JPS637525B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a composition for preventing and treating swine dysentery or for improving pig productivity. More specifically, the present invention relates to the general formula [In the formula, R ¹ is = 0 or

A composition for preventing and treating swine dysentery or for improving the productivity of pigs, which contains a compound represented by the formula: wherein R ² and R ³ each represent hydrogen or an acyl group derived from a carboxylic acid. Swine dysentery is a contagious intestinal infection characterized by mucous and bloody diarrhea caused by Treponema hyodysenteriae, and its occurrence is recognized in most countries where pigs are raised. [Roncalli, RAand
Leaning，WHD：Abstr.4th Congr.Intern.Pig
Vet.Soc., Iowa, USA (1976)], and once they occur, they become endemic and are extremely difficult to clean. For this reason, the reality is that, especially when raising multiple pigs, large economic losses are caused due to the death of affected pigs and reduced growth. Various drugs have been used to prevent and treat swine dysentery, but none of them have been necessarily satisfactory, such as insufficient efficacy or safety issues. Although research into vaccines and the like is progressing, sufficient results have not been obtained, and nothing that is satisfactory for practical use has yet to be completed. As a result of intensive research based on this technical background, the present inventors have obtained new knowledge that the compound () has remarkable preventive and therapeutic effects against swine dysentery that cannot be achieved with conventional drugs. Furthermore, they found that the compound () promotes growth, improves feed utilization, increases pig productivity, and is extremely beneficial for livestock management. That is, the present invention is highly effective against swine dysentery by containing the compound (2), and is highly safe for preventive treatment of swine dysentery, as well as for improving pig productivity by promoting growth and improving feed efficiency. The present invention provides a composition of the invention. Compound () is a compound of Streptomyces rochei var. volubilis, which is collectively called the lankacidin group.
volubilis) or a derivative thereof, which is an antibiotic substance (constituting the antibiotic substance T-2636 group) isolated from a culture of lancascidin A (R ¹ :=0, R ² :H,
R ³ : COCH ₃ ), lankacidin C (R ¹ :=0, R ² :
H, R ³ : H), Rankashij A (R ¹ :

[Formula], R ² : H, R ³ : COCH ₃ ), lancasidinol (R ¹ :

