CA2042138A1 - Agents for preventing or treating bacterial diseases of fishes - Google Patents
Agents for preventing or treating bacterial diseases of fishesInfo
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- CA2042138A1 CA2042138A1 CA 2042138 CA2042138A CA2042138A1 CA 2042138 A1 CA2042138 A1 CA 2042138A1 CA 2042138 CA2042138 CA 2042138 CA 2042138 A CA2042138 A CA 2042138A CA 2042138 A1 CA2042138 A1 CA 2042138A1
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, a pleuromutilin derivative.
The present invention further relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, tiamulin and the derivatives thereof.
The present invention relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, a pleuromutilin derivative.
The present invention further relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, tiamulin and the derivatives thereof.
Description
2 ~ ~ ~1t3 S~CIEL~IQN.
TITLE
Agents for Preventing ox Treating Bacterial Diseases of Fishes FIELD OF THE INVENTION
The present invention relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, a pleuromutilin derivative (designated as the Derivative hereinafter).
The present invention further relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, tiamulin and the derivatives thereof.
B~CKGROUND..~E T~IE I~YFL~TION
The Derivatives are the known substarlces described .in Japanese Patent L-O-P Nos. 199870/1985 and 71~7/1~82.
The Derivatives are semi-synthetic derivatives of pleuromutilin. The precursor, pleuromutilin, is a diterpene antibiotics obtained from the cultivation filtrate of Pleurotus multilus by Kavanagh et al.~ in 1951 and the Derivatives are synthesi~ed from the precursor pleuromutilin by chemical modification.
~%~3~
In recent years, cultivation of sea and fresh water fishes such as yellowtail, young yellowtail, eel, salmon, trout, sweet fish ("ayu"), carp and -the like has become prosperous with the development of cultivation fishery and -there is a continuous demand for development of more economic cultivation technology and also safer and more effec-tive agents for prevention and treatment of diseases.
There have been a number of precedents in which antiblotics are administered to fishes in order to inhibit 0 fish disease-causative bacteria and to prevent or treat the diseases caused by such bacteria. Many antibiotics such as oxytetracycline, ampicilin, erythromycin and so on are known as a medicament usable in the aquatlc industry.
On the other hand, certain literature describes that resistant strains have been frequently found in the wild stralns due to an increase ln the arrlount of commonly used antibiotics and therefore any possible means for resolvln~
the problem has been sought.
Among many kinds o~ flsh dlseases of rnany kinds of fishes, streptococcal infection of yellowtail is a problem to be resolved by all means in the young yellowtail cultivation which is becoming prosperous from year to year. Development of new therapy has ben demanded for such diseases in view of emergence of resistant strains. In addition, outbreaks of ~5 bacterial kidney disease in fishes of Salmonidae are recently 2 ~
becoming a problem, and appropriate agents for prevention and treatment of the disease are earnes-tly demanded.
Since the Derivatives exhibit significantly excellent antibacterial activities against the pathogen of the above-5 mentioned fish disease, i.e., streptococcus sp. and thepathogen of bacterial kidney disease, i.e., Renibacterium sp.
without being accompanied by cross resistance between these derivatives and widely used antibiotics, they are expected to be useful as an agent for prevention and treatment of f ish 1~ diseases. There have been no literature or publication describing the use of the derivatives in the prevention or treatment of fish diseases.
ORJE~T OF THE INVEN~I.QM
The present invention has been achieved in view of the prior art mentioned above, and an object of the i.nvent.ion is to provide agents for prevention and treatmen-t of bacterial diseases of fishes comprisiny, as an active in~J:redient, a pleuromutilin derivative.
A further object of the .inventi.on is to provide agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, tiamulin and the derivatives thereof.
