CN1638770A - Composition and potentiating method - Google Patents

Abstract

The invention discloses a composition, which contains clopidogrel (3,5-dichloro-2,6-dimethyl-4-pyridylphenol) or its analog dinitramine (2-methyl-3 , 5-dinitrobenzamide) and a synergist containing at least one of the following substances: colistin, benzoic acid or its derivatives, salicylic acid or its derivatives sulfaquinoxaline (4-amino-N-2-quinoxalinylbenzenesulfonamide) or amantadine (tricyclo-[3.3.1.1]decane-1-amine). The composition can be used as a medicine, a synergistic method or for controlling fungal infections in animals. The composition has the effect of anti-coccidiosis and the effect of preventing coccidiosis.

Description

Composition and Synergistic Method

The present invention relates to a new composition, a composition for use as a medicine, especially for treating coccidiosis, and also relates to the use of the composition in the production of a medicine for treating diseases caused by fungal infection in animals.

Coccidiosis is a disease of the intestinal wall of poultry, such as chickens, caused by coccidioid parasites of the protozoan Eimeria genus, such as Eimeria tenella, Eimeria tenella Eimeria necatrix, Eimeria acervulina, Eimeria brunetti, Eimeria maxima, Eimeria placidum mitis), Eimeria mivati, Eimeria praecox and Eimeria hagani. Species of this genus cause clinical disease in chicks, and immunity of a bird to any one species does not protect it from infection by other species. Coccidiosis is most common in chicks between 3 and 6 weeks of age. Coccidiosis is caused by protozoans of the family Eimeriaceae. Infection can occur in various places in the intestine. The course of the infection is rapid (4-7 days), characterized by the replication of the parasite in the host cells with considerable damage to the intestinal mucosa. Susceptible birds develop clinical disease only after ingesting relatively large numbers of sporulated oocysts. The feces of both clinically infected and cured birds contain oocysts, which contaminate food, dust, water, litter, and soil.

There are commercially available anticoccidiostats to prevent and treat coccidiosis, especially in chickens and turkeys. Coccidiostats are generally given to poultry in the feed to prevent acute disease. For therapeutic use, water medicaments are generally preferred over feed medicaments. Antibiotics are also sometimes used to increase cure rates and prevent reinfection.

Clopidogrel (i.e. 3,5-dichloro-2,6-dimethyl-4-pyridinol) and its analog dinitrotropium (i.e. 2-methyl-3,5-dinitrobenzamide ) is currently the most commonly used anticoccidial drug. There is a need in the art to provide a drug with enhanced efficacy in treating coccidiosis. To meet this need, the present invention provides a composition comprising, in addition to clopidol and analogs thereof, at least one synergistic component selected from the group consisting of: polymyxin E, benzoic acid or its derivatives, salicylic acid or its derivatives, 4-amino-N-2-quinoxalinylbenzenesulfonamide and tricyclic (3.3.1.1.) decan-1-amine. Said components are named synergistic components. The mechanism by which the enhanced activity is obtained is outside the scope of the present invention. Experiments have shown that enhanced activity is obtained, see experimental results stated in this specification. Furthermore, it was found quite unexpectedly according to the present invention that an antifungal effect is also achieved when the composition is used as a medicament for the treatment of eg poultry.

Contents of the invention

In a first aspect, the present invention relates to a composition as claimed in claim 1 .

In a second aspect, the present invention relates to a composition as claimed in claim 2 for use as a medicament.

In a third aspect, the present invention relates to a synergistic method as claimed in claim 3 .

In a fourth aspect, the present invention relates to the use of a composition of the kind defined above for the manufacture of a medicament for the treatment of diseases caused by fungal infections in animals. According to this aspect, said animals include, for example, poultry.

