POTENTIATION OF ANTHELMINTICS

Abstract: An anthelmintic preparation comprising a benzimidazole carbamate anthelmintic compound and a microtubule inhibitor being a substituted benzimidazole compound. A method is also disclosed for potentiating benzimidazole carbamate anthelmintic compounds in mammalian animals comprising administering the anthelmintic compound to the animal in association with a microtubule inhibitor being a substituted benzimidazole compound.

Description: The present invention relates to a method of potentiating anthelmintic compounds and to anthelmintic preparations in which the anthelmintic properties of known anthelmintic cou pounds are potentiated. It is known that conventional orally administered anthelmintics rely upon absorption from the alimentary canal of the animal followed by a sustained concentration of anthelmintically active material in the bloodstream of the animal. In the case of the benzimidazole group of anthelmintic compounds the original member of this group, thiabendazole (TBZ) , is metabolised and completely excreted within 36 hours of dosing. Later members of this group have contained substituents in the metabolically labile 5(6) position of the benzimidazole molecule which has stantially slowed the rate of metabolism of the .pounds. Thus the plasma concentration of active material is prolonged with a concomitant elevation in efficacy. ■ The development of parasite resistance to a wide range of known anthelmintic compounds has led to research into new anthelmintic compounds, into alternative drenching strategies and into methods and compounds which will potentiate the activity of existing anthelmintic compounds. The latter strategy offers advantages as the testing required for regulatory approval can often be reduced for the potentiation of a known active compound as compared with that required for a totally new active compound. The present inventors have discovered that when conventional anthelmintic compounds are administered to animals in association with a microtubule inhibitor it results in an increase in the plasma level of the anthelmintic compounds and a corresponding increase in efficiency of the anthelmintic compound than when administered in the absence of the microtubule inhibitor. It is known that in all eukaryotic cells, tubulin (a dimer of . and A tubulin) undergoes a reversible polymerisation to form microtubules which are involved in the structure and function of cells and in particular are involved in such functions as cell division, determination of cell shape and the excretion or absorption of chemicals. Microtubule inhibitors act to increase the rate and extent of depolymerisation of the microtubules to form the tubulin proteins and/or to decrease the rate and extent of polymerisation of the tubulin proteins to form microtubules. It has previously been proposed to potentiate the anthelmintic of certain benzimidazole compounds (see Australian Patent Specification 10311/83, U.S. Patent Specification 4,173,632 and European Patent Specification 0059074) . None of these prior art publications discloses the idea that the action of the benzimidazole carbamates, or any other benzimidazole compound, could be potentiated by administration with a microtubule inhibitor. As the potentiating compounds of the prior art fall into clearly distinguishable chemical categories from the potentiating compounds _ of the present invention persons skilled in the art would not have been led to the present invention by the art herein cited. The present invention consists in an anthelmintic preparation containing as active components at least one anthelmintic benzimidazole carbamate or a compound which may be converted in