R:

GOCH_CH "Ph) and lankacidin C i4-nicotinate (R ¹ : = O, R ² : H,

3 R: nicotinoyl), among others, processes for their preparation and their pysikochemical and biological properties are described, for example, in Journal of Antibiotics, 2! 6_, 647-657 (1973). Lankacidin C i4-formate (R: = O, R: H, R ³ : COH), a process for its preparation and its physicochemical properties are described, for example, in US Pat. No. 3,626,055.

235154 6

The organism Streptorayces rochei var. Volubilis, which produces lankacidin A, lankacidin C, lankacidinol A and lankacidinol, is deposited at the Institute for Fermentation in Osaka, Japan under the accession number IFO 12507 and in the American Type Culture Collection under the accession number ATCC 21250.

The derived from the carboxylic acid acyl group (R and R in the above general formula (I)) is preferably a lower fatty acid residue (in particular r is one having 1-7 carbon atoms, such as formyl, acetyl, propionyl, butyryl, Isobutyryl, valeryl, hexanoyl) or an aromatic carboxylic acid radical, such as an arylcarboxylic acid radical, such as benzoyl, or a heteroaromatic carboxylic acid radical, such as nicotinoyl. The fatty acid residue may be substituted on the terminal carbon atom by a phenyl group, eg, phenylacetyl, phenylpropionyl, or the like.

Particularly preferred examples of compounds of the formula (i) which can be used according to the invention are compounds in which R and R 1 denote either hydrogen or a fatty acid radical having 2-4 C atoms. Among others, lankacidin A, lankacidin C, lankacidin C i4-propionate, lankacidin C 8 -acetate, lankacidin C 8-propionate, lankacidinol A, lankacidinol and mixtures of these compounds are preferably used. Particularly advantageous is the use of lankacidin A and / or lankacidin C.

The composition according to the invention for the treatment of pigs may contain a compound of formula (i) or simultaneously two or more compounds of formula (i), e.g. a mixture with a predominant content of lankacidin A with lankacidin C. In addition, fermentation

235154 6

tion media, which are obtained in the cultivation of the above-mentioned organism Streptomyces rochei var. volubilis, be used in the form of dried products or extracts.

The composition for the prevention or treatment of swine dysentery or for increasing porcine prodromity according to the invention may be prepared by formulating the compound of formula (i) in dosage forms such as powders, granules, tablets, liquids, pastes, capsules. Injections, solutions, and the like, either dispersed together with a solid or liquid diluent, without diluent, or after stabilization by coating, or by placing the feed or drinking water directly or as a premix in a diluent. Suitable diluents are the usual carriers, vehicles and diluents.

The diluent may be a physiologically acceptable agent, conveniently one which is itself a feed or feed ingredient. In general, the compound of formula (i) is formulated into a feed or converted into a premix, which is then incorporated into the feed to be administered. Solid diluents are e.g. Basic feed for pigs, e.g. Barley, wheat * rye, corn or soybean meal, soybean meal, rapeseed meal, chaff, rice bran, defatted rice bran, sweet potato powder, white potato powder, soybean cake, starch, lactose, sucrose, glucose, fructose, yeast, waste yeast, fish meal and the like, and inorganic materials such as Talc, white tone and sound. As liquid diluents, e.g. Water, physiological salt solutions or physiologically acceptable organic solvents.

235 154 6

Suitable adjuvants such as emulsifiers, dispersants, suspending agents, wetting agents, thickening agents, gelling agents, solubilizing agents and stabilizers may be added in suitable amounts. Furthermore, an antiseptic, fungicidal, antibiotic agent, a yeast preparation and / or a Lactobacilluspräparat be incorporated into the formulation. The composition may also contain vitamins, minerals and amino acids. Examples of minerals are manganese, for example manganese carbonate, manganese sulfate, iron, eg ferrofumarate, ferrosulfate, cobalt, eg cobalt (o) sulfate, cobalt (o) chloride, copper, eg cuprisulfate, cupriphosphate, cupric chloride, zinc, eg zinc carbonate, zinc chloride, iodine to name, for example, calcium iodate, calcium iodide, sodium iodide. Vitamins include water-insoluble vitamins such as vitamin A and vitamin D and water-soluble vitamins such as vitamin B ₁ and vitamin Cj. Examples of suitable amino acids are essential amino acids such as D, L-methionine and lysine.

