AU2002337534A1 - Composition and potentiating method - Google Patents

Description

WO2004/024151 PCT/SE2002/001640 1 COMPOSITION AND POTENTIATING METHOD The present invention relates to a novel composi tion, a composition for use as a medicament, especially for treating coccidiosis, and use of a composition for the manufacture of a drug for treating deseases cused by 5 fungi in animals. Coccidiosis is a disease of the intestinal lining of poultry, for example chickens, caused by protozoan cocci dial parasites of the genus Eimeria, such as Eimeria te nella, Eimeria necatrix, Eimeria acervulina, Eimeria bru 10 netti, Eimeria maxima, Eimeria mitis, Eimeria mivati, Ei meria praecox and Eimeria hagani. Species belonging to said genus cause clinical disease in chickens and immuni ty to any one species does not protect birds against in fection with other species. Coccidiosis is seen most com 15 monly in chickens between 3 and 6 weeks of age. Coccidio sis is caused by protozoa of the family Eimeriidae. Va rious sites in the intestine are infected. The infectious process is rapid (4-7 days) and is characterised by para site replication in host cells with extensive damage to 20 the intestinal mucosa. Clinical disease occurs only after ingestion of relatively large numbers of sporulated oocysts by susceptible birds. Both clinically infected and recovered birds shed oocysts in their droppings, which contaminate feed, dust, water, litter and soil. 25 Anticoccidial drugs are available on the market for prevention and treatment of coccidiosis in especially chickens and turkeys. Anticoccidials are generally given to poultry in the feed to prevent acute disease. Water medication is generally preferred over feed medication 30 for treatment. Antibiotics are sometimes used to improve rate of recovery and prevent secondary infections. Clopidol, i.e. 3,5-dichloro-2,6-dimethyl-4-pyridi nol, and its analogue Dinitolmide, i.e. 2-methyl-3,5-di nitrobenzamide are today the most frequently used anti 35 coccidial drugs. There is a need in the art to provide a WO2004/024151 PCT/SE2002/001640 2 drug having enhanced effect in the treatment of coccidio sis. This need is met according to the invention by pro vision of a composition comprising besides Clopidol and its analogue at least one potentiating component selected 5 from the group consisting of Colistin, benzoic acid or derivatives thereof, salicylic acid or derivatives there of, 4-amino-N-2-quinoxalinylbenzenesulfonamide and tri cyclo(3.3.1.1.)decan-l-amine. Said components are named potentiating agents. The mechanism, by which the enhanced 10 activity is obtained, is not for the present understood. Tests have shown, that enhanced activity is obtained, and reference is made to test results presented in this spe cification. Further, according to the invention, it has quiet unexpectedly been found, that an antifungal effect 15 is achieved when the composition is used as a drug for treating for example poultry. SUMMARY OF THE INVENTION In a first aspect the invention relates to a compo 20 sition as claimed in claim 1. In a second aspect the invention relates to a compo sition for use as a medicament as claimed in claim 2. In a third aspect the invention relates to a poten tiating method as claimed in claim 3. 25 In a fourth aspect the invention relates to use of a composition of the kind defined above for the manufacture of a drug for treating deseases caused by fungi in ani mals. According to this aspect, the animals comprise for example pultry. 30 Below is a brief description of Clopidol and its analogue and the potentiating agents contained in the composition.