[Formula], R ² : H, R ³ : H) and other producing bacteria, manufacturing methods, and physicochemical/biological properties can be found in, for example, The Journal of Antibiotics, Vol. 24, 1. −41 pages (1971
), lankacidin A8-propionate (R ¹ :=0, R ² :COCH ₂ CH ₃ , R ³ :COCH ₃ ),
Lancasidin C8-acetate (R ¹ :=0, R ² :
COCH ₃ , R ³ :H), 8-propionate (R ¹ :=0, R ² :COCH ₂ CH ₃ , R ³ :H), 14-
Propionate (R ¹ :=0, R ² :H, R ³ :
COCH ₂ CH ₃ ), 8,14-diacetate (R ¹ :=
0, R ² , R ³ : COCH ₃ ), 8,14-dipropionate (R ¹ :=0, R ² , R ₃ :COCH ₂ CH ₃ ), 8-benzoate (R ¹ :=0, R ² :COPh,
R ³ :H), 14-benzoate (R ¹ :=0, R ² :
H, R ³ : COPh), 14-phenylpropionate (R ¹ :=0, R ² : H, R ³ : COCH ₂ CH ₂ Ph),
14-nicotinate (R ¹ :=0, R ² :H, R ₃ :
Manufacturing methods such as nicotinoyl) and physicochemical
Regarding the biological properties, for example, The Journal of Antibiotics, Vol. 26, pp. 647-657 (1973) describes the properties of lancasidin C14-formate (R ¹ :=0, R ² :H, R ³ :COH). Regarding the production method and physicochemical properties, see
Each is described in Publication No. 74. Streptomyces rothiei val volubilis, which is the producing bacterium of lancasidin A, C, lancasidinol A, and lancasidinol, has been given a microorganism accession number by the Fermentation Research Institute and the American Type Culture Collection.
Deposited as IFO12507 and ATCC 21250, respectively. The acyl group derived from carboxylic acid as R ² and R ³ in the above general formula () is a lower fatty acid residue (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexylyl, etc., preferably having 1 to 7 carbon atoms). preferred) and aromatic carboxylic acid residues (e.g., aryl carboxylic acid residues such as benzoyl, heteroaromatic carboxylic acid residues such as nicotinoyl), and these lower fatty acid residues are substituted at the terminal with a phenyl group. (eg, phenylacetyl, phenylpropionyl, etc.). Among the compounds () used in the present invention, those in which R ² and R ³ are each hydrogen or a C ₂ -C ₄ fatty acid residue are particularly preferred. Among them, lankacidin A, lankacidin C, lankacidin C14-
It is preferable to use propionate, 8-acetate, 8-propionate, lancasidinol A, lancasidinol, or a mixture thereof. In particular, lankacidin A or/and lankacidin C are advantageously used. The composition for pigs of the present invention may contain one type of compound represented by compound (), or may contain several types of compounds () at the same time. Furthermore, the above-mentioned fermentation medium of Streptomyces rothiei vulubilis can be used as it is as a dried product or an extract thereof. The composition for preventing and treating swine dysentery or for improving swine productivity of the present invention is prepared by diluting the compound () with a solid or liquid diluent, or without diluting it, or stabilizing it by coating, etc. It is manufactured in the form of powders, granules, tablets, liquids, pastes, capsules, injections, etc., or by adding it directly or once dispersed in a diluent to feed, drinking water, etc. Any diluent may be used as long as it is physiologically harmless in itself, and it is more preferable to use a diluent that can be used as feed or a component of feed. Examples of solid carriers include barley flour, wheat flour, bare wheat flour, corn flour, soybean flour, soybean meal, rapeseed meal, rice hulls, rice bran, de-fingered rice bran, corn flour, potato flour, tofu meal, starch, lactose, sucrose, Glucose, fructose, yeast, waste yeast, fishmeal, talc, acid clay, clay, etc. are used, and examples of liquid carriers include water, physiological saline, and physiologically harmless organic solvents. Other appropriate adjuvants such as emulsifiers, dispersants, suspending agents, wetting agents, thickening agents, gelling agents, and solubilizing agents may be added in appropriate amounts. Furthermore, preservatives, bactericides, antibiotics, enzymes, lactic acid bacteria preparations may be added, and vitamins, minerals, amino acids, etc. may also be added to these compositions. The dosage of the composition for preventing and treating swine dysentery or for improving swine productivity of the present invention can be appropriately selected depending on the age of the pig, symptoms, administration method, etc.; () about 0.05 to 25 mg/
Kg/day is preferably administered, in which case the concentration of compound () is about 1-500 ppm, especially 2-500 ppm.
It is best to add it to feed at a concentration of 200ppm. In addition, for the purpose of treating swine dysentery, it is preferable to administer the compound () at about 0.1 to 25 mg/Kg/day, in this case about 2 to 500 ppm, especially about 2.5 mg/kg/day.
It is best to add it to feed at a concentration of ~200ppm. On the other hand, for the purpose of improving the productivity of pigs, it is preferable to administer the compound () as about 0.025 to 10 mg/Kg/day, and in this case, it should be added to the feed at about 0.5 to 200 ppm, especially about 1 to 100 ppm. It is better. The toxicity of compound () to animals is extremely low; for example, in an acute toxicity test using mice,
The LD ₅₀ by oral administration was 14-
10000 for both propionate and lankacidin A
mg/Kg or more, the LD ₅₀ by intraperitoneal administration is 8000 to 10000 mg/Kg for lancasidin A;
For C14-propionate, it was more than 10,000 mg/Kg, and for lankacidin C, it was 4,500 mg/Kg. This not only indicates that it is highly safe for humans during manufacturing and distribution, but also has a wide tolerance to the target animals, so when administered by mixing it with feed, for example, there is a considerable degree of non-uniformity in the mixture. This shows that it is possible to guarantee the safety of target animals even if Next, the present invention will be explained in more detail using experimental examples and examples, but it goes without saying that these do not limit the scope of the present invention. Experimental Example 1 An in vitro antibacterial activity test against Treponema hyodei senteriae, the causative agent of swine dysentery, was conducted using Kashiwazaki et al.'s ``Method for measuring drug susceptibility of Treponema hiodei senteriae'' (Summary of the 82nd Japanese Veterinary Medical Association Conference)
Page 101: Measured according to 1978). As shown in Table 1, lankacidin C showed strong antibacterial activity, but all other antibiotics used for comparison were ineffective.

[Table] Experimental Example 2 An in vitro antibacterial activity test was conducted on a representative example of compound () in the same manner as in Experimental Example 1. The results are shown in Table 2, and although there was a slight difference in the minimum inhibitory concentration, all showed significant antibacterial activity against Treponema hyodei centeriae.

[Table] Experimental Example 3 An in vitro antibacterial activity test was conducted on compound () in the same manner as in Experimental Example 1. The result is the third
As shown in the table, all of them showed remarkable antibacterial activity against Treponema hyodei senteriae.

[Table] Experimental Example 4: Lancascidin A, Lancascidin C, and Lancascidin C8 in experimental swine dysentery infection using mice
- Acetate, lancasidin C14-propionate, lancasidinol A, and lancasidinol were tested for their anti-swine dysentery effects. For example, Infection and Immunity Vol. 25, pp. 757-760 (1979), American
Journal of Veterinary Research Volume 41
A mouse experimental swine dysentery infection model similar to that of Ziens et al., described in Veterinary Records, Vol. 107, pp. 527-529 (1980), was used. That is, a field isolate of Treponema hyodysenteriae cultured anaerobically on a Trypticase soy agar (BBL) plate supplemented with 5% horse blood was ground together with the medium.
2 with Pros (Trypticase soy broth; manufactured by BBL)
The twice diluted infectious material was inoculated into the stomach of mice.
The drug was suspended in a 5% gum arabic solution and administered orally by force from 1 day to 4 days after infection. Seven days after infection, lesions in the cecum were observed, and the cecum and contents were crushed to determine the number of Treponema hyodysenteriae bacteria. As summarized in Table 4, all drug administration groups showed excellent efficacy.