The composition according to the invention in the form of a feedstuff advantageously contains maize meal and / or soybean meal as diluent; in the form of a precursor mixture it advantageously also contains a mineral or several of the minerals normally contained in feedstuffs.

The compound of formula (I) according to the invention may advantageously be formulated into a premix and then administered to the pigs in the form of a mixture of premix and diluents. Such a premix advantageously contains the compound of the formula (i) in a concentration of about 0.5 to 80% by weight, preferably about 1 to 50% by weight.

The composition containing the compound of formula (i) according to the invention may e.g. by mixing the compound

235 154 6

of formula (i) with the diluents listed above. When starting from the premix according to the invention, the composition can be prepared by further mixing with one or more minerals.

The composition may, in view of its practical application, i. Stabilization of compound I, distribution and administration, preferably in the solid state.

The proper dosage level of the compound of formula (I) for the prevention or treatment of swine dysentery or for the enhancement of porcine productivity depends on the age and condition of the pigs, the mode of administration and the like.

In general, the compound of formula (i) is administered orally to the pigs in dosage levels of about 0.025 to about 25 mg / kg of body weight, in practice a feed containing a compound of formula (i) in a concentration of about 0.5 to about 500 ppm (by weight), to be administered to the pigs at will.

More specifically, in the prevention of swine dysentery, it is preferred to administer the compound of formula (i) in dosage levels of from about 0.05 to about 25 mg / kg / day, conveniently by incorporating a compound of formula (I) into a feed in a concentration of about 1 to about 500 ppm, preferably from 2 to 200 ppm. In the treatment of swine dysentery, the compound of formula (i) is preferably administered at dosage levels of from about 1 to about 25 mg / kg / day, conveniently by incorporating the compound of formula (i) into a feed

235 1 54 .6

60 133 11

at a concentration of about 2 to about 500 ppm, preferably from about 2.5 to about 200 ppm. Purely the increase in porcine productivity will be the "compound of formula (I) at dosage levels of from about 0.025 to about 10 mg / kg / day, suitably by incorporation into a feed at a concentration of from about 0.5 to about 200 ppm, preferably from about 1 to about 100 ppm.

The toxicity of the compound of formula (I) to animals is very low. For example, in acute toxicity tests with mice, the peroral LD, Q-ratio was greater than 10,000 mg / kg for each of lankacidin C, lankacidin C 14-propionate, and lankacidin A and. the intraperitoneal LDcq was 8,000 to 10,000 mg / kg for lankacidin A, more than 10,000 mg / kg for lankacidin C 14-propionate, and 4,500 mg / kg for lankacidin C.

From this fact comes out not only the high safety for man in the production and distribution, but also a greater tolerance for the animals. Therefore, when administering the compound of formula (I), when incorporated in a feed, some degree of inhomogeneity in mixing is not dangerous to the animals concerned.

embodiment

The invention will be further illustrated by the following nonlimiting experimental examples and dosage form examples.

Test Example 1

Several agents have been tested for their antibacterial effect in vitro against Treponema hyodysenteriae, the pathogenic bacteria causing swine dysentery, by the method of testing the sensitivity of Treponema

hyodysenteriae tested against drugs, see Kashiwazaki et al. contained in the abstract of the work presented at the 82nd session of the Japanese Society of Veterinary Science (p.1O1, 1976). The results obtained are shown in Table 1. Lankacidin C had strong antibacterial activity, other antibiotics used for comparison were ineffective.

Table 1:

Minimum hem concentration (/ ag / ml) DJ70P1  .MK-2 78 / A Medium / strain CDI 3.13 3.13 3.13 Lankacidin C 3.13 > 100 > 100 > 100 erythromycin > 100 > 100 > 100 > 100 spiramycin > 100 > 100 > 100 > 100 oleandomycin > 100 > 100 > 100. > 100 leucomycin > 100 > 100 > 100 > 100 maridomycin > 100 50 50 50 Lincomycin.