vivo to such a benzimidazole carbamate and at least one microtubule inhibitor being a benzimidazole compound of the formula wherein 0 0 s 0 11 H U u R, is a -NHC-OR,., -NHC-R-., -NHC-R 5 or -NHC-SR-. radical and R is an alkyl group to a maximum size of C g H,_, R- 3 and 4 are each selected from the group comprising H, OH, NH 2 , SH, F, Br, Cl, I, CH 3 , CH 2 CH 3 , NHCH 3 , N(CH 3 ) 2 , SCH 3 , NHCOCH 3 , * 5 NHCOCH 2 Rg, NHCOOCH 3 , NHCOOCI^Rg, CgHg, CF 3 , COOH, COOCH 3 and COOCH 2 R 6 , is the same as R3- and R4-, X is NH, S, 0, CO, or CH 2 , and 10 R 7 is an aliphatic or aromatic radical, or a compound which may be converted in vivo to any one of the abovementioned benzimidazole microtubule inhibitors. The present invention further consists in a method for 15 potentiating in a mammalian animal the action of a benzimidazole carbamate anthelmintic compound or a compound which may be converted in vivo to such a compound, comprising administering the anthelmintic compound to the animal in association with at least one microtubule inhibitor being" a 20 benzimidazole compound of the formula 25 wherein R, R 2 , R 3 and R. are as hereinabove defined. The method and preparation according to this invention are advantageous for the following reasons: 1. at a given dose of an anthelmintic, the activities of 30 the potentiator will increase the toxicity of the anthelmintic to nematodes whether sensitive to or resistant to the anthelmintic; 2. the potentiated combination results in an improved efficacy against species which are only marginally 35 susceptible to present dosages (including Trematodes and OMPI Cestodes) , and 3. against parasites already totally susceptible to the anthelmintic, a lower dose of the anthelmintic can be used with a potentiator to achieve equipotent activity with a resultant cost saving. The anthelmintic compounds most preferably used in the present invention are the anthelmintically active benzimidazole carbamates and compounds which may be converted in vivo to such benzimidazole carbamates. Included in the latter category are the phenylguanidines, thioallophanates and 1-substituted benzimidazole carbamates. The most preferred members of the foregoing group are oxfendazole (Figure 4 where R- j _ = NHC0 2 CH 3 R 3 ,R 4 , R g , R 7 , '8' R 9 and R 1Q = H and X = SO) , fenbendazole (Figure 4 where R χ = HC0 2 CH 3 R 3' R 4' w 8' R. and R 10 = H and X = S) , albendazole (Figure 2 where R, = HCO2CH.-, R 2 - R 5 X where R-. = CH 2 CH 2 CH 3 X = S, and R 3 ,R 4 =H) and the phenlyguanidine, febantel (Figure 1) . . Figure 1 The preferred microtubule inhibitors for use in the present invention are drawn from the group of benzimidazole compounds having the structural formula shown in Figure 2. Figure ,2 Where R-^ is optimally a carbamate of structure -NHC-OR 5 , where R 5 is an alkyl group to a maximum size of C 0 oH1_ _/ including all possible branched, straight chain, cyclic, saturated and unsaturated combinations within this maximum size. R-, may also be an amide of general structure 0 u NHC -R_. or a thiocarbamate of general structures S 0 -NHC-OR 5 or NHC-SR 5 . R 2 can be represented as in Figure 3, where X is either NH, S, 0, CO or CH 2 and R-. is as previously defined. R 5 -X- Figure 3 R 2 can be also represented as in Figure 4. Where X is as previously defined, R 3 , R., R g , R_-, Rg, R„ and R1, n 0 can be any combination of the following substituents. j** H, OH, NH 2 , SH, F, Br, Cl, I, CH 3 , CH 2 CH 3 , NHCH 3 , N(CH 3 ) 2 , SCH 3 , NHC0CH 3 , NHCOCH^g, NHCOOCH 3 , HNCOOCH 2 Rg, CgH 5 , CF 3 , COOH, COOCH 3 or COOCH 2 Rg. Figure 4 R 2 can also be represented as in Figure 5. Where X is defined as previously, R 3 , R., R g , R 7 , Rg, Rg, R-J