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[Table] Experimental Example 5 An anti-swine dysentery efficacy test of lankacidin C was conducted under experimental infection conditions. Specifically, 16 6-week-old Landrace pigs (4 pigs per group) were tested, and the test drug was added and mixed to a concentration of 100 ppm in home-mixed piglet artificial milk B that does not contain antibacterial substances. ,
Each piglet was allowed to feed freely. Infection of pigs is
The Treponema hyodysenteriae 78/A strain, which had been anaerobically cultured on a 5% horse blood agar plate in advance, was ground together with the medium, mixed with 5% mucin-containing phosphate buffer, and the mixture was directly administered into the stomachs of SPF pigs. Ivy. Next, colon contents and mucous membranes were collected from pigs that had developed typical swine dysentery.
The final infection material was diluted 2 times with phosphate buffer containing 5% mucin, and 100 ml of it was directly injected into the stomach of the test pig when it was 7 weeks old (provided it had not been fed for 24 hours before infection). , infected, and kept for 21 days after infection. As the results are summarized in Table 5, maridomycin was ineffective, but lankacidin C showed excellent efficacy against swine dysentery.

[Table] Experimental example 6 Concentration of lankacidin C in feed
A test was conducted in the same manner as in Experimental Example 5, including further lowering the concentration from 100 ppm and comparing it with Carbadox, which is commonly used as an anti-swine dysentery agent. The results are summarized in Table 6, and it was found that lankacidin C was a superior anti-swine dysentery agent to carbadox in terms of breeding performance.

[Table] Experimental Example 7 In the same manner as Experimental Example 6, an anti-swine dysentery effect test was conducted when lancascidin A and lancascidin C14-propionate were administered at 10 ppm. The results are summarized in Table 7, and both lankacidin A and lankacidin C14-propionate showed clear efficacy against swine dysentery.

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[Table] Experimental Example 8 In this experimental example, medication was administered at the same time as the onset of swine dysentery.
It was carried out under conditions of so-called therapeutic medication. The infection method was the same as in Experimental Example 5, and five animals that developed symptoms on the same day (6th day) after infection were used in the test, and feed containing 50 ppm of lankacidin C was fed at the same time as the onset of symptoms. The result is the 8th
As shown in the table, the mucus and bloody diarrhea stopped in all cases the day after administration, and the stool changed from soft to normal, and the number of bacteria in the stool fell below the detection limit (10 ² CFU/g) on the second day. An autopsy performed on the 15th day after onset (9th day of drug withdrawal) revealed no lesions in the large intestine and no bacteria were detected.

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[Table] Experimental Example 9 In the same manner as Experimental Example 8, the therapeutic effect of lankacidins was tested under the conditions of therapeutic administration for swine dysentery. According to Experimental Example 8, the effect was determined based on the stool properties. As shown in Table 9, lancasidin A, lancasidin C, and 14-propionate were found to have therapeutic effects when administered at 50 ppm.

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[Table] * Indicates the feeding date of drug-added feed.
As is clear from the results of Experimental Examples 1 to 9 above,
Compound () is extremely effective as a preventive treatment for swine dysentery, and is superior to similar antibiotics or anti-swine dysentery agents that are already commercially available and in frequent use, making it extremely effective for livestock management. be. Experimental Example 10 The effect of compound () on the growth of pigs in the absence of swine dysentery was tested. That is, 1
We tested 40 5-month-old Landrace pigs in 5 litters.
Five groups were established, each consisting of 8 animals (4 males, 4 females). The concentrations of lankacidin C added to the feed were 0 (control), 1, 2.5, 5, and 10 ppm, and from the start
For 5 months, add to artificial milk B without adding antibacterial agents until the age of 4 months and mix with pig meat production ability test feed (also without addition of antibacterial agents) from 4 months of age to 6 months of age (completed). Each group was fed continuously over a period of time. The results are summarized in Table 10. As the concentration of lankacidin C increases, growth of pigs is promoted, feed utilization is improved, and compound ()
is useful for improving pig productivity even under normal breeding conditions.

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[Table] Experimental Example 11 Forty-eight 35-day-old Landrace pigs (6 litters) were tested, and 6 groups of 8 pigs (4 males, 4 females) were established. The concentration of lankacidin A added to feed is 0.
(control), 1, 2.5, 5, 10, and 20 ppm, and from the start to 3 months of age, artificial milk B without antibacterial agents.
Then, from 4 months of age to 6 months of age (end), they were added to and mixed with pig meat production ability test feed (also without the addition of antibacterial agents). The growth results after continuous administration for 5 months are summarized in Table 11, as the growth of pigs was promoted in proportion to the increase in the added concentration of lancascidin A, and feed utilization improved.

[Table] Example 1 For example, by blending the following basic feed or some of its raw materials with an arbitrary concentration of the compound (),
The composition of the present invention for preventing and treating swine dysentery and for improving pig productivity, or its premixes can be produced.

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Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is =0 or [Formula], and R ² and R ³ each represent hydrogen or an acyl group derived from a carboxylic acid]. A composition for improving productivity.