(1) strains: the strains belong to Treponema hyodysenteriae,

that stem from the bloody-slimy feces of dysentery-infested swine-in Japan «

(2) Antimicrobial Action: Agar Dilution

Method.

(3) Size of inoculum: 1 loop with bacterial suspension

(10 ⁶ CFU / ml).

(k) culture conditions: anaerobic system (GasPak, BBL), 37 ° C,

2 days.

- 10 -

Test Example 2:

Following the procedure described in Example 1, typical compounds of formula (i) were tested for their antibacterial effect in vitro. The results are shown in Table 2. All tested agents showed strong antibacterial activity against Treponeraa hyodysenteriae, although different MIC values were shown.

Table 2:

^ v trunk connection ^, Minimum inhibitory concentration (yug / ml) ME-2 78 / A CD-I Lankacidin A DJ70P1 3.13 3.13 6.25 Lankacidin C 6.25 1:56 1:56 1:56 Lankacidinol A 3.13 25 12.5 25 Lankacidino1 25 25 12.5 12.5 Lankacidin C 8-acetate 25 12:39 12:39 12:39 Lankacidin C 8-propionate 0.78 1:56 1:56 1:56 Lankacidin C14 propionate 1:56 1:56 1:56 3.13 3.13

Note: The experimental conditions are the same as those listed in SES.T Example 1 (Table 1).

Test Example 3;

Following the procedure described in Example 1, agents containing the compound of formula (i) were tested for their anti-bacterial activity in vitro. The results are shown in Table 3. All investigated

154 6

The agents had strong antibacterial activity against Treponema hyodysenteriae.

table 3: ME-2 78 / A CD-I ^ "^" --- ^^^ stem 6.25 5.15 6.25 Compound (I) ^ "" "- ~ - ^ _ ^^ 0.78 0.78 0.78 Lankacidin A Low inhibitory concentration (pg / ml) 6.25 6.25 6.25 Lankacidin C 8-butyrate DJ7OP1 3.15 1:56 5.I5 Lankacidin C 8-isobutyrate 3.13 0.1 0.1 0.1 Lankacidin C 8-valerate 0.78 5.15 0.78 1:56 Lankacidin G 8-benzoate 3.13 25 12.5 25 Lankacidin C 14-butyrate 1:56 6.25 5.15 · 6.25 Lankacidin C 14-isobutyrate o.i 6.25 6.25 6.25 Lankacidin C 14- vale rat · 1:56 6.25 6.25 12.5 Lankacidin C14 benzoate 12.5 1:56 5.I5 5.15 Lankacidin C 14 format 3.13 O.78 0.78 1:56 Lankacidin C 8,14-diacetate 6.25 3.13 1.56 3-13 Lankacidin C 8,14-dipropionate 6.25 6.25 6.25 6.25 Lankacidin C 8,14-dibutyrate 3.13 Lankacidin A 8-propionate 0.78 3.13 6.25 1

Test Example K:

Lankacidin A, lankacidin C, lankacidin C 8 -acetate, lankacidin C i4-propionate, lankacidinol A and lankacidinol were tested for their efficacy against swine dysentery by experimental infection of pig dysentery mice.

235154

5154 p

An experimental infection model of pig dysentery in mice similar to that of Joens et al. in Infection and Immunity, 2j5, 757-760 (1979), American Journal of Veterinary Research, 4j, 1225-1226 (198O) and Veterinary Record, 107 , 527-529 (1980). Accordingly, a field isolate of Treponema hyodysenteriae, which had been obtained by anaerobic culture on 5 $ defibrated horse blood soy agar plates (Trypticase, BBL), was crushed together with the culture medium and doubly diluted with Trypticase (BBL) -sojaculture broth , With this infection dilution mice were intragastrically inoculated. Each agent to be tested was suspended in a 5% gum arabic solution and administered perorally from day 1 to day k post-infection. Seven days after infection, the cecum (the cecum) was examined for lesions, crushed with its contents and subjected to analysis for involvement with Treponema hyodysenteriae. The results are summarized in Table h The compositions of the invention showed excellent activity in each of the groups to which they were administered.

