Impact of doramectin treatment at the time of feedlot entry on the productivity of yearling steers with natural nematode infections.

OBJECTIVE: To measure the reduction in fecal nematode egg counts and productivity impact of treatment of yearling steers with doramectin at entry into the feedlot, compared with control steers treated only with fenthion. ANIMALS: 6,096 crossbred yearling steers with a mean (+/- SD) body weight of 377.0 (+/- 37) kg. PROCEDURE: Steers were implanted with zeranol and alternately separated to fill each of 24 pens. Groups of steers within 12 matched pairs of pens were randomly allocated to treatment with doramectin or no treatment with doramectin for internal nematodes. Fecal samples were collected from approximately every twentieth steer from each pen at day 0 and at reimplant (approx day 60). Each steer was weighed on day 0 and at reimplant and then mean body weights of steers per pen were determined at 120 to 140 days after trial initiation. RESULTS: Treatment steers had a significantly lower fecal egg count at reimplant than control steers. Treatment steers had a significantly greater mean daily gain during the study, significantly greater feed consumption, significantly lower feed-to-gain ratio, and significantly better quality carcass grades at slaughter. CONCLUSIONS AND CLINICAL RELEVANCE: Under the conditions of our trial, there was a significant fecal egg count reduction response to doramectin treatment, which resulted in significantly improved productivity. Results of economic analysis of return on investment indicated that even with low egg counts in heavy body weight cattle, nematode egg count reduction with doramectin significantly improved returns.

Production-based control of parasitic nematodes of cattle.

Nematode parasite control in cattle is the goal of the parasitologist and the cattle producer. However, the language used to express the impact of that control has been a source of confusion between the two groups. Veterinary parasitologists speak in terms of reduction in worms or worm eggs, and cattle producers in terms of weight gain, milk production or calving rate. During the development of doramectin for cattle in temperate climates worldwide, the point came when we began to look for a different set of parameters to guide trial design and to communicate the results. In this paper, a series of published papers resulting from the yearling portion of this development programme are reviewed from the viewpoint of weight gain in relation to forage/feed availability. A pattern emerged that indicated that yearling cattle, when parasite control was effective (as indicated by egg counts) and forage was sufficient (as indicated by weather patterns), gained from 0.75 to 0.95 kg day(-1) in trials from the USA, Europe and Argentina. When parasite control or forage supply or both were insufficient, these rates of weight gain were significantly reduced. If more attention is spent on forage availability and weight-gain parameters when parasite-control programmes are designed, then researchers might communicate more meaningful information to producers on the value of parasite control.

Nematode reinfection following treatment of cattle with doramectin and ivermectin.

A study was conducted to investigate reinfection with nematodes in calves following treatment with doramectin or ivermectin administered subcutaneously at a dose rate of 200 micrograms kg-1 of body weight under conditions of natural challenge. Thirty calves were allocated to three groups of 10 calves each based on body weight, sex, breed and pre-treatment faecal egg counts (FEC) after grazing together on a common pasture for three months. Treatments were doramectin, ivermectin and no treatment. Calves were returned to the same pasture for 56 days, placed on dry lot from days 56 to 63 and then necropsied over days 64-66. Faecal egg counts were done at days -1 and 0, then bi-weekly from day 14 to 56 and day 63. Mean FEC in control calves continued to rise throughout the grazing period. Trichostrongyle FEC were significantly (P < 0.05) greater in the control group compared to either treated group at each sample time following treatment. At necropsy, a total geometric mean of 19,847 nematodes per calf was recovered from untreated controls, of which eight genera were identified. The predominant nematode genera were Ostertagia (8749), Nematodirus (3702) and Cooperia (1927). In the ivermectin-treated calves, geometric mean worm burden was similar to that of the untreated controls: A total of 20,349 nematodes per calf was present including the genera Nematodirus (8633), Ostertagia (4700) and Cooperia (1740). In contrast, the geometric mean worm burden in doramectin-treated calves was 12,173, including Ostertagia (4310), Cooperia (1141) and Nematodirus (1667). Doramectin was more effective than ivermectin in protecting calves from reinfection over a 56-day post-treatment grazing period under conditions of natural challenge as measured by accumulated mean worm burdens.

Comparative persistent efficacy of doramectin, ivermectin and fenbendazole against natural nematode infections in cattle.