WO 2004/024151 PCT/SE2002/001640 3 Benzoic Acid Benzoic acid has the formula COOH Benzoic acid is used for preservation and for manufacture of soap, perfume and pigments. It is present in almost 10 all berries in amounts of 0,05%, where it functions as a natural preservative. Yoghurt may contain up to 30 mg/kg. It is, according to the invention, possible to use the following derivatives of benzoic acid instead of benzoic acid. 15 Benzoic acid derivatives 3-acetamido-5-aminobenzoic acid 2-acetamido-2-aminobenzoic acid 4-acetamidobenzoic acid 4-acetamidobenzoic acid methyl ester 20 4-acetamido-N-butyl benzoic acid 2-acetamido-5-chlorobenzoic acid methyl ester 4-acetamido-5-chloro-2hydroxy benzoic acid methyl ester 4-acetamido-2-hydroxy benzoic acid 4-acetamido-2-methoxy benzoic acid 25 2-acetamido-4-nitrobenzoic acid 4-acetoxybenzoic acid 2-acetylbenzoic acid 5-acetyl-2-hydroxy benzoic acid 4-allylbenzoic acid ethyl ester 30 3-aminobenzoic acid 3-amino-5-(aminosulfonyl)-4-phenoxy benzoic acid 4-aminobenzoic acid butyl ester 4-aminobenzoic acid ethyl ester 4-amino-2-butoxy benzoic acid 35 2-amino-3-chloro benzoic acid 4-amino-3,5-dichloro benzoic acid 2-amino-4,5-difluoro benzoic acid WO 2004/024151 PCT/SE2002/001640 4 2-amino-4,5-dimethoxy benzoic acid 2-amino-5-fluoro benzoic acid 2-amino-3-hydroxy benzoic acid 3-amino-4-hydroxy benzoic acid 5 2-amino-6-methoxy benzoic acid 4-amino-3-methyl benzoic acid 4-(aminomethyl)-benzoic acid 4-amino-3-nitro benzoic acid 2-amino-4-sulfo benzoic acid 10 5-aminosulfonyl-2,3-dimethoxy benzoic acid 4-amylbenzoic acid 2-anilinobenzoic acid Benzoic acid 2 methylbutyl ester 4-benzoyl benzoic acid 15 5-benzyl-2-mercaptobenzoic acid 2-(benzyloxy)-benzoic acid 2,2'-dibenzoic acid 4,4'-dibenzoic acid 4-bromobenzoic acid 20 3-bromo-2-6-dimethoxy benzoic acid 4-butoxybenzoic acid 4-tert-butylbenzoic acid 4-carbmethoxy-3,5-dimethoxy benzoic acid 4-chloro-2-nitrobenzoic acid 25 4-cyanobenzoic acid-4-propylphenyl ester 3-(1-cyanoethyl)-benzoic acid 3,5-diaminobenzoic acid 4-(diamylamino)-benzoic acid 3,5,di-tert-butylbenzoic acid 30 2,6-difluorobenzoic acid 2,5-dihydroxy benzoic acid 2,6-dimethoxy benzoic acid 3,5-dimethoxy-4-hydroxybenzoic acid 2,4-dimethylbenzoic acid 35 3, 5-dimethyl-4-hydroxybenzoic acid 4-ethoxybenzoic acid 4-formylbenzoic acid WO2004/024151 PCT/SE2002/001640 5 4-guanidinobenzoic acid 4-heptylbenzoic acid 4-hydrazinobenzoic acid 4-hydroxybenzoic acid 5 4-isothiocyanato benzoic acid 4-mercapto benzoic acid 4-phenyl benzoic acid 4-(phenylthio)-benzoic acid 4-propoxy benzoic acid 10 selenino benzoic acid 4-sulfo benzoic acid 4-sulfonamido benzoic acid 3,4-5-6-tetrahydro benzoic acid thiobenzoic acid 15 trimethoxy benzoic acid Salicylic acid This has the formula COOH OH 20 and is a weak acid used for relief of pain, disinfection and as febrifuge. It inhibits the enzyme cyclooxygenase that stimulates the production of prostaglandines, which 25 have pain-, fever- and inflammationpromoting effects. In some skin diseases salicylic acid is applied to the skin as a keratin-dissolving drug. Clopidol Clopidol (3,5-dichloro-2,6-dimethyl-4-pyridinol) is known 30 as an agent in the prevention of coccidiosis in chickens and turkeys. It is administered orally by addition to the feed. H C N CH a c(t 35

OH

WO2004/024151 PCT/SE2002/001640 6 Dinitolmide Dinitolmide or 2-methyl-3,5-dinitrobenzamide has the formula and is used in veterinary medicine as a coccidiostat. Amantadine 10 Amantadine (tricyclo[3.3.1.1]decan-l-amine) is used as an antiparkinsonian although the mode of action is not completely known. It effects the incapability of moving, the stiffness and the shakings. Amantadine is also known to have some antiviral effect on influenza virus type A, 15 as it inhibits the propagation of virus in the attacked cells.