table 4: Number of mice with cecal lesions / number of mice examined medium Dose (mg / kg / day) Number of mice in which pathogenic infestations were found / total number of mice examined 3.5 infected control -   5.5 0/5 Lankacidin A VJI 1.5 0/5 Lankacidin G 5 1.5 0/5 Lankacidin C 8-acetate 5 0/5 0/5 Lankacidin C IA propionate. VJL 1.5 0/5 Lankacidinol A VJL 1.5 0/5 Lankacidinol VJI 0/5

Test Example 5:

Lankacidin C was tested under experimental infection conditions for its action against swine dysentery. 12 six-week-old Landrace pigs (k per group) were examined. The test agent was mixed in a concentration of 100 ppm with the commonly formulated starter feed for pigs without antibiotics. The animals were given full access to

Granted SPF feed. Infection of the pigs was achieved by direct intragastric administration of an inoculum grown in anaerobic culture of the Treponema hyodysenteriae 78 / a strain on a 5 $ horse blood agar plate, crushing the culture together with the culture medium and mixing with 5 $ mucin Phosphate buffer had been obtained. The contents of the large intestine and the mucous membranes of the pigs, which showed typical symptoms of swine dysentery, were collected and incubated with 5 $ mucin-added phosphate buffer.

diluted. The dilution was used as the final inoculum, 100 ml of which was injected directly into the stomachs of seven week old test pigs had been kept .nüchtern 2h hours before infection. The pigs were fed after infection for 21 days. The results obtained are summarized in Table 5. While maridomycin was ineffective, lankacidin C showed excellent activity against swine dysentery.

Table 5 :

~~ - --___ ^^^ Group of investigated counterparts ~ - ^ _ ^ Infected control group Lankacidin. C 100 ppm Maridomycii 100 ppm swine 4A 8.5 14.8 4 4 0/4 0 0 0 0 3/4 53 11.0 4 4 Number of pigs showing signs of infection / number of pigs used Number of days on which bloody-slimy stool was observed during the 2 1-day trial period Number of days on which during the 2 1 Diarrhea was observed during the course of the day. Number of pigs in which pathogenic infestation was found in the faeces in the large intestinal mucous membrane

Continued Table 5

^ ~ ^ ~~ * ~~ - ^ _ ^ _ ^ group; investigated counterpart "- ^ __ Infi ned control group Lankacidin C 100 ppm - 13.6 Maridomycin 100 ppm Number of pigs with colon lesions  Λ 0 28. ₅ ' ^b Fütterunsser ^ ebnisse 708 ^b 27.5 Body weight (kg) 1.85 at the time of infection 12.5 12.8 at the time of termination of the investigation 17.8 ^a 21.9 ^from Body weight gain (grams / day) Feed consumption (kg) 251 ^a 16.3 430 ^a . 18.8 feed conversion , 3:07 2:09

Note: The data is the mean per capita for the 21-day period from infection to autopsy. Different alphabetic letters on a line mean that. significant difference between the data to which they are assigned (Ρ <0.05). e.g. significant difference between a and b;

no significant difference between b

and from.

Test Example 6;

Lankacidin C was tested at concentrations in feeds of 100 ppm and less according to the method described in Example 5. For comparison, a known anti-swine dysentery agent marketed under the trade name Carbadox was used. It is also apparent from the feeding results that lankacidin C is far superior to the commercial agent Carbadox as an agent against swine dysentery, see Table 6.