2 0 ~
.SUMMARY OF' THE I~VE~TION
(l) An agent for the prevention or treatment of bacterial diseases of fishes according to the present invention comprises, as an active ingredient, a pleuromutilin derivative of the formula:
~R2 R4CH2CSCH2CCO CE~13 1 ~
wherein Rl is ethyl or vinyl, R2 is hydrogen or methyl, R3 is hydrogen or methyl, and Rg is dialkylamino or Rs-CONH- (Rs being 5-membered saturated heterocycle or aminoalkyl which is unsubstituted or substituted with hydroxy in the alkyl moiety, in the free form or in the form of an aci.d add:itior salt or a quaternary ammonium salt).
LE~ILEn_DFSCRIPTION OY THE JNVENTION
The agent for prevention and treatment of bacteri.al diseases of fishes according to the present invention comprises, as an active ingredient, a pleuromutilin derivative of the formula:
2~2~3~
R~
R~CEI2CSCH2C~X) CH3 o r3 wherein R1 is ethyl or vinyl, R2 is hydrogen or methyl, R3 is hydrogen or methyl, and R4 is dialkylamino or Rs--CONH- (Rs being 5-membered saturated heterocycle or aminoalkyl which is unsubstituted or substituted with hydroxy in the alkyl moiety, in the free form or in the form of an acid addition salt or a quaternary amrnonium salt).
Among the pleuromutilin derivatives, particularly preferred is 19-deoxy-14-[(2-D-valylamino-1,1-dimethylethyl)-thioacetoxy]mutilin (designated as the Derivative No. 1 hereinafter).
Tiamulin (R1 = vinyl, R2 - H, R3 = f~, R9 = diethylamirlo IS in the above formula) and derivat:ives t:hereof in the form of acid addition salts or quaternary ammonium salts are also preferred among the pleuromutilin derivatives. Among the tiamulin derivatives, particularly preferred is tiamulin hydrogenfumarate (designated as the Derivative No. 2 hereinafter).
~21~
Though the Derivatives may be administered per se directly to fishes, they may preferably be administered in the form of powders, granules, wettable powders, solutions, tablets, etc., prepared by mixing the Derivatives with an extender, a carrier, etc., such as starch, glucose, dextran, natural salt, calcium carbonate, kaolin, corn flour, soybean cake, fish meal, rice bran, lucerne meal, alcohols, fats and oils, cotton seed oil, sodium asparginate, sorbitan monostearate, Tween ~trade name of a surfactant, from Atlas Powder Co.), lactose, etc., or they may preferably be administered in combination with feed or living prey, as practiced in usual administration.
The amount of the Derivatives to be administered may vary depending on the kind of fishes, etc., but is suitably about 0.1 to 1000 ppm and preferably 1 to 500 ppm in the normal situa-tion.
[Example]
The preserlt invention will be illustrated in more detail with reference to the Eollowlng examples, but it should be construed that the invention is in no way limited to these examples.
Example 1 (Solution) The Derivative No. 1 (1 part), ethanol (~9.9 parts) and Sorpol (0.1 part, trade name of a surfactant, from Toho --` 2~2.~38 Kagaku Kabushiki Kaisha) were homogeneously mixed to form a solution.
Example 2 (Dust or powder) The Derivative No. 1 (2 parts), sodium chloride (79.9 parts) and Sorpol (0.1 part, trade name of a surfactant, Toho Chemical Co., Ltd.) were homogeneously mixed and pulverized to give a dust (a powder).
E~ample 3 (Feed) The Derivative No.1 (10 parts) was dissolved in 0 acetone (90 parts) to form a solution (100 parts). The solution was sprinkled over young fish feed (999900 parts, from Nippon Haigo Shiryo Kabushiki Kaisha) and the solution and the feed were homogeneously mixed while acetone was removed to give feed containing 10 ppm of the Derivative No.
15 1.
Example 4 (Feed) The Derivative No. 1 (0.2 part) and a soybean cake powder (99.8 parts) were homogeneously mixed and the mixture was pulverized to gi.ve a powder mixture (100 parts). The powder mixture was homogeneously mixed with young fish feed (9900 parts, from Nippon Haigo Shiryo Kabushikl Kaisha) to give feed containing 20 ppm of the Derivative No. 1.
[Effects]
The preventing and treating effects of the Derivative No. 1 on bacterial diseases of fishes are now ~0~2~38 particularly illustrated by means of the ~ollowing Test Examples.