NH

2 20 Colistin Colistin is a cyclopolypeptide antibiotic produced by Bacillus colistinus isolated from Japanese soil. It is 25 used as an antibacterial agent for both humans and ani mals. Sulfaquinoxaline (QS) Sulfaquinoxaline or 4-amino-N-2-quinoxalinylbenzene sulfonamide has the formula 30 2NH, v Nf 0 0 35 and is used as a coccidiostat. Other sulfonamides can be used WO2004/024151 PCT/SE2002/001640 7 According to a preferred embodiment Roxarsone is used in the composition (not as a potentiating agent). Roxarsone or 4-hydroxy-3-nitrophenylarsonic acid has the following formula 5 0 II 2N A OHx OTH HOa:, OH It is used as an antibacterial and in veterinary medicine 10 to control enteric infections and improve growth and feed efficiency. Examples of concentrations and carriers. It is the treating veterinary's choice to decide the concentrations suitable for treatment. However, it is re 15 commended that the concentration of Clopidol and that of its analogue according to the invention should be at least 20 ppm and at most 125 ppm. The concentration of benzoic acid or its derivatives or salicylic acid or de rivatives thereof should range from 9-110 ppm, the con 20 centration of Sulfaquinoxaline should range from 9-55 ppm, the concentration of Roxarsone should range from 5 15 ppm, the concentration of Amantadine should range from 4-27 ppm and the concentration of Colistin should range from 4-100 ppm. 25 The concentrations of the compositions are based on the feed or drinking water preparations ad lib, i.e. for free feed or drinking water consumption during a normal practical fattening or rearing period. All feed formula tions conventional in the poultry industry are suitable 30 as carriers for the compositions according to the inven tion. Examples are feedstuffs based on some types of ce real grains which contain vitamin concentrates, mineral concentrates or other active substances and feed additi ves in any concentration. Both conventional dry mealy or 35 pelletised feedstuffs but also liquid feed suspensions including feedstuffs such as distillers' residues and WO2004/024151 PCT/SE2002/001640 8 milk by-products can be used in the case of the composi tions according to the invention. To prepare the poultry feed a concentrated premix is usually first made which contains Clopidol or its analo 5 gue and at least one of the components of the composition in high concentration, for example 0.2-75% by weight. For this purpose the components are either dispersed or mixed in inert carrier substances, such as vermiculite, diato maceous earth, attapulgite, calcium carbonate, etc., to 10 gether with physiologically harmless carriers, such as propylene glycols, polyethylene glycols, inert oils, such as vegetable oils, highly refined mineral oils, ethanol, water, or aqueous alcohols. Organic carrier material, such as wheat bran, shredded maize, soybean flour, lucer 15 ne meal, rice husks or ground maize cobs and any other organic carrier substances from vegetable products are likewise suitable for this purpose. As mentioned above, the compositions according to the invention may further also be administered to poultry 20 together with the drinking water. Their inclusion in the drinking water is achieved by adding a form of the compo sition concerned, which is soluble in water or can be suspended in water to the drinking water in a suitable quantity. Such preparations are in general produced by 25 selecting a water-soluble form of the composition. Water insoluble forms, for example suspensions, may also be used. In such cases physiologically harmless auxiliary agents which keep the composition according to the inven tion in suspension in water over a prolonged period are 30 used. Auxiliary agents, which are suitable for this pur pose, are swelling agents, such as alginates, gelatine, carboxymethylcellulose or polyvinylpyrrolidone. Surfac tant compounds, such as for example naphthalenesulfona tes, alkylbenzenesulfonates, or polyoxyethylene sorbitan 35 esters may be used for bringing the compositions into suspensions. Normally, a concentrated suspension or a dry formulation of the composition according to the invention WO2004/024151 PCT/SE2002/001640 9 and the suspension agents is produced in certain mixing ratios and is then diluted with the drinking water to the required application concentration or the premixes are mixed in suitable concentrations with the feedstuffs nor 5 mal in practice. The drinking water or feed so medicated is then fed to the poultry either initially ad lib or for a certain period. Although the invention has been described above with particular reference to the treatment of poultry against 10 coccidia infections, treatment of other domestic and use ful animals, for example other birds, rabbits, pigs and ruminants is also within the scope of the invention. Biological Examples Anticoccidiocidal activity 15 Materials and Methods Chickens One day old Habbared X breed chickens were used in the tests. In the 7 different tests the chickens were al located into 10 equal groups (20-30 birds in each group), 20 one group serving as a control group and one as a positi ve control group. The control group was infected but re ceived no treatment, the positive control group was also infected and received a known, reference anti-coccidial drug (Clopidol 125 ppm or Salinomycin 60 ppm). 25 The chickens were reared in 1*1 m pens (each in its group) on medicated feed from the first day of their li ves to day 15. Each group in each test was given a diffe rent mixture of Clopidol together with at least one com ponent selected from the group consisting of Colistin, 30 benzoic acid or derivatives thereof, salicylic acid or derivatives thereof, Sulfaquinoxaline, and Amantadine. On the 16 th day the chickens were infected orally with a mixture of 6000-8000 mature sporulated field col lected oocysts, containing different Eimeria strains; 35 Eimeria acervulina, Eimeria maxima, Eimeria necatrix, Eimeria tenella and Eimeria brunetti.

