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Five groups of 10 lambs each were grazed on comparable, 0.8-hectare, helminth-contaminated pastures from May through August 1972. One group served as unmedicated control lambs. Beginning 29 June, 4 groups were dosed 3 times at 4-week intervals with either levamisole hydrochloride (LVS) at 8 mg/kg, morantel tartrate (MT) at 8 mg/kg, cambendazole (CBZ) at 40 mg/kg, or mebendazole (MBZ) at 20 mg/kg. Evaluation of the treatments for helminth control was based upon biweekly parasite surveillance and clinical data, mortality, and necropsy worm counts. Two lambs in the control group and 2 in the MBZ-treated group died of parasitism early in August; no other lambs died. All 4 drugs effectively controlled Nematodirus spp., Oesophagostomum venulosum, and possibly Ostertagia spp., which were present in relatively small numbers. The drugs differed in their ability to control Haemonchus contortus, Trichostrongylus spp., Strongyloides papillosus, and Trichuris spp. LVS was effective against H. contortus, Trichostrongylus spp., and S. papillosus but was less effective against Trichuris spp.; MT was effective against H. contortus and Trichostrongylus spp. but was less effective against Trichuris spp., and was ineffective against S. papillosus; CBZ was effective against Trichostrongylus spp., S. papillosus, and Trichuris spp. but only moderately effective against H. contortus; MBZ was effective against Trichuris spp. but was less effective against H. contortus, Trichostrongylus spp., and S. papillosus. Only CBZ was effective against Moniezia expansa. Dosing at 4-week intervals, even with the most effective of the test drugs, did not fully eliminate the clinical effects of haemonchosis. Since the discovery of thiabendazole (Brown et al., 1961), first of the modem broad-spectrum agents for the treatment of gastrointestinal worm infections, additional drugs of similar anthelmintic scope have been found and are in various stages of development. Among these of special interest for use in domestic ruminants are levamisole hydrochloride (Thienpont et al., 1966), morantel tartrate (Howes, 1968), cambendazole (Hoff et al., 1970), and mebendazole (Brugmans et al., 1971). Levamisole has been widely tested in sheep (Kates et al., 1971, 1973b; McFarland, 1972; and others). Outstanding efficacy against most gastrointestinal nematodes and lungworms of sheep has led to the wide use of levamisole throughout the world in sheep helminth control programs. Morantel, cambendazole, and mebendazole have been developed more recently thani levamisole and need further evaluation, particularly in comparative trials under similar conditions and in tests against resistant nematode populations. We previously reported Received for publication 6 May 1974. * Animal Parasitology Institute, ARS, Beltsville, Maryland 20705. t Nutrition Institute, ARS, Beltsville, Maryland 20705. results of controlled tests with levamisole, morantel, and cambendazole against gastrointestinal helminths of sheep (Colglazier et al., 1971, 1972, 1974a, b; Kates et al., 1971, 1973a, b). Comparatively few studies have been reported with mebendazole against sheep helminths (Guilhon, Gaillier, and Hubert, 1972). The present trials were designed to compare the degree of helminth control achieved in lambs on pasture by periodic treatments with levamisole, morantel, cambendazole, and mebendazole during a normal grazing season. Levamisole served as a reference standard for the other drugs against most of the helminth species involved (Colglazier et al., 1974b). MATERIALS AND METHODS Crossbred lambs, raised in dry-lot, were purchased in Virginia and shipped to Beltsville, Maryland, early in May 1972. At the start of the experiment, the lambs averaged 28 kg in weight and were relatively helminth-free. A 4-hectare pasture was contaminated with parasite eggs by grazing it for several weeks with about 100 ewes lightly infected with several helminth species, including H. contortus resistant to thiabendazole, parbendazole, and cambendazole. The pasture was then subdivided into five 0.8-hectare plots by fencing. Throughout the experimental period