Clopidol and its analogs and synergists contained in the composition are briefly described below.

benzoic acid

Benzoic acid has the formula

Benzoic acid is used in embalming and in the manufacture of soaps, fragrances and pigments. It is present in almost all berries in an amount of 0.05%, at which point it functions as a natural preservative. The content in yogurt can be as high as 30mg/kg. According to the present invention, it is possible to use the following benzoic acid derivatives instead of benzoic acid.

Benzoic acid derivatives

3-acetamido-5-aminobenzoic acid

2-acetamido-2-aminobenzoic acid

4-acetamidobenzoic acid

Methyl 4-acetamidobenzoate

4-Acetamido-N-butylbenzoic acid

Methyl 2-acetamido-5-chlorobenzoate

Methyl 4-acetamido-5-chloro-2-hydroxybenzoate

4-acetamido-2-hydroxybenzoic acid

4-acetamido-2-methoxybenzoic acid

2-acetamido-4-nitrobenzoic acid

4-Acetoxybenzoic acid

2-Acetylbenzoic acid

5-Acetyl-2-hydroxybenzoic acid

Ethyl 4-allylbenzoate

3-aminobenzoic acid

3-Amino-5-(aminosulfonyl)-4-phenoxybenzoic acid

Butyl 4-aminobenzoate

Ethyl 4-aminobenzoate

4-Amino-2-butoxybenzoic acid

2-Amino-3-chlorobenzoic acid

4-amino-3,5-dichlorobenzoic acid

2-amino-4,5-difluorobenzoic acid

2-amino-4,5-dimethoxybenzoic acid

2-Amino-5-fluorobenzoic acid

2-amino-3-hydroxybenzoic acid

3-amino-4-hydroxybenzoic acid

2-Amino-6-methoxybenzoic acid

4-amino-3-methylbenzoic acid

4-(aminomethyl)-benzoic acid

4-Amino-3-nitrobenzoic acid

2-Amino-4-sulfobenzoic acid

5-Aminosulfonyl-2,3-dimethoxybenzoic acid

4-pentylbenzoic acid

2-anilinobenzoic acid

2-Methylbutyl Benzoate

4-Benzoylbenzoic acid

5-Benzyl-2-mercaptobenzoic acid

2-(Benzyloxy)-benzoic acid

2,2′-dibenzoic acid

4,4'-dibenzoic acid

4-bromobenzoic acid

3-Bromo-2,6-dimethoxybenzoic acid

4-butoxybenzoic acid

4-tert-butylbenzoic acid

4-Carbomethoxy-3,5-dimethoxybenzoic acid

4-Chloro-2-nitrobenzoic acid

4-cyanobenzoic acid-4-propylphenyl ester

3-(1-Cyanoethyl)-benzoic acid

3,5-diaminobenzoic acid

4-(Dipentylamino)-benzoic acid

3,5-di-tert-butylbenzoic acid

2,6-Difluorobenzoic acid

2,5-Dihydroxybenzoic acid

2,6-Dimethoxybenzoic acid

3,5-Dimethoxy-4-hydroxybenzoic acid

2,4-Dimethylbenzoic acid

3,5-Dimethyl-4-hydroxybenzoic acid

4-Ethoxybenzoic acid

4-Formylbenzoic acid

4-guanidinobenzoic acid

4-Heptylbenzoic acid

4-hydrazinobenzoic acid

4-Hydroxybenzoic acid

4-isothiocyanatobenzoic acid

4-Mercaptobenzoic acid

4-Phenylbenzoic acid

4-(Phenylthio)-benzoic acid

4-propoxybenzoic acid

Selenous carboxybenzoic acid

4-sulfobenzoic acid

4-sulfonylaminobenzoic acid

3,4,5-6-Tetrahydroxybenzoic acid

Thiobenzoic acid

trimethoxybenzoic acid

salicylic acid

It has the structural formula:

It is a weak acid used for pain relief, disinfection, and as an antipyretic. It inhibits the enzyme cyclooxygenase that stimulates the production of prostaglandins, which promote pain, fever, and inflammation. Salicylic acid is applied to the skin as a keratin-dissolving drug in some skin conditions.

