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4-Chlorobenzaldehyde 1-(4-chlorophenyl)-4(1H)-pyridinylidene hydrazone fluorusulfonate (4) was found to have excellent anticoccidial activity in chickens. The synthesis and biological evaluation of related analogues are presented. Presumably 4 shares a common mechanism of action with robenidine (25) since it was not active on a robenidine tolerant strain of E. tenella. Structural comparisons of the two molecules are presented.
Anticoccidial drugs were evaluated for activity and for the development of resistance in a model of Toxoplasma gondii growing in human fibroblast cultures. Of 13 anticoccidial drugs tested, 9 had selective antitoxoplasma activity (50% inhibitory concentration, in micrograms per milliliter): decoquinate (0.005), arprinocid-N-oxide (0.015), robenidine (0.03), the aryl triazine CP-25,415 (0.2), toltrazuril (0.4), clopidol (1), dinitolmide (Zoalene; Dow) (10), and the carboxylic acid ionophores monensin (0.001) and salinomycin (0.04). Glycarbylamide, amprolium, nicarbazin, and the 6-(p-bromophenoxy)-7-chloro analog of halofuginone (Stenorol; Roussel-UCLAF) (CP-63,567) were toxic for the fibroblasts. Since Eimeria tenella has a similar drug susceptibility profile, anticoccidial drugs can be viewed as a potential source of new antitoxoplasma therapies. The development of resistance has limited the usefulness of most of these drugs as anticoccidial agents; in coccidia, resistance to all except the ionophores occurs readily in vivo. We explored the development of resistance in T. gondii by attempting to select mutants in vitro from parasites mutagenized with ethylnitrosourea. Mutants that had 20- to 50-fold-reduced susceptibility to decoquinate, arprinocid-N-oxide, and CP-25,415 were obtained. Ionophore-resistant T. gondii mutants were also selected in vitro; however, there was only a twofold difference in susceptibility between these mutants and the wild type. For three drugs (clopidol, robenidine, and toltrazuril), we were unable to select resistant mutants. For experimental anticoccidial drugs, there is currently no in vitro method for assessing the risk of development of resistance in Eimeria species. Our results suggest that T. gondii may offer a useful surrogate for this assessment.
Two experiments were conducted to determine the effects of anticoccidial agents on production and reproduction of broiler breeders. In Experiment 1, nicarbazin (NCZ) was fed at 20, 50, and 100 ppm. There was no depression in egg production, egg weight, or fertility from feeding these levels. As level of NCZ increased, there was a linear decrease in hatchability. The amount of 4,4'-dinitrocarbanilide (DNC) in the egg yolks increased linearly as the levels of NCZ went up; the degree of egg-shell depigmentation was directly related to the level of NCZ fed starting at 50 ppm. Experiment 2 utilized a different strain of broiler breeders. Halofuginone (3 ppm), maduramicin (5 ppm), monensin (100 ppm), narasin (70 ppm), NCZ (125 ppm), robenidine (33 ppm), and salinomycin (60 ppm) were fed to broiler breeders at the levels listed. Only NCZ reduced egg production. Narasin induced a reduction in egg weight. Both narasin and salinomycin caused a significant drop in hatchability. Feeding NCZ also induced a rapid and more severe decrease in hatchability. Monensin was the only anticoccidial agent that reduced fertility. Halofuginone, maduramicin, and robenidine had no biologically significant effect on henday production, egg weight, hatch of fertile eggs, or shell depigmentation. Feeding NCZ at 125 ppm caused a complete bleaching of brown-shell eggs by the 3rd consecutive day of treatment; but 7 days after NCZ was withdrawn from the feed, pigmentation returned to the pretreatment level.
Two studies were conducted to determine the effects of anticoccidial agents on the production and reproduction of White Leghorns. In Experiment 1, nicarbazin (NCZ) was fed at 0, 20, 50, and 100 ppm. Hen-day egg production, egg weight, the egg-yolk DNC (4-4'-dinitrocarbanilide) level, and egg-yolk mottling were affected by the treatments. When response was evidenced, the relationship between those variables and the level of NCZ was basically linear. Decreased egg production occurred from Days 5 and 6 of the treatment through Days 1 and 2 of withdrawal. On Days 9 and 10 of treatment, the control hens peaked at 92% hen-day production, while hens fed 20, 50, and 100 ppm of NCZ peaked late--at 90, 82, and 80%, respectively. Compared to the controls, egg weight was reduced linearly as the level of dietary NCZ increased. The egg-yolk DNC level increased from Days 3 and 4 of treatment through Days 9 and 10 of withdrawal. Egg yolk mottling generally increased along with the level and duration of feeding NCZ. If the NCZ was mistakenly fed to White Leghorn layers, ill effects would be alleviated within 10 days after drug withdrawal. In Experiment 2, halofuginone (3 ppm), maduramicin (5 ppm), monensin (100 ppm), narasin (70 ppm), nicarbazin (125 ppm), robenidine (33 ppm), and salinomycin (60 ppm) were fed to White Leghorn hens at the levels specified in parentheses. Nicarbazin reduced egg production, depressed egg weight, reduced shell thickness, and caused egg-yolk mottling; but internal egg quality, as measured by Haugh Units, was unaffected. Halofuginone, maduramicin, monensin, narasin, robenidine, and salinomycin did not have a meaningful effect on the variables measured when fed to White Leghorn layers.