Te.~t ~xam~le 1 The solution was dissolved in methanol or distilled S water. The resultant solution was diluted stepwise to have concentrations of the Derivative No. 1 of 100 ~g/ml, 50 ~giml, 5 ~g/ml and 1 ~g/ml, and assayed for antibacterial activity at each of the concentrations. Tha-t is to say, a paper disk 8 mm in diameter was impregnated with one of the 0 diluted solutions, air dried in a clean bench for 1 hour, transferred on an agar medium ~*2) inoculated with a fish pathogen (0.1 ml) (*1) by means of Conradi and incubated (*3). The antibacterial activity was judged by the presence or absence of an inhibiting circle.
*1) amount of inoculated bacteria: 108 CUF
*2) medium for judgement: medium for a sensitivity disk *3) conditions for incubation: 26.5C for 40 hours The results are shown in Table 1 wherein ~
designates very effective, ~ designates intermediately effective, -~ designates slightly effective and - designates ineffective.
TITLE
Agents for Preventing ox Treating Bacterial Diseases of Fishes FIELD OF THE INVENTION
The present invention relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, a pleuromutilin derivative (designated as the Derivative hereinafter).
The present invention further relates to agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, tiamulin and the derivatives thereof.
B~CKGROUND..~E T~IE I~YFL~TION
The Derivatives are the known substarlces described .in Japanese Patent L-O-P Nos. 199870/1985 and 71~7/1~82.
The Derivatives are semi-synthetic derivatives of pleuromutilin. The precursor, pleuromutilin, is a diterpene antibiotics obtained from the cultivation filtrate of Pleurotus multilus by Kavanagh et al.~ in 1951 and the Derivatives are synthesi~ed from the precursor pleuromutilin by chemical modification.
~%~3~
In recent years, cultivation of sea and fresh water fishes such as yellowtail, young yellowtail, eel, salmon, trout, sweet fish ("ayu"), carp and -the like has become prosperous with the development of cultivation fishery and -there is a continuous demand for development of more economic cultivation technology and also safer and more effec-tive agents for prevention and treatment of diseases.
There have been a number of precedents in which antiblotics are administered to fishes in order to inhibit 0 fish disease-causative bacteria and to prevent or treat the diseases caused by such bacteria. Many antibiotics such as oxytetracycline, ampicilin, erythromycin and so on are known as a medicament usable in the aquatlc industry.
On the other hand, certain literature describes that resistant strains have been frequently found in the wild stralns due to an increase ln the arrlount of commonly used antibiotics and therefore any possible means for resolvln~
the problem has been sought.
Among many kinds o~ flsh dlseases of rnany kinds of fishes, streptococcal infection of yellowtail is a problem to be resolved by all means in the young yellowtail cultivation which is becoming prosperous from year to year. Development of new therapy has ben demanded for such diseases in view of emergence of resistant strains. In addition, outbreaks of ~5 bacterial kidney disease in fishes of Salmonidae are recently 2 ~
becoming a problem, and appropriate agents for prevention and treatment of the disease are earnes-tly demanded.
Since the Derivatives exhibit significantly excellent antibacterial activities against the pathogen of the above-5 mentioned fish disease, i.e., streptococcus sp. and thepathogen of bacterial kidney disease, i.e., Renibacterium sp.
without being accompanied by cross resistance between these derivatives and widely used antibiotics, they are expected to be useful as an agent for prevention and treatment of f ish 1~ diseases. There have been no literature or publication describing the use of the derivatives in the prevention or treatment of fish diseases.
ORJE~T OF THE INVEN~I.QM
The present invention has been achieved in view of the prior art mentioned above, and an object of the i.nvent.ion is to provide agents for prevention and treatmen-t of bacterial diseases of fishes comprisiny, as an active in~J:redient, a pleuromutilin derivative.
A further object of the .inventi.on is to provide agents for prevention and treatment of bacterial diseases of fishes comprising, as an active ingredient, tiamulin and the derivatives thereof.