Clopidogrel

Clopidol (3,5-dichloro-2,6-dimethyl-4-pyridinol) is known as an agent for preventing coccidiosis in chickens and turkeys. It is administered orally by addition to feed.

Dinitramide

Dinitramine or 2-methyl-3,5-dinitrobenzamide has the formula

And used as a veterinary drug to inhibit coccidia.

Amantadine

Amantadine (tricyclo[3.3.1.1]dec-1-amine) is used as an anti-Parkinson's drug, and its mode of action is not fully understood. It affects movement disorders, stability and tremors. Amantadine is also known to have antiviral effects against influenza A virus because it inhibits the virus from multiplying in the cells under attack.

colistin

Colistin is a cyclic polypeptide antibiotic produced by Bacillus colistinus isolated from Japanese soil. It is used as an antimicrobial for humans and animals.

Sulfaquinoxaline (QS)

Sulfaquinoxaline or 4-amino-N-2-quinoxalinylbenzenesulfonamide has the formula

And used as an anticoccidiostat. Other sulfonamides can also be used.

According to a preferred version, roxarsone is also used in the composition (not as a synergist).

Roxarsine or 4-hydroxy-3-nitrophenylarsine has the following structural formula:

It is used as an antimicrobial and also in veterinary medicines to control intestinal infections and improve growth and feed efficiency.

Examples of concentrations and vehicles.

The appropriate therapeutic concentration is determined by the treating veterinarian. However, it is recommended that the concentration of clopidogrel and its analogues according to the invention should be at least 20 ppm and at most 125 ppm. The concentration range of benzoic acid or its derivatives, salicylic acid or its derivatives should be 9-110ppm, the concentration range of sulfaquinoxaline should be 9-55ppm, the concentration range of rosarsone should be 5-15ppm, amantadine The concentration range of colistin should be 4-27ppm, and the concentration range of colistin should be 4-100ppm.

The concentrations of the compositions are based on an unrestricted feed or drinking water formulation, ie ad libitum consumption of feed or drinking water for the usual actual fattening or rearing phase. All feed formulations customary in the poultry industry are suitable as carriers for the compositions of the invention. An example is a feed based on certain types of rice which contains vitamin concentrates, mineral concentrates or other active substances and feed additives in any concentration. Conventional dry powder or pelleted feeds and liquid feed suspensions (including feeds such as brewery residues and dairy by-products) may also be used in the compositions of the present invention.

To prepare poultry feed, it is usually necessary to prepare a concentrated premix containing clopidol or an analogue thereof and a high concentration (eg, 0.2 to 75% by weight) of at least one composition component. For this purpose, these components are dispersed or mixed in an inert carrier substance (such as vermiculite, diatomaceous earth, attapulgite, calcium carbonate, etc.) and a physiologically harmless carrier (such as propylene glycol, polyethylene glycol, inert oils such as vegetable oils, highly refined mineral oils, ethanol, water or ethanol in water). Organic carrier materials such as wheat bran, chopped corn, soybean meal, alfalfa meal, rice bran or comminuted corn cobs, as well as other organic carrier materials derived from plant products, are equally suitable for this purpose.

As mentioned above, the compositions of the present invention may also be administered to poultry together with drinking water. They may be contained in drinking water by adding to drinking water an appropriate amount of a certain form of the composition concerned which is either soluble or suspendable in water. Such formulations are generally produced by selecting the form of the composition to be soluble in water. Water-insoluble forms, such as suspensions, may also be used. Physiologically harmless excipients are used here which enable the compositions according to the invention to be suspended in water for a prolonged period. Excipients suitable for this purpose are bulking agents such as alginates, gelatin, carboxymethylcellulose or polyvinylpyrrolidone. Surfactant compounds, such as naphthalene sulfonates, alkylbenzene sulfonates or polyoxyethylene sorbitan esters, can be used to bring the composition into suspension. Usually, the concentrated suspension or dry preparation of the composition and suspending agent of the present invention is produced in a certain mixing ratio, and then diluted with drinking water to the required application concentration, or the premix is mixed into practice at an appropriate concentration commonly used feed. The poultry are then fed with such formulated drinking water or feed, which can be done ad libitum or only for a specific period of time.