Observations were made for the second grazing season (April through September of 1960) on the effects of management systems, including medication, on the development of internal parasitism in lambs. The systems included drylot confinement (Band 1), transfer of animals to "clean" pastures at biweekly intervals (Band 2), and rotation among separate, contaminated pastures at approximately biweekly intervals (Bands 3 and 4). Purified phenothiazine (average particle size 6.9 A) was used for all medication involving animals in Bands 1, 2, and 4. A National Formulary (N.F.) grade product (average particle size 7.0 A) was used for Band 3. All bands had free access to a 1:9 phenothiazinemineral mixture, and therapeutic doses for the most part were given in accordance with a predetermined plan. Antemortem data, including hematocrit determinations and parasite egg counts, were obtained from 20 lambs of each band; worm counts were obtained at necropsy from 10 lambs of each band. Bands 1 and 2 did not develop clinical parasitism. The average minimum hematocrit levels for the two bands were 33.0 and 33.1%, respectively. Bands 3 and 4 developed haemonchosis despite the treatment regimens employed. The packed red-cell volumes (PCV) remained below 30% in Band 3 during the entire posttreatment phase. The PCV in Band 4 dropped below those in Band 3 during July and early August but markedly improved following therapeutic treatment. The necropsied lambs of Band 3 (N.F. phenothiazine) had more worms, especially Haemonchus contortus, than those of Band 4 (purified phenothiazine), even though doses of N.F. phenothiazine were increased to 50 g, or double those of the purified product. Under the conditions of these experiments, purified phenothiazine was superior to an N.F. grade product of comparable particle size for the control of Haemonchus infections in lambs. A study of the effects of different management systems on the development of internal parasitism in lambs was initiated at Beltsville, Maryland, in 1959. In the first year (Lindahl et al., 1963) the average levels of parasitism acquired by the lambs were related directly to the degree of exposure to infective larvae. Also, clinical haemonchosis in lambs was not controlled satisfactorily by medication with N.F. phenothiazine. Limited evidence indicated, moreover, that the ineffectiveness of phenothiazine may have been due to a tolerance of the parasite for the drug. Phenothiazine resistance had been reported by Drudge Received for publication 20 September 1967. * Animal Disease and Parasite Research Division, ARS, Beltsville, Maryland. t Animal Husbandry Research Division, ARS, Beltsville, Maryland. tPresent Address: Division of Research Grants, NIH, Bethesda, Maryland. $ Present Address: Animal Disease and Parasite Research Division, ARS, University Park, New Mexico. ? Present Address: Food and Drug Administration, BSSE, DTE, Washington, D. C. II Biometrical Services, ARS, Beltsville, Maryland. et al. (1957a, b), Leland et al. (1957), and Levine and Garrigus (1961). A relationship between the purity of phenothi zine and its efficacy against gastrointestinal nematodes was noted by Douglas et al. (1959) and Baker et al. (1959). Therefore, it seemed desirable to compare the efficiency of N.F. and purified phenothiazine products of comparable particle size in controlling haemonchosis in lambs as a phase of long-term investigations at Beltsville, Maryland. Studies conducted in 1960, the 2nd year of the project, were designed to make this comparison. MATERIALS AND METHODS The general plan was similar to that followed during the 1st year, 1959, and involved three basic management systems, namely: drylot confinement (Band 1), transfer of animals to "clean" pastures at biweekly intervals (Band 2), and grazing of animals on contaminated pastures (Lindahl et al., 1963). However, in the present study two bands of lambs were included in the system involving contaminated pastures to permit comparative evaluations of N.F. (Band 3) and purified phenothiazine products (Band 4) under similar conditions. During the pretrial period, all lambs were creepfed with pellets containing 65% alfalfa meal, 30% ground barley, and 5% soybean oil meal.