WO2004/024151 PCT/SE2002/001640 10 Fresh faecal droppings were collected daily from the 5 th day post experimental infection until the l0 th day post infection. The oocysts were counted and the mean number of oocysts per gram faeces for each group was cal 5 culated using the Mc-Master technique according to Souls by (1984). The number of dead birds per day was also counted and the cause of death was recorded after a post mortem examination. Medication groups: 10 Each composition to be tested was mixed in a suf ficient amount of feed for each group and was used for daily feeding from the day zero of the test. Fresh water was supplied ad-libetum. Evaluation of the efficacy 15 The efficacy of the prophylactic effect was evalua ted by comparing the total number of shed oocysts in the medicated groups with the number in the non-medicated group during the whole period of the experiment. The weight of the birds as well as the amount of consumed 20 feed were determined at the end of the experiment. From this the mean body weight and mean amount of consumed feed per bird were calculated. The results are shown in the tables below. As for the treatment-column, the composition of the 25 medicament is given in ppm. Appropriate abbreviations are used.

WO 2004/024151 PCT/SE2002/001640 11 0 Q) 0 0 0v 0 0 -0 0 0 -r-- 00 -Hd o 0 L0 0H 0 , "- 0 0 00 , . 0 0 0 o4 o 0 0 0 0 00 0o : C) o V) -. m - C-4 0" 0 00 0 CD 0 0 C 0 000- 0 0 00 • .o o 0, 0 V2m C C) C'4 CD C C) C) C) lr 00 4-4 -0 CD CD taC) 0 0n 00 0 0D 0 0 0 00 CD) 0 C >1 + + + ri0 .- .- .4 m~ k 0 000 0o 0U W)~ 00 ' Cd 0 ; 0 '30 a) 0r) 00 0 0 0

C,

WO 2004/024151 PCT/SE2002/001640 12 o 0 00 0 00 C 0 0~ CCC 0 C)l Cl C) C> C\ 0 CD CD C) C ()( CH 0 0 I > 0 0 C, ' z 0 t- - 00 00 >1) 0U - 0 C) 0 0~ ~ ~ on 0DC ) C 0 0n 0C o -0 00 0 01 00 C) CD 0 C> 0 \0 0 00 C a) li _ _ - C) CDC 04 ~ g 0 0Z Z 0 0> C Z 'a M \g 00 0~~~ C)-- m - 0 44 Q ~ 'D C) C) Q 0 CDO (UH~- 00 0 1" 0 0 0M 0u-~ - 0 0 0 0D 0D 004 :C C) 0 0D 0 CD0 0O 00C>0 0 0n 0 0 Q0 U w 0 0 C, 0 0 0D 0 0 0 o 0 r. 00 0 0 + + U C-4, CAf >4ciC> 0 + +- 0 040 + ~~ 0 0 0 0 -t: ., oC 2 H H-- WO 2004/024151 PCT/SE2002/001640 13 00 0 0~ .0 )4-1 4J Q ci)0 wJ U)