Table 6:

^ "\ ^^ group nichtinfi- infected Lankacidin C 50 ppm 0 100 ppa 0 carba gracious control control 10 ppaj 0 0 50 ρ not s. object ^ "" \. (without medecine) pork dysentery 0/4 0 0/4 0 Number of pigs that 0/4 4.4 0/4 0/4 signs of Infection shows number of investigated pigs 0 0 Number of ta 0 9.5 0 0 ge, at which 11.1 11.1 bloody-shifting Mige excrement 25.3 ^a • 25.5 during the 2T 673 ^off 689 ^b daily Ver 25.3 1.7 ^C 25.6 1.77 search period Were observed 0 0 Number of days at which 0.5 14.5 0 3.0 during the 21-day Versuchsperi or diarrhea observed has been number of Pigs in which patho- generous infestation was determined in the faeces 0 4 - 0 0 in the dick 0 4 0 0 bowel movement skin number of 0 4 0 C Pigs in what a dick intestinal lesions detected were Fruit tasting results Body weight (kg ") at the time of infection 11.1 10.2 10.5 11 at the time the termination of the investigation 22.7 ^a 13.0 ^b 20.7 ^a 21 Body weight;> increase (Gramyl = g> 551 ^abc 133 ^d 484 ^aC Feed consumption Feed conversion (Sg) 21.7 ig 1.87 9.7 3.45 18.4 1.81 C 2

» O O! D 4 O

Note: The data represent the mean per capita for the 21-day period from infection to autopsy. Different alphabetic letters on a line indicate that there is a significant difference between the data to which they are assigned (P <CO, O5) · eg significant difference between abc and d; no significant difference between abc and ac.

Test Example 7 '·

Following the procedure described in Example 6, the effect of 10 ppm each of lankacidin A and lankacidin C 14-propionate was investigated as an agent against swine dysentery. The results obtained are summarized in Table 7. Lankacidin A and lankacidin C i4-propionate are very effective against swine dysentery.

235

O - 18 -

Table 7

60 133 11

"^ v ^ group ί examined ^ ^^: subject ^ v i Uninhibited control (without medication ^: infected control Lancacidin A 10 ppm Lancacidine C 14 propionate j 10 ppm Carba dox 50 ppmi Swine dysentery j 1 i Number of pigs showing signs of! Infection showed / number of pigs examined 0/4 4.4 0/4 0/4 t 0/4 ' Number of days on which bloody mucous excreta were observed during the 21-day experimental period 0 11.3 0 0 0 Number of days on which diarrhea was observed during the 21-day trial period 0 15.3 0 0 0 Number of pigs in which pathogenic infestations were found in the faeces I o 4 0 0 0 in the large intestine mucous membrane 0 4 0 0 0 Number of pigs in which diarrheal lesions were confirmed 0 4 0 0 0

- 19 - Continued Table 7 :

\ Group unteinsuchra *. Object \ uninfected control without medication) infected control Lancacidin A 10 ppm Lancacidine C i4 propionate 10 ppm Carboxox 50 ppm Feeding results Body weight (kg) at the time of infection 10.7 10.8 11.0 11.4 11f1 at the time of the completion of the investigation 22.8 16.0 22.9 23.1 22.7 Body weight increases (grams / day) 576 ^a 248 ^b 567 ^a 562 ^a 552 ^a Feed Verbide (kg) 21 .2 12.7. 21.0 21. 1 21.2 Feed conversion 1.75 2:44 1.76 1.81 1.83

Note: The data is the mean per capita for the 21-day period from infection to autopsy. Different alphabetic letters on a line indicate that there is a significant difference between the data to which they are assigned (P <0.05).

Test Example 8:.

This study was conducted under the conditions of so-called therapeutic administration. Administration was started immediately when the pigs showed clinical signs of swine dysentery. The infection method was as described in Example 5. Five pigs were examined, in which at the same

235

4 ö - 20 -

Day, i. the 6th day, after the infection. Disease symptom <occurred. Simultaneously with the onset of symptoms, the pigs were fed a feed containing 50 pj lankacidin C. The results obtained are summarized in Table 8. In all cases no bloody-diarrhea was observed from the day following the administration; the excreted faeces were loose or normal. After 2 days, the number of viable pathogenic bacteria in the faeces had dropped below the detection limit (10 CFU / g). The autopsy performed 15 days after the onset of symptoms (9 days after discontinuation of administration) showed no colon lesions, no pathogenic bacteria were detected

- 21. Table 8:

Pig no. Days after onset of symptoms 1 2 3 k 5 Ο Condition of faeces (number of path. Bacteria) Condition of the faeces (number, path Condition of the faeces (number of path. Bacteria Condition of the faeces (number of path. Bacteria Condition of laeces (number path. Ι * © (8.0) © (6.0) © (7.1) © (6.8) © (7.1) 2 * φ (4.3) O (2-3) Φ (4.4) φ (2.0) O "(2.0) 3 * O (-) -OC-) O (-) O. (-) O (-) 4 * O (-) O (-) O (-) O (-) O (-) 5 * O (-) O (-) O (-) O (-) OC) 6 *. O (-) O (-) OC) O (-) OC ') 7 O (.-) O (-) O (-) O (-) O (-) 8th O (-) O C -> O (-) O. (-) O (-) 9 OC) O (-) O "(-) O (-) O C-) 10 O (-) O C-) O (-) O (-) O (-) 11 O (-) O C -) O (- ') O (-) O (-) 12 O (-) OC) O (-) O (-) O (-) 13 O (-) O (-) O (-) O (-) O C -) 14 O (-) O (-) O (-) O (-) O (-) (Autopsy) OC) O (-) O (-) O (-) O C-) Large intestine lesions O (-) O (-) O ('-) O (-) O C-) Number of path. Bactaden in the Dxckdarm negative negative negative negative negative C -) (-) (-) (-) C-)

Note: The condition of the faeces was evaluated in the following four classes: (J normal, (T) - loose, - diarrheal, (Tj) "slimy and bloody.) The values concerning the number of viable bacteria are in log (g) means that the value is below the detection limit

235154 6

(ΙΟ ² CFU / g).

The symbol * indicates that feed containing 50 ppm lankacidin C was administered on these days.

Test Example 9 ι

In the manner described in Example 8, the therapeutic effect of lankacidines in swine dysentery was investigated under therapeutic conditions. The effect was evaluated on the basis of the condition of the faeces. The results obtained are shown in Table 9, which show that lankacidin A, lankacidin G and lankacidin C-i4-propionate are therapeutically effective at a dose level of 50 ppm.

Table 9;

group

infected control (without medication)

Group administered 50 ppm lankacidin A

Group administered lankacidin C ppm

Group administered 50 ppm lankacidin C 14 propionate

after the occurrence of the

pig

No.

Geectüecht

10

11

12

13

15

Φ Φ

O O O O O O C O O O

-c

O O O O O O

O O O O O O O O O O O O O O O O

O-O-O-O-O-O-O-O-O-O-O-O

O OOOOOOOOOOOOOOOOOOO OO OOOOOOOOOOOOOOOOOOOO

O O O O O O O O O O O O O O O O

O O O O O O O O O O O O O O O

O O O O O O O O O O O O O O O

O-O-O-O-O-O-O-O-O-O-O-O

O C O O O O O O O O O O O O O O

O O O

φ φ

φ φ φ φ φ φ φ φ φ φ φ

φ φ φ φ φ

φ φ φ φ

φ φ ο φ

Note: The condition of the faeces was rated according to the following four classes: ^ Λ- normal; Π) blocker;

23515Λ

diarrhöeal; (O) "slimy and bloody The symbol * means that on these days the feed containing 50 ppm of the drug was administered.

From the results of the foregoing Experimental Examples 1-9, it can be seen that the compound of the formula (i) gives excellent results as an agent for preventing and treating pork dysentery and superior to similar commercial antibiotic agents against swine dysentery and therefore very useful for livestock.

Experimental Example 10:

This study relates to the effect of compound dei formula (i) on the growth of pigs that are not infected by the swine ho one month old Landrace pigs (5 shots) were in groups of eight (four males and four females) divided. Lankacidin C was used in concentrations of 0 (control), 1, 2.5, 5 and 10 ppm of a starter without the addition of other anti-bacterial agent for the period from the beginning of the study to the age of three months and the feed for testing pigs for meat production (also without the addition of antibacterial agents) from many months to six months (late). In each of the groups dietary lankadicin C was given continuously for five months.