Q are as previously defined, R,, and R-, 2 are defined as for R-3/ 4 ' a r R 7 ' s' ^^ R ιo* It is believed that the - substituent is non-critical to the activity of the compound and could in effect be almost any organic radical of small or medium size. The microtubule inhibitors useful in the present invention also include compounds such as substituted phenylguanidines and thioallophanates which can be me abolically activated in vivo to any of the benzimidazole microtubule inhibitor compounds specified above. The constituents of the anthelmintic preparation according to this invention may be administered simultaneously or sequentially provided that the administration of a second one of the ingredients to the animal is during the period of biological activity in the animal of the other of the ingredients, i.e. they should be administered "in association" with one another. The anthelmintic and the microtubule inhibitor may be administered orally, intraruminally, intramuscularly, intravenously, subcutaneously or der ally. They may be administered as a single dose, an implant or a bolus type dosage including any sustained release devices including intraruminal sustained release devices and sustained release devices delivering a continuous or pulsed release. The potentiated anthelmintic preparation may be used against any parasite, insect or organism which is deleterously affected by the active anthelmintic alone. It will be recognised by those skilled in the art that some of the microtubule inhibitors are known themselves to have some anthelmintic properties. In general the OM microtubule inhibitors are used at concentrations at which the compounds have relatively little anthelmintic activity of their own. It has also been found that the potentiation is not merely an additive effect of the anthelmintic activity of the two compounds. There has been found to be a true potentiation in that the plasma concentration profiles are much greater than would be expected by the mere additions of the effects of the two compounds individually. The anthelmintic and the microtubule inhibitor are each preferably administered to the animal in an amount of from 0.1 to 20mg/kg, preferably 3 to 12 mg/kg. Hereinafter given by way of examples only is a preferred embodiment of the present invention. Example 1 METHODS Twenty four 12-month-old Merino-Border Leicester cross-bred wether sheep were housed in two group pens and offered a daily ration of 600g wheaten chaff. Water was offered ad libitum. After weighing they were divided into 8 groups of 3 sheep, each group having a similar range of body weight. At T = 0, sheep in 7 of the 8 groups were orally administered with oxfendazole (hereinafter called OFZ) (Synanthic 22.65g OFZ/1; Batch No. 8179 Syntex Australia) at a dose rate of 4.53mg/kg. The 3 sheep in each of the 7 groups were co-administered with the microtubule inhibitor parbendazole (hereinafter called PBZ) (Wormguard 90g PBZ/1, Smith Kline Australia) at either 0, 1.35, 2.70, 4.5, 9.0, 18.0 and 36.0 mg/kg respectively. The remaining group of 3 sheep were given OFZ at lOmg/kg. A blood sample was taken from the sheep by jugular venipuncture using evacuated heparinised blood sampling tubes at T = 0, 1, 2, 4, 6, 8, 10, 12, 16, 22, 26, 30, 36, 48, 56, 72, 80 and 96 hours post administration. Plasma was separated by centrifugation and stored at -10 C. _OTE OMPI Analysis of OFZ and Albendazole (hereinafter called ABZ) Metabolites Plasma to be assayed was allowed to thaw and OFZ and its metabolites exctracted following a method slightly modified from that described by Allan et al. (1981) J. Chromatography 183: 311-319 employing disposable Sep Pak C 18 cartridges (Part No. 519.10 Water Associates Milford, Massachusetts 01757 USA) . The Sep Pak was prepared by washing successively with 5.0ml High Performance Liquid Chromatography (HPLC) grade methanol followed by 5.0ml 0.017M H 4 H 2 P0 4 buffer pH 5.5. One ml of plasma to be assayed was spiked with 0.5 ju.q of ethyl (5(6) phenylsulphinyl benzimidazol-2-yl) carbamate (Et-OFZ) internal standard. After application of spiked plasma the Sep Pak was successively washed with 1. 