2 0 ~
.SUMMARY OF' THE I~VE~TION
(l) An agent for the prevention or treatment of bacterial diseases of fishes according to the present invention comprises, as an active ingredient, a pleuromutilin derivative of the formula:
~R2 R4CH2CSCH2CCO CE~13 1 ~
wherein Rl is ethyl or vinyl, R2 is hydrogen or methyl, R3 is hydrogen or methyl, and Rg is dialkylamino or Rs-CONH- (Rs being 5-membered saturated heterocycle or aminoalkyl which is unsubstituted or substituted with hydroxy in the alkyl moiety, in the free form or in the form of an aci.d add:itior salt or a quaternary ammonium salt).
LE~ILEn_DFSCRIPTION OY THE JNVENTION
The agent for prevention and treatment of bacteri.al diseases of fishes according to the present invention comprises, as an active ingredient, a pleuromutilin derivative of the formula:
2~2~3~
R~
R~CEI2CSCH2C~X) CH3 o r3 wherein R1 is ethyl or vinyl, R2 is hydrogen or methyl, R3 is hydrogen or methyl, and R4 is dialkylamino or Rs--CONH- (Rs being 5-membered saturated heterocycle or aminoalkyl which is unsubstituted or substituted with hydroxy in the alkyl moiety, in the free form or in the form of an acid addition salt or a quaternary amrnonium salt).
Among the pleuromutilin derivatives, particularly preferred is 19-deoxy-14-[(2-D-valylamino-1,1-dimethylethyl)-thioacetoxy]mutilin (designated as the Derivative No. 1 hereinafter).
Tiamulin (R1 = vinyl, R2 - H, R3 = f~, R9 = diethylamirlo IS in the above formula) and derivat:ives t:hereof in the form of acid addition salts or quaternary ammonium salts are also preferred among the pleuromutilin derivatives. Among the tiamulin derivatives, particularly preferred is tiamulin hydrogenfumarate (designated as the Derivative No. 2 hereinafter).
~21~
Though the Derivatives may be administered per se directly to fishes, they may preferably be administered in the form of powders, granules, wettable powders, solutions, tablets, etc., prepared by mixing the Derivatives with an extender, a carrier, etc., such as starch, glucose, dextran, natural salt, calcium carbonate, kaolin, corn flour, soybean cake, fish meal, rice bran, lucerne meal, alcohols, fats and oils, cotton seed oil, sodium asparginate, sorbitan monostearate, Tween ~trade name of a surfactant, from Atlas Powder Co.), lactose, etc., or they may preferably be administered in combination with feed or living prey, as practiced in usual administration.
The amount of the Derivatives to be administered may vary depending on the kind of fishes, etc., but is suitably about 0.1 to 1000 ppm and preferably 1 to 500 ppm in the normal situa-tion.
[Example]
The preserlt invention will be illustrated in more detail with reference to the Eollowlng examples, but it should be construed that the invention is in no way limited to these examples.
Example 1 (Solution) The Derivative No. 1 (1 part), ethanol (~9.9 parts) and Sorpol (0.1 part, trade name of a surfactant, from Toho --` 2~2.~38 Kagaku Kabushiki Kaisha) were homogeneously mixed to form a solution.
Example 2 (Dust or powder) The Derivative No. 1 (2 parts), sodium chloride (79.9 parts) and Sorpol (0.1 part, trade name of a surfactant, Toho Chemical Co., Ltd.) were homogeneously mixed and pulverized to give a dust (a powder).
E~ample 3 (Feed) The Derivative No.1 (10 parts) was dissolved in 0 acetone (90 parts) to form a solution (100 parts). The solution was sprinkled over young fish feed (999900 parts, from Nippon Haigo Shiryo Kabushiki Kaisha) and the solution and the feed were homogeneously mixed while acetone was removed to give feed containing 10 ppm of the Derivative No.
15 1.