A study was conducted in Argentina, to investigate the period of protection of a single injection of doramectin administered subcutaneously (s.c.) at 200 micrograms kg-1 (1 ml/50 kg) compared with single treatments of ivermectin (200 micrograms kg-1 s.c.) and fenbendazole (5 mg kg-1 p.o.), against field infections of gastrointestinal parasites of cattle. Eighty-three animals were selected and ranked on the basis of serial fecal egg counts (e.p.g.'s). From this group, three animals were slaughtered before treatment and their lungs, abomasum, small and large intestines, were processed for parasite counts and identification. The remaining 80 animals were allocated in ranked groups of four to a control or one of three treated groups. Animals of the four groups were grazed together in the same pasture for the duration of the study. Treatments were administered on Day 0. Individual fecal samples were collected at weekly intervals for the first 49 days post-treatment and twice a week from Day 52 to Day 84 (end of study). At each collection day fecal samples were pooled for coprocultures. On Day 28 and 56, two animals from each group, previously identified on Day 0, were killed and their parasite burdens determined. The duration of protection of a single injection of doramectin was longer than ivermectin or fenbendazole treatment. On Day 56, the total number of parasites found in doramectin-treated animals was significantly (P < 0.05) lower than parasite burdens found in either ivermectin- or fenbendazole-treated animals. The longer persistent activity of doramectin was expressed by the lower number of adults and L4 stages of Ostertagia ostertagi. Data from this experiment demonstrated the limitations of using fecal egg counts to evaluate the persistent efficacy of anthelmintics. The duration of activity of doramectin was demonstrated more accurately by parasite counts in cattle from each group since decreasing e.p.g.'s were seen in non-medicated animals without changes in total parasite burdens.

Therapeutic and protective efficacy of doramectin injectable against gastrointestinal nematodes in cattle in New Zealand: a comparison with moxidectin and ivermectin pour-on formulations.

Two similar studies were conducted in New Zealand to compare the therapeutic and persistent activity of doramectin injectable, moxidectin pour-on, ivermectin pour-on and oxfendazole oral drench when administered to nematode-infected cattle which were then grazed on common pastures. On day 0 (treatment day), 40 cattle were weighed, faecal sampled and allocated on the basis of day--3 faecal egg counts (FEC) to four treatment groups. Cattle were then treated with either doramectin by subcutaneous (s.c.) injection, moxidectin and ivermectin by topical application, or oxfendazole orally using label-recommended dosages. Oxfendazole treatment served primarily as a control to monitor reinfection without persistent activity. Faecal samples for nematode egg counts and coprocultures for larval differentiation were collected six times between day 0 and day 56 and all cattle were reweighed on day 56. Doramectin reduced pretreatment FEC by 99.1% in the first study and by 100% in the second study when assessed at 14 days posttreatment. Corresponding reductions for moxidectin were 80.8% and 85.2%, for ivermectin 86.0% and 80% and oxfendazole 78.3% and 100%, respectively. Posttreatment rise in FEC indicated that reinfection of moxidectin-treated animals occurred at the same time as oxfendazole controls in both trials. Posttreatment rise in FEC with ivermectin pour-on was similar to moxidectin and oxfendazole in one study, but in the other study ivermectin pour-on delayed the rise by 14-21 days. The rise in FEC for doramectin was delayed for 14-21 days in one study and at least 21 days in the other. The better parasite control provided by doramectin resulted in greater weight gains for cattle over the 56-day period as compared to moxidectin pour-on, ivermectin pour-on and oxfendazole in both trials. Gains of doramectin treated cattle were significantly (p < 0.05) greater than those of ivermectin and moxidectin groups in one trial and the oxfendazole group only in the other.

Efficacy of doramectin in the protection of neonatal calves and post-parturient cows against field strikes of Cochliomyia hominivorax.

Two studies were conducted in Latin America, one in Venezuela and one in Argentina, using a common protocol to investigate the efficacy of a single s.c. injection of doramectin in the prevention and control of field infestations of Cochliomyia hominivorax in newborn calves and post-parturient cows. In both experiments, pregnant cows were paired on the basis of their calving time. The first cow that calved was assigned to a medicated group, and both cow and calf were treated with doramectin. The cow received a dose of 200 micrograms kg-1 and the calf 1 ml of a 1% doramectin solution. The second cow and calf were assigned to a saline-treated group, and the cow received saline at 1 ml per 50 kg and the calf 1 ml. The procedure was repeated until all animals were allocated to the two treatments. Animals were examined on the treatment day and at 2, 4, 6 and 12 days post-treatment. At each observation day, the navel of newborn calves and external genitalia of the cows were inspected and the presence of C. hominivorax infestations was recorded. Doramectin was 100% effective in the prevention and control of screwworm strikes in newborn calves and in post-parturient cows exposed to continuous field challenge of C. hominivorax. Over the 12 day duration of the studies, 48% and 57% of the saline-treated calves had screwworm navel strikes in the studies in Venezuela and Argentina, respectively. Infested animals required repeated therapeutic treatment, whereas none of the doramectin-treated calves were affected (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic and persistent efficacy of doramectin against Boophilus microplus in cattle.