.H

Q -0 N- 0 00 kd) O\ O 00 00 00 N-W n - - l - q 00 - C 00 00 00 00 r -H 0 'd CD C 0 C 0 a ;j ~ Q t4- r. -Hc5) 0 0 0 0 CD C 0 I-4 C ) 0 0 l C0 0 04 0~ 0. l - CD k) C 00 4-) 0000 0 00 C 4-4 N- 0o 00) 0 en0 00 4) 0 0 0 0 0 0 0 0 0 0) ______ + P, C>4 0) + o P- 0 H~ 0 o 0 a)) '3 U)C W)00 0 0N o Cd -__e) WO 2004/024151 PCT/SE2002/001640 14 0 a) 0 0 UC C. C a) o ) , cal C>o o 00 '-0 t- CD 0 (o r C ) 0 00 0) 0C 0 0 0 0~C 0~ 0 (Dt-i 0 0 0 'IT C) V '0W )0 C\- - ) r- C14i 0 ci u C)) 00C 0 ~ \0 0 0D 00 0 -l m~ V4 ci i (N -q \0 s 0 0> 0> 0 C. 0C) Lk 0 R C 0 C>C> CD C> 0 co 0i = 0 0 0 0 0) bl) C) \ -0 0z C10 V0 W J a) -6 . Ni - c Ni Q a.Z 044 0 0 0 00 0C> 0 0 0 10 00 '0 00 ifl ' 0 C, V 0 0 u 0) 0 0 C'40 0 r o 0 + 0) 0N~' +~ + +-L - + Z- - 0- P., 0* ) 00 0. p 13 -0 0 oo '0 60 0 Q uo -- U t 0 r C.) ' U- 0n + -C, 0 +o 0 + O (5C>61( 5 ( WO 2004/024151 PCT/SE2002/001640 15 0 00 N-CH 0 u 0 -H 04V2 00 0q U4 0 U 0 4. 00 00 0 rJ . t-:' M r QQ)~r~~ P4 0 0-0 C) 1 4- gi o C) C 04 +~0= C 00 0o C> 0 0 q0 WO 2004/024151 PCT/SE2002/001640 16 00 0 C 04 0 0 u 4) to ~L 00 0q 000 oo (N -H EaC 00 -H E-~.~j ~ ~00 C0 \0 00 Cr4 - q 0= 00 - ~ ~ - \0 eN m 00 4 oU N 0 0n 01 L4-4 C 4 ~ CD C 0 CD z 4-30 0 0 0 04004 4-4 4 o4 o 0 0 4 >C1 o ~k ± D 04 0 040 0. 0+ t .0 F-i H0 WO 2004/024151 PCT/SE2002/001640 .1v 0 0 0 S 0 0 0 ~o Ca

-H

.00 00 0 "O b4e . o oO o \o o0 ec' 0 " 0 1 0 , , " r Ol o .lr r. 1 cq C4 ol C14 - 0 .H 'n .o Ln 0 44 u 00 I 0' N) o '0 040 o . o*R 0 -o 0 t44 ( -l -n Ln m co o 0 EnE -0 0 0 0 0 ~ Cd C) 0J s- C14 0 OOv) ON C% 0. o oo C C o Ca 00 0 n% C> 0C .0Z 0~ co 0 4 4- 0doc N ___ 0 CN tn ~ _____ ____- WO 2004/024151 PCTISE2002/001640 18 00 Goq 00 0 en 0 OG) o 00 -. 0 q 0 w l44 0 a)0 0 0 N1 U 00 0 u 0 0 C 44 0 - 00 0 6 44 > Q) 0 00 44 u . -~ %- (= o c 0 00 on N 0 00 0 4 0900 1 -1 C> C> C *M 00 0)0 090 -H I 0 0 . P P-4 E-4__ w _ C__ ,_ 4 _ - WO 2004/024151 PCT/SE2002/001640 19 Antifungal effect The following compositions were tested. Toxy-nil is produced by Nutri-AD Company, Belgium 5 Mycobond is a mycotoxin binding agent. Both are used herein as controls. [1] I gram of 50 clopidol + 36colistin + 14 benz (1004)....(1) not testedas anticoccidial. [2] I gram of 80 clopidol + 5 5 colistin + 15 benz ( 5 04).(2).not tested for coccidia. [3) I gram of 120 clopidol + 90 colistin + 40 benz (904).............(3) has good anticoccidial 14] I gram of 50 dopidol + 40 colisti + 40 benz (204) ..... (4) has good naticoccidial [5] I gram of 60 clopidol + 45colistin + 35 benz (304)............(5) not tested for coccidia. [6] I gram of 100 clopidol + 71 colistin + 29 benz (704).......(6)not tested for coccidia. dilution DAY NAME 11" 10 i 1 DAY 64 9 1 2 " DAY ToxyuiJ dry 48 7 2 3y DAY .45 5 0 5 DAY _51 5 1 1I DAY Mycobond 100 24 2 , DiAY QZ 10 1 3 DAY 66 28 5 5' r DAY 25 7 1 1" DAY T gram af 100 clopidol + 71 113 iA 4 2 "d DAY colisin - 29 beniz (704) 76 6 2 3 DAY 65 17 3 5" DAY 50 30 3 1 DAY Igram of 110 clupidul 4 76 IHK 25 1 2i 1 DAY colimin 14 hey (m84) 43 7 1 3' DAY 75 13 4 V1 T)AY 741 32 4 1' DAY I gram of 120 elnpidlol t+ 90 10 15 5 2 a " DAY culitir + 40 benz (9504) 73 9 1 "' DAY 65 15 I DAY 46 13 2 I" DAY I gTram of50 clopidol+ 98 20 3 2" DAY 36cojisiiu I 14 bnaz (104) 52 19 I 3"DAY50 13 2