Example 4 (Feed) The Derivative No. 1 (0.2 part) and a soybean cake powder (99.8 parts) were homogeneously mixed and the mixture was pulverized to gi.ve a powder mixture (100 parts). The powder mixture was homogeneously mixed with young fish feed (9900 parts, from Nippon Haigo Shiryo Kabushikl Kaisha) to give feed containing 20 ppm of the Derivative No. 1.
[Effects]
The preventing and treating effects of the Derivative No. 1 on bacterial diseases of fishes are now ~0~2~38 particularly illustrated by means of the ~ollowing Test Examples.
Te.~t ~xam~le 1 The solution was dissolved in methanol or distilled S water. The resultant solution was diluted stepwise to have concentrations of the Derivative No. 1 of 100 ~g/ml, 50 ~giml, 5 ~g/ml and 1 ~g/ml, and assayed for antibacterial activity at each of the concentrations. Tha-t is to say, a paper disk 8 mm in diameter was impregnated with one of the 0 diluted solutions, air dried in a clean bench for 1 hour, transferred on an agar medium ~*2) inoculated with a fish pathogen (0.1 ml) (*1) by means of Conradi and incubated (*3). The antibacterial activity was judged by the presence or absence of an inhibiting circle.
*1) amount of inoculated bacteria: 108 CUF
*2) medium for judgement: medium for a sensitivity disk *3) conditions for incubation: 26.5C for 40 hours The results are shown in Table 1 wherein ~
designates very effective, ~ designates intermediately effective, -~ designates slightly effective and - designates ineffective.
3 ~
Table 1 _ .
Compound Dose Streptococcus Renibacterium (~a/ml) sp. *Salmoninarum 5 Derivative100 +++ -~++
No. 1 50 +-~+ +++
+++ + ~+
~ + ~ + + +
Comparative 100 ++-~ -10 compound 50 ++
No. 3 5 - --- _ Comparative 100 -~++ ++
compound50 +-~+ -~
15 No. 4 5 ++-~ -+ ,~
Note) No. 1: 14-deoxy-14-[(2-~-valylam:ino-1,1 dimethyletilyl)-th.ioacetoxy]muti.lin No. 3: ampilicilin No. 4: erythromycin *: pathogen for streptococcosis of young yellowtail st F,xample 2: Effect on streptococcosis of young yellowtail 2~2 3 3~
1 o Groups of young yellowtail (one group consisting of lG
fishes) were intramuscularly chal1enged by living bacteria (107/fish) of streptococcus sp. (the pathogen for streptococcosis of young yellowtail).
S Immediately thereafter, the infected fishes were placed in a water bath (100 liter) containing 1, 5 or 100 ppm of the Derivative No. 1 (as described above) and maintained in the bath ~or 10 days. After this period, all the fishes o~ the medical bath-treated group survived without onset of disease, 0 whereas all the fishes of the untreated infected control group died within 2 weeks from infection, presenting necrosis at the infected site.
Test EYample ~: Effect on bacterial kidney disease of salmon Groups of salmons (one group consisting of 20 fishes) were combined with 10 salmons per group suffering from bacterial kidney disease. The fishes were kept with feed containing 2 ppm of the Derivative No. 1 (as descrlhed above) for 15 days. After one month, the survival rate was measured. The group treated with the Derivative No. 1 showed a survival rate of 80~, whereas the untreated group showed a fatality rate of 85%.
The above results have proved tha~ the Derivatives are effective as agents for preventing or treating bacterial diseases of fishes.
2 1 3 ~
F.~m~ 5 (Solution) The Derivative No. 2 (1 part), ethanol (89.9 parts) and Sorpol (0.1 part, trade name of a surfactant, from Toho Kagaku Kabushiki Kaisha) were homogeneously mixed to form a solution.
~ampl~_~ (Dust or powder) The Derivative No. 2 (2 parts), sodium chloride (79.9 parts) and Sorpol (0.1 part, trade name of a surfactant, Toho Chemical Co., Ltd.) were homogeneously mixed 0 and pulverized to give a dust (a powder).