Although the invention has been described above with specific reference to the treatment of coccidia infection in poultry, the scope of the invention also includes the treatment of other domestically useful animals such as other birds, rabbits, pigs and ruminants.

biological example

Anticoccidial activity

Materials and Methods

chick

One-day-old chicks incubated with Habbared X were used in the experiment. In 7 different experiments, chicks were divided into 10 equal groups (20-30 birds each), one as a control group and one as a positive control group. The control group was infected but received no treatment, and the positive control group was also infected and took a known control anticoccidiostat (clopidogrel 125 ppm or salinomycin 60 ppm).

Chicks were housed in 1 x 1 m pens (separately in respective groups) and fed the medicated feed from the first day to the 15th day of life. Each group in each experiment was fed a different mixture of clopidogrel and at least one component selected from the group consisting of colistin, benzoic acid or its derivatives, salicylic acid or its derivatives, sulfonamides Quinoxaline and Amantadine.

On day 16, chicks were orally infected with 6000-8000 mature sporulated field-collected oocysts containing a different Eimeria strain: Eimeria acumenia ( Eimeria acervulina), Eimeria maxima, Eimeria necatrix, Eimeria tenella, Eimeria brunetti.

Fresh faeces were collected daily from day 5 post-infection until day 10 post-infection. The number of oocysts was counted and the mean number of oocysts per gram of feces per group was calculated using the Mc-Master technique according to Soulsby (1984). The number of chicks that died each day was also counted, post-mortem examined and the cause of death recorded.

G:

Each of the compositions to be tested was mixed into the feed of each group in sufficient quantities for daily feeding from day 0 of the experiment. Fresh water was provided without restriction.

Efficacy evaluation

The efficacy of the prophylactic effect was evaluated by comparing the total number of oocysts excreted in the treated group with the number in the non-treated group throughout the experimental period. At the end of the experiment, the body weight of the chicks and the amount of feed consumed were determined. From this the average body weight and the average amount of feed consumed per chick were calculated. The results are shown in the table below.

For the therapeutic columns, pharmaceutical compositions are given in ppm. Appropriate abbreviations are used.

Table (1): The preventive effect of the product on experimental coccidiosis in roast chicken feed (see 2001.5) Treatment (group) (25 per group) Average number of Eimeria oocysts/gram excrement/group (number per thousand oocysts) during feeding of experimental products 4d.pi 5d.pi 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi total number of oocysts Number of deaths (%) Final body weight/g in conclusion Group 4}, [50 clopidogrel + 36 colistin + 14 benzoic acid] 0 50 3000 1200 2000 2200 450 300 10000 315.47 very good Group 5}, [80 clopidogrel + 55 colistin + 15 benzoic acid] 0 100 700 500 1200 1200 1500 500 5700 367.38 very good Group 6}, [60 clopidogrel + 45 colistin + 35 benzoic acid] 0 300 4200 3000 2400 2000 1300 300 13400 329.65 good Group 9 (125ppm clopidogrel) 0 100 800 1500 2800 3600 4000 1200 14000 355.77 standard Group 10 (untreated infection) 0 500 4000 8000 3000 2000 3000 1500 22000 301.55 unprocessed