As can be seen from the results summarized in Table 10, the growth of pigs increased almost in proportion to the extent of addition of lankacidin C, so feed utilization was improved. The compound of formula (i) is therefore useful even in usual feeding conditions for increasing meat production in pigs

- 25 Table 10:

- ^ ^ ^ group under ^^^^^ subject "~~ - ~ -__ ixoiitsroiJü 1 ppm Lankacidin C 5 ppm 10 ppm Body weight (kg) 7.4 31.7 ^a a. 10t. 4 2 5 ppm at the beginning with feed change at the end 24.3 ^a 94.0 ^a 7.4 32.7 ^a ..afc 102.4 7.4 36.9 * 109.o ^aD 7.4 37.5 * 110.2 * Body weight gain (kg) 49.9 280.2 25.4 ^al: 95.o ^al 7.4 34.2 ^at 104.6 ^al} 30.1 * L02.8 * during the starter feed period throughout the perxode 2.05 2.98 29.5 * 101.7 ^a * 51.2 284.8 Feed consumption (kg) 49.4 275.6 26.9 * _{97> 2} at during the period of starter feed throughout the period. 1.95 2.90 50.7 284.6 1.70 2.77 Futtermittelunrwandluns 49.1 278.0 1.72 2.80 during the period of starter feed throughout the period 1.83 2.86

Note: The data represent the average per capita. Different "alphabetic letters on the same line mean there is a significant difference between the data to which they are assigned (P <0.05).

 e.g. significant difference between a and b;

no significant difference between ab

and a or ab and b.

Experimental Example 11:

35-day-old Landrace pigs (6 litters) were divided into six groups of eight (four males and four females). Lankacidin A was in concentrations of 0

? 3 5 1 5 4

(Control), 2.5, 5, 10 and 20 ppm of the starter feed without the addition of an antibacterial agent during the period from the beginning of the study to the age of three months and for the analysis of the pigs for meat production (also without the addition of antibacterial agents ) are added to the feed from the age of four months up to the age of six months (the end).

The growth data obtained during the five months continuous administration are summarized in Table II. The growth of the pigs was promoted proportionally to the increase of the addition amount of lankacidin £ and correspondingly improved feed efficiency.

Table 11:

unterucirtessv ^^^: subject ^ ~ "" ^ - ~ J. control Lankacidin A 1 ppm 2.5 ppm • ρ ρτιτπ 10 .ppm 20 pp Body weight fag) 9.19 32.9 ^a 108.2 ^a 9.18 34.0 ^from 111.6 ^onwards 9.16 113.5 ^at 9.16 9.15 120. 5 ° 9.18 123.4 ^b at the beginning * with feed: change of medium | at the end [ 23.7 ^a 99.0 ^a 24.8 ^from 102.4 ^onwards 25.4 ^at 104.4 ^at L09.1 ^al: 27.6 ^b 111.4 ^ body weight; increase (kg) j 48.2 290 _o l 48.1. 294.9 47.6 295.3 47.6 47.7 305.2 ^ 28.2 ^b L14.2 ^b during the period of starting feed ι during the entire period; 2.03 2.93 1.94 2.88 1.87 2.83 1.77 2.79 1.73 Feed consumption (kg) ι 48.2 510.6 during the period of starter feed: during the course of 1.71 2.72 f feed conversion during, Pe-i ripde des.Start-i iuttermittels | while "the ι

4 O - 27 -

Note: The data represent the mean value per k "spf. Different alphabetic letters on the same line indicate that there is a significant difference between the data to which they are assigned (P" <0.05).

Example 1; ~

By incorporating the compound of formula (i) into the following feedstuffs or into a part of the materials intended for them at any concentration, feeds for the prevention or treatment of swine dysentery, or for the increase of porcine productivity can be produced.

Example 2;

By introducing the compound of formula (i) into the vitamin-mineral mixture designated below with a) or b) and a basic feed (eg defatted rice bran) together with an amino acid (eg D, L-methionine, lysine · hydrochloride) Premixes according to the invention can be prepared in any concentration.