E8~mpl~ 1_(Feed) The Derivative No.2 (10 parts) was dissolved in acetone (90 parts) to form a solution (100 parts). The solution was sprinkled over young fish feed (999900 parts, from Nippon Haigo Shiryo Kabushiki Kaisha) and the solution and the feed were homogeneously mixed while acetone was removed to give feed containing 10 ppm of the Derivatlve No.
2.
E~xam~le ~ (Feed) The Derivative No. 2 (0.2 part) and a soybean cake powder (99.8 parts) were homogeneously mixed and the mixture was pulveri~ed to give a powder mixture (100 parts). The powder mixture was homogeneously mixed with young fish feed (9900 parts, from Nippon Haigo Shiryo Kabushiki Kaisha) to give feed containing 20 ppm of the Deriva~ive No. 2.
12 2~4~13~
[EfEects]
The preventing and treating effects of the Derivative No. 2 on bacterial diseases of ~ishes are now particularly illustrated by means of the ~ollowing Test 5 Examples.
~:L~
The solution was dissolved in methanol or distilled water. The resultant solution was diluted stepwise to have concentrations of the Derivative No. 2 of 100 ~g/ml, 50 0 ~g/ml, 5 ~g/ml and 1 ~g/ml, and assayed for antibacterial activity at each of the concentrations. That is to say, a paper disk 8 mm in diameter was impregnated with one of the diluted solutions, air dried in a clean bench for 1 hour, transferred on an agar medium ~*~) inocula-ted with a fish pathogen (0.1 ml) ~*1) by means of Conradi and incubated ~*3). The antibacterial activity was judged by the presence or absence of an inhibiting circle.
*1) amount of inoculated bacteria: 10~ C~F
*2) medium for judgement: medium for a sensitivity disk *3) conditions for incubation: 26.5C for ~0 hours The results are shown in Tabl.e 2 wherein -t+-~
designates very effective, ++ designates intermediately effective, + designates slightly effective and ~ designates ine~ective.
~21~
Table 2 Compound Dose Streptococcus Renibacterium ~a/ml) sp. * Salmoninarum.
5 Derivative100 +-~+ ~+~
No. 2 50 +++ ++.~
-t++ -~+
+ + +
Comparative 100 ~+-~ -0 compound 50 ++
No. 5 5 _ _ Comparative 100 t-~ +
compound 50 -~++ +
15 No. 6 5 -~++
-~ + ~ _ Note) No. 2: tiamulin hydrogenfumara-te No. 5: ampilicilin 20No. 6: erythromycin *: pathogen for streptococcosis of young yellowtail Test F,xampl~_~: Effect on streptococcosis of young yellowtail Groups of young yellowtail (one group consisting of 10 2~ fishes) were intramuscularly challenged by living bacteria - 2~%~
(107/fish) of streptococcus sp. (the pathogen for streptococcosis vf young yellowtail).
Immediately thereafter, the infected fishes were placed in a ~ater bath (100 liter) containing 5 or 100 ppm of the Derivative No. 2 (as described above) and maintained in the bath for 10 days. After this period, all the fishes of the medical bath-treated group survived without onset of disease, whereas all the fishes of the untreated infected control group died within 2 weeks from infection, presenting necrosis at the infected site.
Test E~ample 6: Effect on bacterial kidney disease of salmon Groups of salmons (one group consisting of 20 fishes) were combined with 10 salmons per group suffering from bacterial kidney disease. The fishes were kept with feed containing 2 ppm of the Derivative No. 2 (as described above~ for 15 days. After one month, the survival rate was measured. The group treated with the Derivative No. 2 showed a survival rate of 70~, whereas the untreated group showed a fatality rate of 85~.
The above results have proved that the Derivatives are effective as agents for preventing or treating bacterial diseases of fishes.
Table 1 _ .