Forty-nine ram lambs similarly exposed on pasture to common gastrointestinal helminth infections were assigned to 7 groups of 7 lambs each in a controlled anthelmintic trial involving 2 dose levels of each of 3 anthelmintics. All lambs were necropsied 5 to 7 days posttreatment for residual worm counts. Both mature and immature stages of some nematode parasites were recovered from the lambs. The most numerous species in the unmedicated controls were Ostertagia spp. (mainly 0. circumcincta), Haemonchus contortus, and Trichostrongylus spp. (mainly T. vitrinus). The drugs and dosages were: pyrantel tartrate 25 and 50 mg/kg; parbendazole 15 and 20 mg/kg; levamisole 8 and 12 mg/kg; unmedicated controls. The calculated efficacies at the 2 dose levels were, respectively, H. contortus: pyrantel tartrate 99 and 100%, parbendazole 54 and 78%, levamisole 99 and 99%8; Ostertagia spp.: pyrantel tartrate 86 and 96%, parbendazole 88 and 87%, levamisole 82 and 88%; Trichostrongylus spp.: pyrantel tartrate 98 and 99%, parbendazole 99 and 100%, levamisole 99 and 98%; Nematodirus spathiger: pyrantel tartrate 100 and 100%, parbendazole 85 and 91%, levamisole 91 and 96%; Oesophagostomum venulosum: pyrantel tartrate 96 and 100%, parbendazole 100 and 100%, levamisole 100 and 100%. In most instances, the higher dosages of the 3 anthelmintics appeared to be more efficacious than the lower dosages, but in most cases these differences were not statistically significant. Both 4thand 5th-stage H. contortus were somewhat resistant to parbendazole at the 2 dose levels used, but they were highly susceptible to pyrantel tartrate and levamisole. Three of the newer broad-spectrum anthelmintics for use in sheep are pyrantel tartrate (Austin et al., 1966), parbendazole (Actor et al., 1967), and levamisole, the active isomer of dl-tetramisole (Thienpont et al., 1966; Bullock et al., 1968). Although the accumulated data indicate that all three drugs have a similar spectrum of activity in sheep, each has been somewhat ineffective occasionally against certain species, stages, or strains when administered as a drench at the recommended therapeutic dose. The purpose of this trial was to compare the efficacy of two dose levels of the three drugs against naturally acquired multiple species infections in sheep. Most of the reports on the activity of parbendazole and levamisole against gastrointestinal nematodes of sheep were summarized recently by Kates et al. (1971). Parbendazole at 15 mg/kg of body weight does not compare favorably with other available anthelmintics against certain strains of H. contortus and Received for publication 6 April 1971. * National Animal Parasite Laboratory, Veterinary Sciences Research Division, ARS, Beltsville, Maryland 20705. tAnimal Science Research Division, ARS, Beltsville, Maryland 20705. against Nematodirus spp., whereas levamisole at 8 mg/kg of body weight is not reliably effective against Ostertagia spp. Austin et al. (1966) first published on the anthelmintic activity of pyrantel tartrate against sheep nematodes. Several investigators have confirmed the initial findings that a dosage of 25 mg/kg of body weight was highly effective against many nematode species (Corwell, 1966; Corwell et al., 1966a, b, 1967a, b; Cornwell and Jones, 1969b; Gibson and Parfitt, 1968; Colglazier et al., 1971; Reinecke and Anderson, 1967). Also, low-level continuous administration was effective prophylactically (Cornwell and Jones, 1969a, b), and in certain limited studies dosages of 45 or 50 mg/kg tended to enhance efficacy slightly against some species (Comwell, 1966). MATERIALS AND METHODS Origin and infection of experimental lambs These aspects were similar to those reported previously (Kates et al., 1971). Fifty-three lambs (black-faced, crossbred) were purchased from a dealer in the western United States and shipped by truck to Beltsville, Maryland, in mid-May 1969. Upon arrival the lambs averaged 31 kg in weight, and initial fecal examinations indicated that they had minimal infections of a few nematode species