One therapeutic and one persistent efficacy study were conducted in Brazil to evaluate doramectin at a dose rate of 200 micrograms kg-1 against induced infestations of the single host tick, Boophilus microplus. Doramectin was highly effective in eliminating established tick populations from cattle and also in preventing infestation by the parasite. In the therapeutic study, 12 calves were infested three times a week along the dorsal line with 2500 recently hatched larvae, for a total of 11 times before treatment. Animals were allocated to two groups on the basis of uniformity of established engorged tick burdens. Six calves were treated with doramectin and six received saline solution. From Day -3 to Day 21 post-treatment, individual collections of detached engorged female ticks were made from each calf. In the persistent efficacy study, 12 calves were allocated to two groups of six animals. Six calves were treated with doramectin and six received saline solution. From Day 1 to Day 17 post-treatment, each animal was infested three times a week along the dorsal line with 2500 recently hatched Boophilus microplus larvae, for a total of nine times. From Day 18 to Day 42 post-treatment, daily collections of detached engorged female ticks were made from individual animals. In the therapeutic study, efficacy (reduction of collected engorged female ticks) progressed from 51% at 24 h post-treatment (p.t.) to at least 99% at 4 days p.t., and reached 100% at 8 days p.t. With the exception of one tick that did not lay eggs, recovered from one animal at 11 days p.t., no more ticks were recovered from doramectin-treated calves for the duration of the experiment. For the first 6 days after treatment, only a few detached engorged ticks were collected from treated animals, and their oviposition and hatchability declined rapidly. In the persistent efficacy study, doramectin treatment was highly efficacious in preventing the establishment of Boophilus microplus populations for 20 days after the first ticks completed their cycle in the non-treated group. The oviposition and hatchability of the few ticks that completed their life cycle in the doramectin group were severely reduced.

Therapeutic and persistent efficacy of doramectin against Dermatobia hominis in cattle.

One therapeutic and one persistent efficacy study were conducted in Brazil to evaluate doramectin at a dose rate of 200 micrograms/kg-1 against induced infestations of the tropical warble-fly, Dermatobia hominis. Doramectin was very effective in both the treatment of established infestations and also in the prevention of damage caused by the parasite. In the therapeutic trial, 12 calves were infested along the dorsal line with 25 first instar larvae of recent field isolates of D. hominis but in one calf nodules did not develop. Twenty-four days later animals were allocated to two groups on the basis of the number of parasite nodules present. Six calves were treated with doramectin, and five received saline solution. Animals were examined daily for 11 days post-treatment and the number of nodules mapped and recorded. Larvae that completed development were collected and incubated to evaluate viability. In the persistent efficacy study, 24 calves were allocated to six groups (T1-T6) of four animals each. On the day of treatment, three groups (T1, T3 and T5) were treated with saline and three groups (T2, T4 and T6) with doramectin. At 21 days, 28 days and 35 days post-treatment, 25 first instar D. hominis larvae were seeded along the dorsal line of each calf of T1 and T2, T3 and T4, and T5 and T6, respectively. Animals were examined daily for 18 days and the number of nodules mapped and recorded 6, 12 and 18 days post-infestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Screen for anthelmintics, using larvae of Ascaris suum.

A multiwell culture system was used to assay the effects of 12 known anthelmintic compounds on Ascaris suum larval development from 2nd-stage (L2; hatched from eggs) to early 3rd-stage (L3) and from in vivo-derived late L3 to early 4th-stage (L4). Larval survival, development, and motility were monitored for drug effects. Development of L2 to L3 was sensitive to thiabendazole, albendazole (ABZ), ABZ/sulfoxide, ABZ/sulfone (SO), mebendazole, L-tetramisole, D-tetramisole, piperazine, or closantel at a concentration of 0.01 microgram/ml; however, the effects of these drugs on larval development did not correlate well with known effects in vivo. The development of L3 to L4 was blocked by ABZ or mebendazole at 0.01 microgram/ml, by thiabendazole or ABZ/sulfoxide at 0.1 microgram/ml, and by ABZ/SO at 1.0 microgram/ml; however, except for ABZ/SO, most larvae were viable at these concentrations. In contrast, L-tetramisole or morantel appeared to inhibit development of L3 to L4 and to reduce survival at concentrations of greater than or equal to 1 microgram/ml; however, D-tetramisole was at least 10 times less effective. Haloxon, ivermectin, and closantel blocked development of L3 to L4 at 0.1, 1, and 10 micrograms/ml, respectively, in the absence of serum, but their activity was reduced by the presence of serum. Seemingly, in vitro development of A suum larvae was a convenient and sensitive bioassay for anthelmintic activity and could serve as a screen for anthelmintic residues in edible tissues.