Compound Dose Streptococcus Renibacterium (~a/ml) sp. *Salmoninarum 5 Derivative100 +++ -~++
No. 1 50 +-~+ +++
+++ + ~+
~ + ~ + + +
Comparative 100 ++-~ -10 compound 50 ++
No. 3 5 - --- _ Comparative 100 -~++ ++
compound50 +-~+ -~
15 No. 4 5 ++-~ -+ ,~
Note) No. 1: 14-deoxy-14-[(2-~-valylam:ino-1,1 dimethyletilyl)-th.ioacetoxy]muti.lin No. 3: ampilicilin No. 4: erythromycin *: pathogen for streptococcosis of young yellowtail st F,xample 2: Effect on streptococcosis of young yellowtail 2~2 3 3~
1 o Groups of young yellowtail (one group consisting of lG
fishes) were intramuscularly chal1enged by living bacteria (107/fish) of streptococcus sp. (the pathogen for streptococcosis of young yellowtail).
S Immediately thereafter, the infected fishes were placed in a water bath (100 liter) containing 1, 5 or 100 ppm of the Derivative No. 1 (as described above) and maintained in the bath ~or 10 days. After this period, all the fishes o~ the medical bath-treated group survived without onset of disease, 0 whereas all the fishes of the untreated infected control group died within 2 weeks from infection, presenting necrosis at the infected site.
Test EYample ~: Effect on bacterial kidney disease of salmon Groups of salmons (one group consisting of 20 fishes) were combined with 10 salmons per group suffering from bacterial kidney disease. The fishes were kept with feed containing 2 ppm of the Derivative No. 1 (as descrlhed above) for 15 days. After one month, the survival rate was measured. The group treated with the Derivative No. 1 showed a survival rate of 80~, whereas the untreated group showed a fatality rate of 85%.
The above results have proved tha~ the Derivatives are effective as agents for preventing or treating bacterial diseases of fishes.
2 1 3 ~
F.~m~ 5 (Solution) The Derivative No. 2 (1 part), ethanol (89.9 parts) and Sorpol (0.1 part, trade name of a surfactant, from Toho Kagaku Kabushiki Kaisha) were homogeneously mixed to form a solution.
~ampl~_~ (Dust or powder) The Derivative No. 2 (2 parts), sodium chloride (79.9 parts) and Sorpol (0.1 part, trade name of a surfactant, Toho Chemical Co., Ltd.) were homogeneously mixed 0 and pulverized to give a dust (a powder).
E8~mpl~ 1_(Feed) The Derivative No.2 (10 parts) was dissolved in acetone (90 parts) to form a solution (100 parts). The solution was sprinkled over young fish feed (999900 parts, from Nippon Haigo Shiryo Kabushiki Kaisha) and the solution and the feed were homogeneously mixed while acetone was removed to give feed containing 10 ppm of the Derivatlve No.
2.
E~xam~le ~ (Feed) The Derivative No. 2 (0.2 part) and a soybean cake powder (99.8 parts) were homogeneously mixed and the mixture was pulveri~ed to give a powder mixture (100 parts). The powder mixture was homogeneously mixed with young fish feed (9900 parts, from Nippon Haigo Shiryo Kabushiki Kaisha) to give feed containing 20 ppm of the Deriva~ive No. 2.
12 2~4~13~
[EfEects]
The preventing and treating effects of the Derivative No. 2 on bacterial diseases of ~ishes are now particularly illustrated by means of the ~ollowing Test 5 Examples.
~:L~
The solution was dissolved in methanol or distilled water. The resultant solution was diluted stepwise to have concentrations of the Derivative No. 2 of 100 ~g/ml, 50 0 ~g/ml, 5 ~g/ml and 1 ~g/ml, and assayed for antibacterial activity at each of the concentrations. That is to say, a paper disk 8 mm in diameter was impregnated with one of the diluted solutions, air dried in a clean bench for 1 hour, transferred on an agar medium ~*~) inocula-ted with a fish pathogen (0.1 ml) ~*1) by means of Conradi and incubated ~*3). The antibacterial activity was judged by the presence or absence of an inhibiting circle.
*1) amount of inoculated bacteria: 10~ C~F
*2) medium for judgement: medium for a sensitivity disk *3) conditions for incubation: 26.5C for ~0 hours The results are shown in Tabl.e 2 wherein -t+-~
designates very effective, ++ designates intermediately effective, + designates slightly effective and ~ designates ine~ective.