Observations were made for the third grazing season (April through September of 1961) of the effect of management systems, including medication, on the development of internal parasitism in lambs at Beltsville, Maryland. The systems included the feeding of soilage to lambs in dry lot (Band 1), transfer of lambs to "clean" pastures at biweekly intervals (Band 2), and rotation among separate parasite-contaminated pastures at approximately biweekly intervals (Bands 3 and 4). The soilage was cut daily from areas that had not been grazed since the pastures were plowed and reseeded. The soilage was fed only to the lambs. The feeders were placed behind a creep so that the ewes could neither consume any of the soilage nor contaminate the forage with feces. National Formulary (N.F.) phenothiazine (avg particle size, 7.0 jt) was used for low-level and therapeutic dosing of animals in Band 3 until 7 July, and purified phenothiazine (avg particle size 6.9 A/) was used thereafter. Only the purified product was used for the lambs of Bands 1, 2, and 4. Antemortem data, including hematocrit determinations and parasite egg counts, were obtained from 20 lambs of each band. Worm counts, obtained at necropsy from 10 lambs of each band, showed that lambs in Band 1 (zero-grazing) remained essentially worm-free throughout the period of observation. Effective control of haemonchosis was also obtained in Band 2 by combining "clean" pasture grazing, monthly therapeutic dosing with purified phenothiazine, and low-level purified phenothiazine in a free-choice mineral mixture. Weight gains of lambs in Bands 1 and 2 were significantly greater than those of lambs in Bands 3 and 4 up to weaning. The N.F. phenothiazine, given free-choice and in therapeutic drenches, failed to control haemonchosis in Band 3. Clinical signs developed early in these lambs, despite doubling the therapeutic dose on 7 July. Better control of Haemonchus contortus infections was achieved after changing to purified phenothiazine on 14 July. Lambs in Band 4 developed haemonchosis at a later date than those in Band 3, even though they had received about 50 g less phenothiazine (purified only) per lamb in therapeutic drenches. During the treatment phase of the investigation, PCV in bands 1 and 2 were significantly higher than that in Bands 3 and 4, and were closely related to the number of parasites found in the different bands. Weight gain of lambs in Band 2 were significantly greater than that of lambs in Bands 1, 3, and 4 during phase 2. The weight gain of Band 1 lambs was directly influenced by the feeding program. Under the conditions of these experiments, purified phenothiazine was somewhat superior to N.F. phenothiazine for controlling Haemonchus infections, although neither product controlled clinical haemonchosis satisfactorily. Results of studies conducted at the Agricultural Research Center, Beltsville, Maryland, during 1959 and 1960 (Lindahl et al., 1963; Colglazier et al., 1968) confirmed published reports by other investigators (Hinds et al., 1961; Tiwari et al., 1961) that internal paraReceived for publication 5 May 1970. * Animal Science Research Division, ARS, Beltsville, Maryland. t National Animal Parasite Laboratory, Veterinary Sciences Research Division, ARS, Beltsville, Maryland. + Present address: Division of Research Grants, NIH, Bethesda, Maryland. ? Present address: Food and Drug Administration, BSI, DPT, PRB, Washington, D. C. 11 Biometrical Services, ARS, Beltsville, Maryland. sitism could be controlled by raising lambs in dry lot; that the average level of parasitism acquired by the lambs was related to the degree of exposure to infective larvae (Gordon and Turner, 1946; Spedding, 1954, 1955, 1956; Gibson, 1956; Levine et al., 1956, 1958, 1960; Reinecke and Thomas, 1959; Michel, 1964; Zimmerman, 1965); and that therapeutic treatment with N.F. phenothiazine did not result in effective control of Haemonchus contortus (Drudge et al., 1957a, b; Leland et al., 1957; Levine and Garrigus, 1961; Colglazier et al., 1967). Raising lambs in dry lot has been successful in controlling internal parasitism, but the use of large quantities of concentrates and dry roughages are required. It seemed desirable to