Prophylactic efficacy of clorsulon against Fasciola hepatica in calves and sheep.

A daily oral 5 mg kg-1 dose of clorsulon for 28 days in calves given Fasciola hepatica cysts at 3, 5, and 7 days after initiation of treatment was highly effective in reducing worm burdens (98%) and preventing liver pathology. In similarly infected and treated sheep, clorsulon showed little effect as a prophylactic for delaying the onset of liver pathology. The size of flukes recovered from treated sheep was reduced. Although clorsulon prevented development of fascioliasis in treated calves, the host antibody response was qualitatively similar to that of untreated infected calves, but the magnitude of the response was reduced. Blood clorsulon levels in calves rose to 2.90 micrograms ml-1 within the first week of treatment then fluctuated between 2.65 and 2.90 micrograms ml-1 for the next two weeks. Clorsulon levels in sheep were 0.50-0.60 micrograms ml-1 lower than those in calf blood. The difference in bioavailability of clorsulon between sheep and calves may have contributed to differences in efficacy of the drug.

Interaction of Fasciola hepatica with albendazole and its metabolites.

Adult Fasciola hepatica recovered from sheep 12 and 24 h after a single oral dose of albendazole (20 mg/kg) contained significant amounts of two oxidized metabolites of albendazole (ABZ), a sulphoxide (SX) and a sulphone (SO), but not ABZ. Flukes incubated in vitro with 10 microM SX or SO contained these metabolites at a level two to three times the level observed in flukes recovered from sheep 24 h after a curative oral dose of ABZ. The concentration of ABZ in flukes was 10-fold greater than either SX or SO after a 24 h in vitro incubation in 10 microM of the respective drug. Flukes exposed to ABZ in vitro contained two-fold higher SX levels than SX-treated flukes due to a combination of spontaneous oxidation in media and fluke-mediated oxidation of ABZ. Measurement of end-products of glucose metabolism following 24 h incubation in 10 microM of either ABZ, SX or SO did not show a significant difference between treated and untreated flukes.

Effects of diamfenetide on metabolic and excretory functions of Fasciola hepatica in vitro.

The effect of diamfenetide (DFT) on the time course of production of end-products of glucose metabolism, tissue ATP levels and NH3 production by adult Fasciola hepatica in vitro was determined. Products of glucose metabolism are increased between 6 and 24 hr incubation in 10(-4) M DFT. Tissue ATP levels and NH3 production are decreased during this time period. The observed metabolic effects of DFT are manifested at a much later time after drug exposure than previously described membrane-disruptive events indicating that metabolic effects of DFT on F. hepatica may be secondary to the initial effects on surface membranes.

Fasciola hepatica: effects of diamfenetide free amine on in vitro physiology, biochemistry, and morphology.

Short-term (1-3 hr) incubations in vitro of immature and adult Fasciola hepatica with 10(-4) to 10(-5) M free amine of diamfenetide (DPT-FA) demonstrated a time/dose-dependent, irreversible paralysis that involved an increase in muscular tension and decrease in contraction amplitude. The following events occurred preceding or concomitant with the paralysis: influx of Na+, decrease in surface membrane potential, increase in wet weight, swellings on the ventral surface, and inhibition of 3-O-methyl glucose transport. These events were all consistent with a disturbance in surface membrane functions. The effects of DPT-FA were more severe in immature flukes (3-5 weeks postinfection) than adults which agrees with observed in vivo efficacy.

Oesophagostomum radiatum: glucose metabolism of larvae grown in vitro and adults grown in vivo.

Larval stages of Oesophagostomum radiatum grown in vitro and adults grown in vivo were incubated in complex media or in a simple salt solution containing radioactive glucose. Glucose disappearance and end product accumulation of third-stage larvae in a simple salt solution indicated that they excreted CO2 and acetic, propionic, and lactic acids. Larvae in third molt, fourth stage, and adults all excreted CO2, acetic, propionic, and lactic acids at twice the rate of third-stage larvae plus an additional product, methylbutyric acid. Carbon dioxide arose primarily from the 3 or 4 carbons of glucose. An anaerobic atmosphere (95% N2:5% CO2) had no apparent effect on metabolism. When incubation was done in complex media, isobutyric and 3-methylbutyric acids were seen as major excretion products (10 and 24%, respectively). However, these acids were quantitatively minor when incubations took place in simple salts-glucose medium (1 and 0-3%, respectively).