d.p.i. = days after experimental infection

Table (1): The preventive effect of the product on experimental coccidiosis in roast chicken feed (see 2001.4) Treatment (group) (25 per group) Average number of Eimeria oocysts/gram excrement/group (number per thousand oocysts) during feeding of experimental products 5d.pi 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi 12d.pi total number of oocysts Number of deaths (%) Final body weight/g in conclusion Group 1 [50 Clopidogrel + 33.5 Colistin] twenty four 6600 6000 4200 1500 2000 1500 90 21890 16.7 476.9 group}, [50 clopidogrel + 40 colistin + 40 benzoic acid] 3100 2200 1000 2400 3600 2000 2000 1000 17300 0.0 500.0 good Group 3}, [120 clopidogrel + 90 colistin + 40 benzoic acid] 1800 1000 900 850 4000 3000 3600 600 15800 0.0 510.0 good Group 5}, [30 clopidogrel + 27 colistin + 43 benzoic acid] 116 120 1500 3000 4000 2600 1000 600 13000 0.0 473.0 very good Group 6}, [20 clopidogrel + 22 colistin + 58 benzoic acid] 2100 300 3500 1400 5000 3000 800 700 19500 0.0 444.0 good Group 7}, [30 clopidogrel + 23 colistin + 17 benzoic acid] 450 100 1000 2700 6000 2000 150 800 13200 9.1 426.0 very good Group 9 (125ppm clopidogrel) 160 1200 3600 1500 8000 300 1200 300 19100 4.2 500.0 standard Group 10 (untreated infection) 1900 6000 3000 3500 3600 2000 5000 600 25600 16.0% 405.3 -Ve control

d.p.i. = days after experimental infection

Table (1): The preventive effect of the product on experimental coccidiosis in roast chicken feed (see 2001.2) test group Average number of Eimeria oocysts/gram excrement/group (number per thousand oocysts) during feeding of experimental products Average body weight/final chicks/g (25 per group) 5d.pi 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi Number of deaths (%) total number of oocysts in conclusion Group 3 (50 clopidogrel + 15 benzoic acid + 10 amantadine) 7000 3600 2700 900 600 200 0.0 15000 197.9 5 Group 4 (50 Clopidogrel + 15 Sorbicacid + 10 Amantadine) 6000 4500 7000 1400 2000 400 8.33 21300 190.7 No effect (NO EFFECT) Group 5 (50 clopidogrel + 15 benzoic acid + 10 rosatoma) 3500 3100 4800 1500 600 1000 4.2 14500 188.2 3 Group 6 (30 clopidogrel + 10 benzoic acid + 5 slime mold) 3000 4000 3800 1300 1100 300 9.5 13500 185.4 best 2 combination Group 7 (50 clopidogrel + 15 benzoic acid + 10 amantadine + 10 rosatin) 3700 2500 4000 2000 300 400 4.2 12900 184.21 Best 1 combination Group 9 (125ppm clopidogrel) 6000 5000 2000 2400 1300 300 8.33 17000 177.4 standard Group 10 (untreated infection) 8000 7800 4000 1600 900 200 16.7 22500 157.8 -Ve control

d.p.i. = days after experimental infection

Table (1): The preventive effect of the product on experimental coccidiosis in roasted chicken feed (see 2000.12) test group Average number of Eimeria oocysts/gram excrement/group (number per thousand oocysts) during feeding of experimental products Average body weight/final chicks/g (30 per group) 5d.pi 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi Number of deaths (%) total number of oocysts in conclusion Group 1 (75 Clopidogrel + 25QS + 25 Amantadine) 50 1000 2000 2500 3600 500 900 13.8 10550 242.8 TB# Group 2 (75 clopidogrel + 25QS + 10 amantadine + 18 benzoic acid) 0.0 700 1600 1800 2300 900 450 20.7 7750 222.6 # Group 3 (33 clopidogrel + 67 benzoic acid + 10 amantadine) 0.0 400 3000 2500 1600 1200 300 24.1 9000 245 @ Group 4 (75 Clopidogrel + 10 Amantadine) 50 1000 4000 2600 3000 550 200 20.7 11400 271.7 as standard Group 5 (33 clopidogrel +67 benzoic acid) 0.0 450 2100 2200 1500 1200 1000 37.9 8450 223.6 TB@ Group 6 (50 clopidogrel + 15 benzoic acid + 10 amantadine) 0.0 450 1200 2400 300 700 600 10.3 5650 250 best combination Group 7 (33 clopidogrel + 67 benzoic acid + 5 amantadine) 60 1500 2800 2400 300 240 600 31.0 7900 246 @ Group 8 (75 clopidogrel + 25QS + 5 amantadine + 25 benzoic acid) 0.0 600 1500 4000 2400 2000 500 10.3 11000 230 as standard Group 9 (125ppm clopidogrel) 50 550 1600 2800 2000 2100 1200 13.8 10300 300 standard Group 10 (untreated infection) 600 1000 1700 4400 6600 2500 1600 45.5 18400 219.7 -Ve control