Forty-five ram lambs uniformly exposed to natural infections of various helminths were assigned to 5 groups of 9 lambs each and used to conduct controlled anthelmintic trials. One group of lambs served as unmedicated controls, and 4 groups were treated as follows: (1) thiabendazole 50 mg/ kg; (2) thiabendazole 100 mg/kg; (3) levamisole 8 mg/kg; (4) parbendazole 15 mg/kg. All lambs were necropsied 4 to 6 days posttreatment for residualworm counts. Both mature and immature stages of several parasite species were recovered from the unmedicated control lambs; Haemonchus contortus was the most numerous. For the medicated groups 1, 2, 3, and 4 above, the calculated efficacies of the treatments against all stages of parasites were, respectively, H. contortus 48, 88, 99, and 79%; Ostertagia spp. (mainly 0. circumcincta) 94, 99, 76, and 99%; Trichostrongylus spp. (T. axei, T. vitrinus, and T. colubriformis) 99, 100, 99, and 100%; Nematodirus spathiger 90, 100, 96, and 83%; Oesophagostomum venulosum 98, 100, 100, and 99%. The data indicate the H. contortus strain in these lambs was somewhat resistant to thiabendazole and parbendazole. Fourth-stage larvae were recovered only of H. contortus, Ostertagia spp., and N. spathiger, and generally were not removed as effectively as 5th-stage parasites. However, levamisole was highly effective against 4th-stage H. contortus and N. spathiger, and 100 mg/kg of thiabendazole removed all 4th-stage N. spathiger. The 3 anthelmintics significantly reduced strobilar volume of Moniezia expansa, but had no activity against the scoleces. During the last decade, three new broadspectrum anthelmintics, viz., thiabendazole, tetramisole, and parbendazole, have shown considerable promise against helminths, particularly gastrointestinal nematodes of sheep and other domestic animals. The effective action of thiabendazole [2-(4'thiazolyl)-benzimidazole] against a wide variety of nematode parasites of various animals was first reported by Brown et al. (1961). Since that time a substantial literature (see Gibson, 1965, 1969; Levine, 1968) has accumulated supporting the original findings. Recently, however, Theodorides et al. (1970) and Colglazier et al. (1970a) summarized a number of published reports pertaining to strains of Haemonchus contortus that were resistant to the drug. Thienpont et al. (1966) first reported on the anthelmintic activity of dl-tetramisole [2,3,5,6tetrahydro-6-phenyl-imidazo (2,1-b) thiazole hydrochloride] in man and animals. Subsequently, Bullock et al. (1968) separated the dextro and levo isomers of the drug, and showed that the anthelmintic action was attribReceived for publication 3 September 1970. * National Animal Parasite Laboratory, Veterinary Science Research Division. t Animal Science Research Division, ARS, USDA, Beltsville, Maryland 20705. utable primarily to the levo form. Considerable published data have now accumulated which attest to the broad-spectrum activity of this chemical, and to the fact that the levo isomer (levamisole) is about twice as active as the dl compound (Walley, 1966; Fitzsimmons, 1966; Forsyth, 1966, 1968; Gibson, 1966; Gibson et al., 1968a, b; Hart and Curr, 1968; Hart et al., 1969; Lyons et al., 1968; Pankhurst and Sutton, 1966; Pretorius, 1967; Ross, 1966; Shone and Philip, 1967; Colglazier et al., 1969, 1970b). In 1967, Actor et al. published the first report on another promising livestock anthelmintic, parbendazole [5(6)-butyl-2-benzimidazole carbamate], a benzimidazole compound related chemically to thiabendazole. Parbendazole had an anthelmintic spectrum similar to that of thiabendazole, but it was active at lower dose level. Several studies on the activity of parbendazole against gastrointestinal nematodes of sheep and goats have been reported which essentially confirm and extend the earlier findings, viz., Bennett (1968), Danek et al. (1969), Johns and Mendel (1969), Lammler et al. (1969), Luque Forero et al. (1969), Ross (1968), Theodorides et al. (1968, 1969). Theodorides et al. (1970) also reported that a number of thiabendazole-resistant strains of H. contortus were also cross-resistant to parbendazole.