20.0ml distilled water 2. 0.5ml 40% methanol in distilled water 3. 0.4ml 100% methanol 4. 2.0ml 100% methanol The metabolites eluted in the 2.0ml methanol wash were collected and concentrated to approx. 0.3 - 0.4ml and refrigerated prior to HPLC analysis. HPLC Analysis The analysis of OFZ and ABZ metabolites was performed using a Waters HPLC System. Standards and prepared unknown samples were automatically injected onto a Bondapack column (Part No. 84720) contained in a radial compression module (RCM-100) using a WISP (Model 710B) sample processor. Solvent was pumped using a 6000A model solvent delivery system and the eluent analysed with a M480 variable wavelength absorbance detector. The elution profile was described on a recorder. Peak areas were calculated using a Spectraphysics Intergrater (Minigrater, Model 23000-1010) . " HPLC Conditions Analysis of OFZ, Methyl (5(6) phenysulphonyl benzimidazol-2yl) carbamate (FBZ-S0 2 ) with Et-OFZ internal standard (O.S^g/ml) : Solvent: 33% acetonitrile, 67% 0.01M ammonium carbonate, pH 7.2 Injection volume: 25 l Pump rate: l.Oml/ Wavelength: 292 nm Attenuation: 0.005 AUFS The resulting plasma concentration-time profiles of OFZ, FBZ-S0 2 , methyl (5(6) propyl sulphinyl benzimidazol-2yl) carbamate (ABZ-SO) , and methyl (5(6) propylsulphonyl benzimidazol-2yl) carbamate (ABZ-S0 2 ) were analysed using the SAAM25 simulated analysis and modelling computer program of Berman and Weiss (1974) SAAM Manual, Public Health Service Publication No. 1703, U.S. Dept. of Health Education and Welfare and the area under the respective profiles determined. Plasma OFZ Concentration Profiles The area beneath the plasma concentration-time profiles of OFZ and FBZ-S0 2 are shown in Table 1. From these observations, co-administration of PBZ resulted in a significant increase (p ^ 0.01) in the area for OFZ (r = 0.804). A slight increase in area for FBZ-S0 2 was noted (r = 0.542) although this response was not significant. The optimal effective co-administered PBZ dose appeared to be 4.5mg/kg and was subsequently used for anthelmintic potentiation. The resulting increase in OFZ metabolite area approximated that obtained from a lOmg/kg oral dose. !RE4 OMPI WIPO Table 1 Plasma concentration-time curve area Treatment g/ml . hr OFZ FBZ-SO, Total OFZ+FBZ-SO. 4.53 mg OFZ/kg 12.1 + 3.0 8.8 ± 2.8 20.9 OFZ + 1.35 mg PBZ/kg 14.7 ± 0.6 14.9 + 1.8 29.6 OFZ + 2.70 mg PBZ/kg 16.9 + 1.6 14.2 + 0.8 31.1 OFZ + 4.5 mg PBZ/kg 22.4 + 0.6 19.1 + 4.5 41.5 OFZ + 9.0 mg PBZ/kg 21.9 + 1.8 13.7 + 0.6 35.6 OFZ + 18.0 mg PBZ/kg ' 20.8 + 6.9 19.7 + 5.4 40.5 OFZ + 36.0 mg PBZ/kg 28.3 + 6.0 14.7 + 2.9 43.0 lOmg OFZ/kg 27.0 + 1.8 26.1 53.1 OFZ Anthelmintic Efficacy TBZ-resistant Trichostrongylus colubriformis (VRGS-s rain, .Hogarth Scott et al, 1976, Res. Vet. Sci. 21: 232-237) with a resistance factor at egg hatch of 57 to TBZ and on LE> against adult worms of 150mg TBZ/kg were obtained from stock cultures. TBZ-resistant Haemonchus contortus (VRSG-strain) with an LD go against adult worms of 200mg TBZ/kg were obtained from exsheathed L- larvae stored in liquid nitrogen and then passaged through a sheep. Twenty, 5-month-old Merino-Border Leicester cross-bred ewes, raised under worm-free conditions, were each infected with 8000 