~21~
Table 2 Compound Dose Streptococcus Renibacterium ~a/ml) sp. * Salmoninarum.
5 Derivative100 +-~+ ~+~
No. 2 50 +++ ++.~
-t++ -~+
+ + +
Comparative 100 ~+-~ -0 compound 50 ++
No. 5 5 _ _ Comparative 100 t-~ +
compound 50 -~++ +
15 No. 6 5 -~++
-~ + ~ _ Note) No. 2: tiamulin hydrogenfumara-te No. 5: ampilicilin 20No. 6: erythromycin *: pathogen for streptococcosis of young yellowtail Test F,xampl~_~: Effect on streptococcosis of young yellowtail Groups of young yellowtail (one group consisting of 10 2~ fishes) were intramuscularly challenged by living bacteria - 2~%~
(107/fish) of streptococcus sp. (the pathogen for streptococcosis vf young yellowtail).
Immediately thereafter, the infected fishes were placed in a ~ater bath (100 liter) containing 5 or 100 ppm of the Derivative No. 2 (as described above) and maintained in the bath for 10 days. After this period, all the fishes of the medical bath-treated group survived without onset of disease, whereas all the fishes of the untreated infected control group died within 2 weeks from infection, presenting necrosis at the infected site.
Test E~ample 6: Effect on bacterial kidney disease of salmon Groups of salmons (one group consisting of 20 fishes) were combined with 10 salmons per group suffering from bacterial kidney disease. The fishes were kept with feed containing 2 ppm of the Derivative No. 2 (as described above~ for 15 days. After one month, the survival rate was measured. The group treated with the Derivative No. 2 showed a survival rate of 70~, whereas the untreated group showed a fatality rate of 85~.
The above results have proved that the Derivatives are effective as agents for preventing or treating bacterial diseases of fishes.
Claims (2)
1, wherein said bacterial diseases of fishes are streptococcosis or bacterial kidney disease.
(3) The agent for prevention or treatment according to claim
(3) The agent for prevention or treatment according to claim
2, wherein said pleuromutilin derivative is 19-deoxy-19-[(2-o-valylamino-1,1-dimethylethyl)thioaceotoxy]mutilin.
(4) The agent for prevention or treatment according to claim 2, wherein said pleuromutilin derivative is tiamulin or a tiamulin derivative in the form of an acid addition salt or a quaternary ammonium salt.
(5) The agent for prevention or treatment according to claim 4, wherein said tiamulin derivative is tiamulin hydrogenfumarate.
(4) The agent for prevention or treatment according to claim 2, wherein said pleuromutilin derivative is tiamulin or a tiamulin derivative in the form of an acid addition salt or a quaternary ammonium salt.
(5) The agent for prevention or treatment according to claim 4, wherein said tiamulin derivative is tiamulin hydrogenfumarate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2042138 CA2042138A1 (en) | 1990-04-18 | 1991-05-08 | Agents for preventing or treating bacterial diseases of fishes |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2100430A JPH041131A (en) | 1990-04-18 | 1990-04-18 | Preventive and remedy for bacterial disease of fish |
| CA 2042138 CA2042138A1 (en) | 1990-04-18 | 1991-05-08 | Agents for preventing or treating bacterial diseases of fishes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2042138A1 true CA2042138A1 (en) | 1992-11-09 |
Family
ID=25674606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2042138 Abandoned CA2042138A1 (en) | 1990-04-18 | 1991-05-08 | Agents for preventing or treating bacterial diseases of fishes |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2042138A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7790749B2 (en) | 2002-04-23 | 2010-09-07 | Nabriva Therapeutics Ag | Use of pleuromutilins for the treatment of disorders caused by Helicobacter pylori |
-
1991
- 1991-05-08 CA CA 2042138 patent/CA2042138A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7790749B2 (en) | 2002-04-23 | 2010-09-07 | Nabriva Therapeutics Ag | Use of pleuromutilins for the treatment of disorders caused by Helicobacter pylori |
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