S

4 h DAY 33 17 I 1V DAY I gram of 30 dopidol+ 5 100 20 4 2 " DAY colisfin + 10 benz (14U4) 96 19 2 3d DAY 70 28 7 5' DAY 190 73 10 WO 2004/024151 PCT/SE2002/001640 20 DAY NAME 10-1 &o 16r, )D AY 100 10 1 2 n' DAY Toxyni] dry i60 6 1 3r4 DjAY 40 20 2 S PAY _____ _ 38 5 0 1 " DAY __ ZF _AY _ __ 3 r4 DAY mycobond _____ S DAY _________ _ __ jst DAY I grain of S0 copEdol +-33-5 13 16 z 2 "d DAY coliscin + (104) 115 1s z 3r' D)AY 90 33 5 5SLDAY _____0 12 1 1.t DAY I gra r50 cvpidol+40 140 It 2 2?d DAY eOLstnt +-40 b eci (204) 103 189 3 3r' DAY A4 so 27 7 5DAY __ __ __ _ 6_ __ 1,L MY I Dranm oft60 ciopdal + 125 i1 [ 1 ___ ZrdDAY 4icdistin + 35 benz (304) 107 12 1 ____ 3" DAY 911 28 1' 5 _ r5L'DAY (5) 65 10 14 " PAY I grnrn of 70 clcipidol 45z 139 11 2 in DAY culisLin t48 beca (404) 75 to 1 2 3 DAY 168 38 ilo Vh DAY ___________50 6 j2 Ir DAY-- I g rasiof80 clop!id&L+ 55 100 10on t DAY cotisdin 4 15 benz (504) 60 16 ___ 3" DAY .40 120 12 5: DAY _____________ 0 WO 2004/024151 PCT/SE2002/001640 21 DAY NAME IV 10f I4 1 t DAY 8I 33 2 DAY Texynil dry 76 10 3 DAY 41 8 b DAY 1" DAY 2 d DAY Mycobond 3r DAY 5 DAY 1I DAY I gram of 90 clopidol + 61 120 77 2nd DAY colistin + 9 benz (604) 62 35 3 r DAY 70 25 5' DAY I DAY I gram of 40 clopidol + 31 100 45 2" DAY colistin + 29 benz (1104) 48 37 3Y DAY 70 31 5* DAY 1" DAY I gram of 30 elopidol + 200 162 2'" DAY 27colistin + 43 benz (1204) 78 20 3 DAY 60 20 5" DAY l " DAY I gram of 20 clopidot + 22 107 77 2"d DAY colistin + 58 benz (1304) 100 36 3 'd DAY 80 45 5' DAY 1 DAY I gram of 3 elopidol + 23 170 118 2 Rd DAY colistin + 17 benz (1504) 120 64 3 d DAY 95 64 5

"

DAY

Claims (4)

1. A composition comprising 3,5-dichloro-2,6 5 dimethyl-4-pyridinol or its analogue 2-methyl-3,5 dinitrobenzamide in a mixture with at least one component selected from the group consisting of Colistin, benzoic acid or derivatives thereof, salicylic acid or derivati ves thereof, 4-amino-N-2-quinoxalinylbenzenesulfonamide 10 and tricyclo[3.3.1.1]decan-l-amine.

2. A composition for use as a medicament comprising 3,5-dichloro-2,6-dimethyl-4-pyridinol or its analogue 2 methyl-3,5-dinitrobenzamide in a mixture with at least one component selected from the group consisting of 15 Colistin, benzoic acid or derivatives thereof, salicylic acid or derivatives thereof, 4-amino-N-2-quinoxalinyl benzenesulfonamide and tricyclo[3.3.1.1]decan-l-amine, 3,5-dichloro-2,6-dimethyl-4-pyridinol or its analogue 2 methyl-3,5-dinitrobenzamide and said components being 20 present in therapeutically effective amounts and optio nally in admixture with therapeutically acceptable car riers.

3. Method for potentiating 3,5-dichloro-2,6 dimethyl-4-pyridinol or its analogue 2-methyl-3,5 25 dinitrobenzamide comprising treating 3,5-dichloro-2,6 dimethyl-4-pyridinol or its analogue with 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-quinoxalinylbenzenesul 30 fonamide and tricyclo[3.3.1.1]decan-l-amine.

4. Use of a composition according to claim 1 for the manufacture of a drug for treating deseases caused by fungi in animals.