d.p.i. = days after experimental infection

Table (1): The preventive effect of the product on experimental coccidiosis in roast chicken feed (see 2000.10) test group Average number of Eimeria oocysts/gram excrement/group during feeding of experimental product (number per thousand oocysts) Average % Mortality Average body weight/final chicks/g (20 per group) 5d.pi 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi total number of oocysts in conclusion Group 6 (salinomycin/60ppm) control drug 0.0 1300 2400 3200 1500 480 48 8928 260.5 standard Group 9 (50ppm clopidogrel + 15ppm benzoic acid) 0.0 420 900 2800 2500 120 18 6758 231.5 promising effect Group 10 (untreated infection) 0.0 3000 6000 2000 200 90 90 143800 214.8 -Ve control

d.p.i. = days after experimental infection

Table (1): The preventive effect of the product on its experimental coccidiosis in the feed of broiled chickens (see 2000.7) test group Average number of Eimeria oocysts/gram excrement/group during feeding of experimental product (number per thousand oocysts) Average % Mortality Average body weight/final chicks/g (20 per group) 5d.pi 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 12d.pi total number of oocysts in conclusion 125 2200 420 1200 300 100 20 4365 20 162.5 very good Group 2 (50 clopidogrel + 15 benzoic acid) 8 1400 1000 1100 420 660 26 4614 20 165.8 very good Group 3 (75 clopidogrel + 20 benzoic acid) 3 2000 1100 2000 300 230 18 5633 15 168 good Group 9 control drug (treatment with clopidogrel) 0.0 1500 670 600 350 320 8 3448 10.5 187 standard Group 10 (untreated infection) 20 3000 171 3800 820 636 90 8537 27.3 142 -Ve control

d.p.i. = days after experimental infection

Table (1): Testing the anti-coccidial effect of new compounds in young chickens

(dose 25-30000 mixed Eimeria strain oocysts) (see 2000.6) test group Average number of Eimeria oocysts/gram excrement/group during feeding of experimental product (number per thousand oocysts) Average body weight/final chicks/g (23 per group) 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi 12d.pi 13d.pi total number of oocysts mortality rate% in conclusion 100PPM (clopidogrel) + 25PPM (QS) + 50ppm benzoic acid 36 3000 2460 2420 820 430 236 40 9442 299.7 very good 25PPM (clopidogrel) + 25PPM (QS) + 100PPM benzoic acid 220 680 2580 2000 600 250 72 120 6522 308 very good 75PPM (clopidogrel) + 25PPM (QS) + 25PPM (amantadine) 0 380 800 720 640 215 37 59 2851 266.7 very good (Standard) Clopidogrel (125ppm) 8 9600 1872 3900 420 14 53 250 16117 266.5 infection untreated 588 29200 3309 1950 420 32 17 29 35545 242.1 Group 1425PPM (clopidogrel) + 25PPM (QS) + 100PPM benzoic acid ***** 32 360 3600 2260 2000 1800 166 750 10968 265.7 ##

d.p.i. = days after experimental infection. ***Deaths in these birds were related to infections and causes other than coccidia.