T.colubriformis and 4140 H.contortus benzimidazole-resistant larvae per os. The sheep were " held in group pens on a maintenance diet (600g/d) of equal portions of wheaten chaff, lucerne chaff and oats and water ad libitum. On day 25 the infection was assessed in each sheep using the McMaster faecal egg counting technique. The sheep were than ranked in order of their egg count and subdivided into 5 groups of 4. One sheep from each subdivision was randomly allocated to one of 4 groups, each group then containing 5 animals. The four groups were then treated as follows: 5 Group I: Untreated controls. Group II: Oxfendazole, orally administered as the commercial preparation Synanthic at 4.53mg/kg. Group III Parbendazole, orally administered as the commercial preparation Wormguard at 4.5mg/kg. 10 Group IV: Oxfendazole, 4.53mg/kg + Parbendazole, 4.5mg/kg. Six days after treatment faecal worm egg counts were taken, the sheep killed and their parasite population determined using standard parasitological procedures. OFZ Anthelmintic Efficacy 15 Faecal worm egg counts, taken immediately prior to and 6 days after treatment, together with the total post mortem TBZ-resistant H.contortus and T.colubriformis counts, are shown in Table 2. Also shown are the relative efficacies of the treatment regimes. 20 Oral administration of OFZ at 4.53mg/kg reduced H.contortus by 3.5% and T.colubriformis by 38.2%, the results are not statistically significant. Oral OFZ did, however, significantly reduce total egg production (p 0.01). Oral administration of 4.5mg PBZ alone had no effect on any 25 parameter studied and in fact this group behaved identically to the control animals. Co-administration of 4.5mg PBZ with 4.53mg OFZ/kg was highly effective. Compared to OFZ alone, PBZ alone or untreated controls the anthelmintic mixture significantly 30 reduced total egg production (p <. 0.001) total H.contortus (p ^ 0.01) and T.colubriformis (p < 0.001). Although oral OFZ alone reduced total egg output, the OFZ-PBZ mixture provided a further reduction in egg output (p 0.05). % Example 2 35 Coadministration of 0 , 4. 5mg and 9. 0mg PBZ/kg with Table 2 Faecal worm egg count % % Pre-treatment Post-treatment . H.cont Reduction T.Col Reduction (eggs per gram) Control 17361 19468' 3428 c 5066 c Oxfendazole 4.53 mg/kg 19790 5459 b 3309* 3. 5 3130' 38. 2 Parbendazole 4.5 mg/kg 16704 27992 4029' 4256' 15. 9 Oxfendazole 4.53 mg/kg + 14551 2216° 1552 1 54 340' 93. 6 Parbendazole 4.5 mg/k Values with the same superscript are not significantly different at p -^0.05 4.75mg ABZ/kg was similarly tested in 3 groups of 3 sheep. Plasma sampling and HPLC analysis of ABZ-SO and ABZ-S0 2 using the Et-OFZ internal standard in plasma was performed as described above for OFZ. Similarly, coadministration of PBZ with 4.75mg ABZ/kg increased the area under the plasma concentration-time curve of ABZ-SO and ABZ-S0 2 as shown in Table 3, 4.5mg PBZ/kg subsequently used to test potentiation of ABZ anthelmintic activity. Table 3 Plasma concentration-time curve area Treatment ^g/ml.hr Total ABZ SO ABZ-SO. A ABBZZ--SSOC ABZ-SO. 4.75 mg ABZ/kg 18. 68 + 4. 69 4. 07 + 0. 67 22. 75 ABZ + 4.5mg PBZ/kg 44. 89 + 0. 83 8. 65 + 0 . 50 53 . 54 ABZ + 9.0.mg PBZ/kg 39. 17 + 2. 04 9. 83 + 1. 87 49. 00 ABZ Anthelmintic Efficacy The anthelmintic efficacy of an ABZ-PBZ combination was tested against BZ-resistant T.colubriformis in an experiment identical to that described above for OFZ, OFZ substituted with ABZ at the dose rate of 3.8mg/kg.