235154

Composition of basic feed in

materials start milk Feed for junior research concerning F.leiscnprodukt Corn meal "20.0 22.0 milo 22.0 barley flour 19.0 22.0 wheat flour 14.0 So j deer flour 4.0 wheat bran 6.8 12.0 defatted rice bran 4.0 4.0 fishmeal 3.0 4.0 Sojabohnenachrotmehl 5.0 4.0 Dried skim milk 9.78 dry whey 5 ° Alfaifaschrotmehl 2.5 glucose 5.0. Futtermittelhefe 2.0 fat powder * 1.5 calcium carbonate 1.5 sodium chloride 0.5 calcium triphosphate 0.7 0.8 saccharine 12:02 Vitamin-mineral mixture 0.2 ^a) 0.4 ¹ ^ - - DL-methionine 0.1 A total of 100.0 100.0

a) content per kg: Vitamin A 2,500.OO0IE, 500,000 JE Vitamin ^D 3 "°" S 75 Vitamin E, 1 g Vitamin B ₁ "nitrate, 1.5 g of vitamin B _2, vitamin B ^ 0.25 _S: 1 mg Vitamin B ₁₂ , 3.5 g Calcxumpantothenat, 7.5 g nicotinamide, 50 g choline chloride, 50 g iron, 5 g copper, 25 g zinc, 15 g manganese, 0.25 g cobalt and 0.1 g iodine.

w _ 29 -

b) The following mixtures A, B and C, mixed together in a weight ratio of 0.15: 0 _f 15 'x 0.1 were used.

Mixture A: 5 % manganese, 5 $ iron, 1 $ copper, - - 6 # zinc and 0.1 56 iodine

10,000 IU of vitamin A and 2,000 IU of vitamin D per gram

Blend B Blend C

1g vitamin B «nitrate, 7 g vitamin B ₂ ,

0.5 g vitamin Β-ς, 6 g nicotinamide,

10.9 g of calciurea pantothenate and 57.6 g of choline

Hydrochloride per kilogram; supplemented with

10 pg vitamin B ".

Claims (15)

invention claim 1 ? in the formula of the active ingredient (I) R is = 0 and R and R are each hydrogen or a low fatty acid radical. 1 / ^H 2 3 where R is = 0 or \ qh ^xm '^ ^{i R W1} ^ each for_. Is hydrogen or an acyl derived from a carboxylic acid, is mixed with a physiologically acceptable diluent. A process for the preparation of a composition for the prophylaxis of or treatment of swine dysentery or for increasing the efficiency of pig production, characterized in that an effective amount of one or more compound (s) of the general formula 2. The method according to item 1, characterized in that the composition is present as a pesticide formulation, 3. The method according to item 1, characterized in that the composition is used in F.orm a premix containing the active ingredient in a concentration of about 0.5 to about 80 wt - . % . 4. The method according to item 3, characterized in that the premix contains substantially as a diluent a basic feed for pigs. 60 133 11 - 31 - 5. Method according to item 4 »characterized in that the premix further contains one or more minerals, Method according to item 1, characterized in that the composition is in the form of a feed containing as diluent a basic feed for pigs. Method according to item 6, characterized in that the basic feed contains essentially Ma.isscta.rotme.hl and / or soybean meal. 8 »Method according to item 6, characterized in that the composition contains the active substance of the formula I in a concentration of about 0.5 to about 500 ppm (by weight), 9. The method according to item 8, characterized in that the composition for the prophylaxis of swine dysentery contains the active ingredient of the formula I in a concentration of about 1 to about 500 ppm (weight). 10. The method according to item 8, characterized in that the composition for the treatment of swine dysentery contains the active ingredient of the formula I in a concentration of about 2 to about 500 ppm (weight). 11. The method according to item 8, characterized in that the composition for increasing the efficiency of pig breeding, the active ingredient of the formula I in a concentration of about 0.5 to about 200 ppm (weight). / C 60 133 ^{54 U} - 32 - 12. The method according to item 1, characterized in that 13- method according to item 1, characterized in that in the formula of the active ingredient (I) R ^{2 is} hydrogen and R is a fatty acid radical having 2 to 4 O-atoms. 14. The method according to item 1, characterized in that the composition contains Lankacidin A as active ingredient. 15 »method according to item 1, characterized in that the composition contains as active ingredient a mixture of a predominant amount Lankacidin A with lankacidin C.