*****The group raised in the cage, the same treatment as group 2

Table (1): Testing the anti-coccidial effect of new compounds in young chickens

(dose 25-30000 mixed Eimeria strain oocysts) (see 2000.5) test group Average number of Eimeria oocysts/gram excrement/group during feeding of experimental product (number per thousand oocysts) Average body weight/final chicks/g (22 per group) 6d.pi 7d.pi 8d.pi 9d.pi 10d.pi 11d.pi 12d.pi 13d.pi total number of oocysts mortality rate% in conclusion Group 3 Clopidogrel (100PPM)+QS (10ppm) 17 1100 480 1200 1100 200 80 200 8697 167.9 13.64 $$ Group 7 Clopidogrel (100PPM)+QS (25ppm) 154 1600 1320 1100 800 203 30 120 5327 170.7 13.64 good Group 9 (Standard) Clopidogrel (125ppm) 2 900 1300 980 1500 200 200 130 5212 192.2 9.5 standard Group 10 Infections Untreated 102 1200 10008 1500 280 275 300 220 13885 1670 31.82 control

d.p.i. = days after experimental infection. ***Deaths in these birds were related to infections and causes other than coccidia.

Antifungal effect

The following compositions were tested.

Toxy-nil is produced by Nutir-AD company, Belgium Mycobond is a mycotoxin binder. Both are used here as controls.

[1] 1 g 50 clopidogrel + 36 colistin + 14 benzoic acid (1004)....(1) Not tested as an anticoccidiostat

[2] 1 gram of 80 clopidogrel + 55 colistin + 15 benzoic acid (504)....(2) not tested on coccidia

[3] 1 gram of 120 clopidogrel+90 colistin+40 benzoic acid (904)....(3) better anticoccidiostat

[4] 1 gram of 50 clopidogrel+40 colistin+40 benzoic acid (204)....(4) better anticoccidiostat

[5] 1 gram of 60 clopidogrel+45 colistin+35 benzoic acid (304)....(5) Not tested on coccidia

[6] 1 gram of 100 clopidogrel+71 colistin+29 benzoic acid (704)....(6) Not tested on coccidia