- To test for PBZ potentiation of ABZ flukicidal activity, 40 crossbred ewe and wether sheep were orally infected with 250 Fasciola hepatica metacercaria, the sheep maintained in group pens on a 600g/d ration of lucerne wheaten hay and water ad libitum. At week 11 they were randomly divided into 4 groups of 10 animals, each group treated as follows: Group 1: untreated controls. Group 2: Parbendazole, orally administered as the commercial preparation Wormguard 4.5mg/kg. OMPI Group 3: Albendazole, orally administered as the commercial preparation Valbazen 4.75mg/kg. Group 4: Albendazole 4.75mg/kg + Parbendazole 4.5mg/kg. Twenty-eight days after treatment the sheep were killed and their livers removed. All fluke in the bile ducts and liver parenchyma were counted. ABZ Efficacy: Nematode ABZ alone or PBZ alone were not effective in removing BZ-resistant T.colubriformis. However the combinations of 3.8mg ABZ/kg plus 4.5mg PBZ/kg significantly reduced the worm burden by 67% (p < 0.01). ABZ Efficacy: Trematode Compared to untreated control sheep, PBZ had no effect of F.hepatica numbers, whereas ABZ reduced fluke population b Y 85.6% (p < 0.01). The ABZ/PBZ mixture further reduced the fluke population to 91.6% (p ^ 0.01 against controls) which was a noticeable improvement (p = 0.066) over the response of ABZ alone. Increasing the co-administered dose of PBZ caused a parallel increase in bioavailability, as delineated as area under the plasma concentration curve,, of OFZ and ABZ. At 4.5mg PBZ/kg, the response appeared optimal, the resulting OFZ curve being equivalent to at least that obtained from an OFZ double dose. The increased area under the plasma OFZ concentration curve resulting from OFZ-PBZ and ABZ-PBZ co-administration was expected to cause a significant improvement in anthelmintic efficacy when compared to OFZ or ABZ administration alone. As described above the anthelmintic mixtures were highly effective. Example 3 The effect of variation of benzimidazole potentiator was examined. Substitution of PBZ (I; Figure 4) with methyl (5(6) propyloxybenzimidazol-2yl) carbamate (II), methyl (5(6) phenoxybenzimida2θl-2yl) carbamate (III) , methyl fR O (5(6) (3' ,4'-dichlorophenoxybenzimidazol-2yl) carbamate (IV) and methyl (5(6) (2*-naphoxybenzimidazol-2yl) carbamate (V), compounds known to inhibit the polymerisation of tubulin, was shown to increase the area under the plasma concentration-time curve for ABZ-SO and ABZ-S0 2 (Table 4) . Compound (V) was found to be more potent than PBZ, demonstrating a similar potentiation at less than one-quarter the PBZ dose rate. This experiment has clearly demonstrated that the bioavailability and therefore efficacy of an existing benzimidazole anthelmintic can be significantly increased with the use of a second co-administered benzimidazole acting solely as potentiator for the first. The consequences of these observations indicate that in cases where benzimidazole resistance has become uncontrollable with existing preparations, the abovementioned mixtures may provide the necessary protection. Furthermore, increased bioavailability of a benzimidazole drug can be translated to a less active drug being administered to provide adequate parasite protection at a lower cost. Synanthic, Wormguard and Valbazen are registered trade marks. Table 4 Plasma concentration-time curve area Compound Dose No. R 13 mg/kg IC 50 ABZ - o ABZ-SO 2 - Unpotentiated ABZ - - 18.7+4.5 (3)# 4.3+0.7 (3)# I CH-.CH«CH-CHΛ— 4.5 3.1 41.5 (3) 10.4 (3) II CH 3 CH 2 CH 2 0- 4 2.3 26.3 (2) 11.0 (2) III C 6 H 5 0- 4 3.3 21.7 (2) 6.6 (2) IV 3,4-(Cl 2 )C 6 H 3 0- 4 1.6 27.4 (2) 10.9 (2) V C 10 H 7°- 4 0.79 35.9 (2) 10.0 (2) V C 10 H 7 O- 1 0.79 34.5 (2) 15.5 (2) * Obtained from an oral dose of 4.5mg/kg of ABZ " IC_. 0 was determined using purified sheep tubulin according to method of Friedman and Platzer, Biochim. et Biophys. Acta 544, 605- (1978) # Number of sheep tested.