Comparative efficacy of albendazole against Fasciola hepatica in sheep and calves: relationship to serum drug metabolite levels.

Calves were given albendazole (ABZ) daily in feed at levels of 0,3 or 5 mg kg-1 day-1. None of the ABZ treatment levels was significantly effective in reducing Fasciola hepatica burdens. A dose rate of 5 mg kd-1 day-1 did significantly reduce the fecal egg count. Measurements of serum drug levels from calves following a single dose of ABZ showed ABZ levels to be low, but sulfoxide and sulfone metabolites of ABZ were present in (significant) larger quantities. The total available sulfoxide present in calves, however, was much lower than in sheep receiving the same dose of ABZ. Measurements of serum metabolite levels from sheep and calves which were given daily low-level doses of ABZ also indicated that the serum sulfoxide levels of calves were much lower than those of sheep receiving the same ABZ dose. These results indicated that ABZ is not an effective prophylactic treatment for bovine fascioliasis and the differences in efficacy between sheep and cattle correlated with the differences in serum metabolite levels.

Glucose metabolism of Haemonchus contortus adults: effects of thiabendazole on susceptible versus resistant strain.

Analyses of the in vitro glucose metabolism of Haemonchus contortus adults have confirmed a complex series of end-products: ethanol, n-propanol, propionate, acetate, and CO2 as the major end-products of catabolism. No difference in end-product accumulation was seen between the cambendazole sensitive (BPL) and cambendazole resistant (CR) strains. Thiabendazole (5 mM) in vitro depressed ethanol, propanol, acetate, and propionate accumulation by approximately 42% in the BPL strain. However, in the resistant strain (CR), these end-product accumulations increased by 50% when the worms were exposed to drug in vitro and 80% when exposed in vivo. Resistance manifested by the CR strain appeared to be associated with the ability to increase its carbon flow in the presence of thiabendazole.

Inheritance of cambendazole resistance in Haemonchus contortus.

Fourth-molt larvae (M4) of cambendazole-resistant (CBZ-R) and cambendazole-susceptible (BPL) strains of Haemonchus contortus were recovered from donor lambs and inoculated orally into source lambs to effect mating in 2nd lamb. Eggs produced by these parasitic matings were collected, cultured, and inoculated into lambs to compare the anthelmintic activity of cambendazole (CBZ), given at a dose rate of 20 mg/kg, against the F1 adults with its activity against the 2 parenteral strains (CBZ-R and PBL). In 2 replications, CBZ was 94% and 99% efficacious against the progeny of the cross matings and 91% and 95% against the BPL strain; CBZ was only 39% and 42% efficacious against the CBZ-R strain. In 1 test of F2 progeny of the reciprocal matings, CBZ was 81.2% efficacious against the F2 adults, whereas CBZ was 97.5% efficacious against the BPL strain and 37% against the CBZ-R strain. The results indicated that heredity of resistance to CBZ in H contortus is not sex-linked and is probably a result of a heterozygous recessive allele. The infective larvae of the CBZ-R groups in these 3 trials were from the 20th and 24th passages through lambs without exposure to any anthelmintics, yet the anthelmintic activity of CBZ ranged from 37% to 42%, indicating that there had been no reversion to susceptibility.

Efficacy of albendazole for prevention of fascioliasis in sheep.

Daily doses of albendazole administered as a premix in the feed for 35 days were effective in preventing Fasciola hepatica infections in 17 sheep in three groups: 5 mg/kg/day (6 sheep) was 100% effective; 3 mg/kg/day (5 sheep) was 98% effective; and 1 mg/kg/day (6 sheep) was 42% effective. Infective cysts were given daily for 5 days during the first week of treatment, treatment was continued an additional 28 days, and sheep were necropsied 14 weeks after final cyst inoculation. There were no visible lesions in any livers of sheep given albendazole at the rate of 5 mg/kg/day or in three of five livers of sheep dosed at the rate of 3 mg/kg/day. Sheep treated with albendazole had a mean weight gain of 2.7 kg, 4.0 kg, and 4.0 kg greater than the controls for the dosages of 1, 3, and 5 mg/kg/day, respectively. Determination of bile duct damage by measurement of serum gamma-glutamyl transpeptidase activity at 9 weeks after final cyst inoculation revealed increases of 3.0X, 1.0X, and 1.1X for the dosages of 1, 3, and 5 mg/kg/day, respectively, and 2.3X for the control, as compared with 7 weeks after final cyst inoculation.