dilution sky name ^{10-1 10-2 10-3 1st} day Toxyuil dry 64 9 1 ^2nd day 48 7 2 ^3rd day 45 5 0 ^5th day 51 5 1 ^1st day Mycobond 100 twenty four 2 ^2nd day 62 10 1 ^3rd day 66 28 5 ^5th day 25 7 1 ^1st day 1 g 100 Clopidogrel + 71 Colistin + 29 Benzoic Acid (704) 113 18 4 ^2nd day 76 6 2 ^3rd day 65 17 3 ^5th day 50 30 3 ^1st day 1 g 110 Clopidogrel + 76 Colistin + 14 Benzoic Acid (804) 1{H} 25 1 ^2nd day 43 7 1 ^3rd day 75 13 4 ^5th day 70 32 4 ^1st day 1 g 120 Clopidogrel + 90 Colistin + 40 Benzoic Acid (904) 100 15 5 ^2nd day 73 9 1 ^3rd day 65 15 1 ^5th day 46 13 2 ^1st day 1 g 50 Clopidogrel + 36 Colistin + 14 Benzoic Acid (1004) 98 20 3 ^2nd day 52 19 1 ^3rd day 50 13 2 ^5th day 33 17 1 ^1st day 1 g 30 clopidogrel + 5 colistin + 10 benzoic acid (1404) 100 20 4 ^2nd day 96 19 2 ^3rd day 70 28 7 ^5th day 90 73 10 sky name ^{10-1 10-2 10-3 1st} day Toxynil dry 100 10 1 ^2nd day 60 6 1 ^3rd day 40 20 2 ^5th day 38 5 0 ^1st day Mycobond ^2nd day ^3rd day ^5th day ^1st day 1 g 50 Clopidogrel + 33.5 Colistin + (104) 130 16 2 ^2nd day 115 18 2 ^3rd day 90 33 5 ^5th day 80 12 1 ^1st day 1 g 500 Clopidogrel + 40 Colistin + 40 Benzoic Acid (204) (4) 140 11 2 ^2nd day 103 18 3 ^3rd day 80 27 7 ^5th day 60 6 0 ^1st day 1 g 60 clopidogrel + 45 colistin + 35 benzoic acid (304) (5) 125 11 1 ^2nd day 107 12 1 ^3rd day 90 28 5 ^5th day 65 10 4 ^1st day 1 g 70 clopidogrel + 52 colistin + 48 benzoic acid (404) 119 11 2 ^2nd day 75 10 2 ^3rd day 88 38 10 ^5th day 50 6 2 ^1st day 1 g 80 clopidogrel + 55 colistin + 15 benzoic acid (504) (2) 100 10 1 ^2nd day 60 6 1 ^3rd day 40 20 2 ^5th day 47 2 0 sky name ^{10-1 10-2 10-3 1st} day Toxynil dry 81 33 ^2nd day 76 10 ^3rd day 41 8 ^5th day ^1st day Mycobond ^2nd day ^3rd day ^5th day ^1st day 1 g 90 clopidogrel + 61 colistin + 9 benzoic acid (604) 120 77 ^2nd day 62 35 ^3rd day 70 25 ^5th day ^1st day 1 g 40 clopidogrel + 31 colistin + 29 benzoic acid (1104) 100 45 ^2nd day 48 37 ^3rd day 70 31 ^5th day ^1st day 1 g 30 clopidogrel + 27 colistin + 43 benzoic acid (1204) 200 162 ^2nd day 78 20 ^3rd day 60 20 ^5th day ^1st day 1 g 20 Clopidogrel + 22 Colistin + 58 Benzoic Acid (1304) 107 77 ^2nd day 100 36 ^3rd day 80 45 ^5th day ^1st day 1 g 30 clopidogrel + 23 colistin + 17 benzoic acid (1504) 170 118 ^2nd day 120 64 ^3rd day 95 64 ^5th day

Claims (4)

1. A composition comprising 3,5-dichloro-2,6 dimethyl-4-pyridinol or its analogue 2-methyl-3,5 dinitrobenzamide and at least one selected Mixture of components derived from colistin, benzoic acid or its derivatives, salicylic acid or its derivatives, 4-amino-N-2-quinoxalinylbenzenesulfonamide and tricyclo[3.3. 1.1] Dec-1-amine. 2. A composition for use as a medicine, which contains 3,5-dichloro-2,6-dimethyl-4-pyridinol or its analogue 2-methyl-3,5-dinitrobenzamide and Mixture of at least one component selected from the group consisting of colistin, benzoic acid or derivatives thereof, salicylic acid or derivatives thereof, 4-amino-N-2-quinoxalinylbenzenesulfonamide and tris Cyclo[3.3.1.1]dec-1-amine, in which 3,5-dichloro-2,6-dimethyl-4-pyridinol or its analog 2-methyl-3,5-dinitrobenzyl The amide and said components are present in a therapeutically effective amount, optionally in admixture with a therapeutically acceptable carrier. 3. A method for synergizing 3,5-dichloro-2,6 dimethyl-4-pyridylphenol or its analogue 2-methyl-3,5 dinitrobenzamide, comprising using at least A component selected from the group consisting of colistin, benzoic acid or derivatives thereof, salicylic acid or Derivatives, 4-amino-N-2-quinoxalinylbenzenesulfonamide and tricyclo[3.3.1.1]dec-1-amine. 4. Use of the composition of claim 1 in the manufacture of a medicament for the treatment of diseases caused by fungal infections in animals.