Claims: CLAIMS: 1. An anthelmintic preparation containing as active components at least one anthelmintic benzimidazole carbamate or a compound which may be converted in vivo to such a benzimidazole carbamate and at least one microtubule inhibitor being a benzimidazole compound of the formula wherein 0 0 S 0 u w It R, i s a -NHC-OR 5' -NHC-Rς , -NHC-R 5 or -NHC-SR 5 radical and R f . is an alkyl group to a maximum size of C fl H, _, R 3 and R 4 are each selected from the group comprising H, OH, NH 2 , SH, F, Br, Cl, I, CH 3 , CH 2 CH 3 , NHCH 3 , N(CH 3 ) 2 , SCH.-, NHCOCH-., NHCOCH-.R,-, NHCOOCH-, NHCOOCH-R-, C-H_, 2 6 3 2 6 6 5 CF 3 , COOH, COOCH 3 .and COOCH-R , R c 6 is the same as R3-. and R4 Λ , R 2 is XR 7 , X is NH, S, 0, CO, or CH 2 , and R 7 is an aliphatic or aromatic radical, or a compound which may be converted in vivo to any one of the abovementioned benzimidazole microtubule inhibitors. 2. An anthelmintic preparation as claimed in claim 1 in which the anthelmintic compound is a benzimidazole carbamate selected from the group comprising oxfendazole, fenbendazole and albendazole. 3. An anthelmintic preparation as claimed in claim 1 in which the anthelmintic compound is the phenylguanidine febantel which is capable of forming a benzimidazole carbamate in vivo. OMPI fa y , WIPO 4. An anthelmintic preparation as claimed in any one of claims 1 to 3 in which the microtubule inhibitor is parbendazole. 5. A method for potentiating in a mammalian animal the action of a benzimidazole carbamate anthelmintic compound or a compound which may be converted in vivo to such a compound, comprising administering the anthelmintic compound to the animal in association with at least one microtubule inhibitor being a benzimidazole compound of the formula wherein 0 0 S 0 M u l. u R^ is a -NHC-0R 5 , -NHC-R 5 , -NHC-R 5 or -NHC-SR 5 radical and Re is an alkyl group to a maximum size of CgH, 7 , R 3 and R 4 are each selected from the group comprising H, OH, NH 2 , SH, F, Br, Cl, I, ' CH- CH O CHT, NHCH 3 , N(CH 3 ) 2 , SCH 3 , NHC0CH 3 , NHCOCH 2 Rg, NHCOOCH- NHCOOCH 2 Rg, CgH 5 , CF 3 , COOH, COOCH 3 and COOCH 2 Rg, Rg is the same as R-> and R 4 , Ro S Xv r., X is NH, S, O, CO, or CH 2 , and R 7 is an aliphatic or aromatic radical, or a compound which may be converted in vivo to any one of the abovementioned benzimidazole microtubule inhibitors. 6. A method as claimed in claim 5 in which the anthelmintic compound is a benzimidazole carbamate selected from the group comprising oxfendazole, fenbendazole and albendazole. 7. A method as claimed in claim 5 in which the anthelmintic OMPI σompounα is cne pnenyiguaniαme reσanre wnicπ is capaD_.e ui forming a benzimidazole carbamate in vivo. 8. A method as claimed in any one of claims 5, 6 or 7 in which the microtubule inhibitor is parbendazole. 9. A method as claimed in any one of claims 5 to 8 in which the anthelmintic compound and the microtubule inhibitor are each administered to the animal in an amount of from 0.1 to 20mg/kg. 10. An anthelmintic preparation comprising an anthelmintic compound and a microtubule inhibitor substantially as hereinbefore described with reference to any one of the foregoing examples 1 to 3. 11. A method for potentiating in a mammalian animal the action of a benzimidazole carbamate anthelmintic compound substantially as hereinbefore described with reference to any one of the foregoing examples 1 to 3. - JRE OMPI ^RNAΎ\O

Inventors: HENNESSY DESMOND RONALD, LACEY ERNEST, PRITCHARD ROGER KINGSLEY, HENNESSY, DESMOND, RONALD, LACEY, ERNEST, PRITCHARD, ROGER, KINGSLEY
Applicants: COMMW SCIENT IND RES ORG, COMMONWEALTH SCIENTIFIC AND INDUSTRIAL RESEARCH OR
Application year: 1984
Main classification: A61K31
IPC codes: A61K31