The spectrum of resistance to seven currently used anticoccidial drugs in isolates of Eimeria obtained from farms two broiler complexes was examined. All isolates were resistant to monensin, salinomycin, and narasin. Lasalocid was more effective in controlling coccidiosis than the other ionophores, although most isolates were classified as resistant to the drug. The majority of isolates were sensitive or showed reduced sensitivity to robenidine, clopidol, and decoquinate. It was concluded that for drugs that have been used extensively (e.g., monensin and salinomycin), examination of isolates from one or two farms may give results applicable to the entire complex. For drugs that have been used infrequently, however (such as robenidine, clopidol, and decoquinate), examination of isolates from at least five farms would be desirable to establish the spectrum of drug sensitivity.
Coccidia were isolated from 122 Belgian broiler farms without clinical coccidiosis. Shuttle programs including robenidin or nicarbazine in the starter (7-14 days) followed by an ionophore or diclazuril in the grower ration were most commonly used. Out of 215 coccidiosis-positive groups, 146 Eimeria acervulina, 65 E. maxima, and 88 E. tenella isolates were tested without further laboratory propagation in 17 sensitivity profiles. For each profile, oocytes were pooled from 9 +/- 4 farms (mean +/- SD) that used the same anticoccidial program and that belonged to the same integrated broiler operation. Each suspension contained an equal number of isolates and oocyst numbers from each farm tested. Each profile included an unmedicated uninfected group, an unmedicated infected group, and 11 medicated infected groups, consisting each of three replicates of three Ross chicks. Medication started at 8 days of age, and each inoculated bird received 50,000 sporulated oocysts at 10 days. Results were related to the anticoccidial program that had been in use. Chemical drugs showed the highest activity against Eimeria, whereas ionophores were less efficacious. Of the latter, monensin (110 ppm) was least active; narasin (70 ppm), salinomycin (60 ppm), and maduramicin (5 ppm) took an intermediate position, and lasalocid (90 ppm) was most active. A 50% improvement in weight gain was obtained in 7 to 10 out of 17 profiles with 100 + 8.35 ppm clopidol/methylbenzoquate (10), 125 ppm nicarbazin (9), 3 ppm halofuginone (8), and 1 ppm diclazuril (7). A 50% improvement in feed conversion was obtained in 7 to 11 profiles with nicarbazin (11), halofuginone (10), diclazuril (9), 33 ppm robenidine (9), clopidol/methylbenzoquate (7), and lasalocid (7). Based on relative oocyst output, the highest activity against E. acervulina was obtained with clopidol/methylbenzoquate (8/16); the highest activity against E. maxima was obtained with lasalocid (6/6), diclazuril (5/6), and halofuginone (5/6); and the highest activity against E. tenella was obtained with diclazuril (8/8), amprolium/ethopabate (5/8), halofuginone (4/8), maduramicin (4/8), and nicarbazin (4/8).
The investigations were performed on 6 farm rabbitries in Wrocław district. Average extensiveness of coccidia infection was 95%, while intensity ranged from 50 to 408,700 ocysts/g of faeces. Nine species of coccidia were identified. Eimeria perforans (84.5%) and E. stiedai (73.2%) dominated, E. coecicola was noticed most seldom (20.7%). In young rabbits up to 3 months of life the infections were caused by 5-9 species of coccidia. However, in animals from breeding herd there prevailed infections caused by 1-3 species. Congeneric infections were stated very rarely, i.e. in 5.7% of infected animals only. Dynamic changes in the intensity of coccidia infections in rabbits in the course of one year breeding cycle on one of the farms demonstrated the occurrence of two peaks in females used for reproduction: the first one in the perinatal period and the second one in the period preceding weaning. The letter one, higher than the first one, was caused by keeping young rabbits with mothers for 8-10 weeks. The studies on the effectiveness of anticoccidial drugs were carried out on California White rabbits (age 5-7 weeks), infected naturally with 9 species of coccidia. Rabbits were given for 5 weeks the following anticoccidials: lasalocid (Avatec), maduramycin (Cygro), robenidine (Cycostat), salinomycin (Sacox), monensin (Elancoban), clopidol + methylbenzoquate (Lerbek) and narasin (Monteban). The best results were obtained with salinomycin at the dosages of 35, 50, 25 ppm and maduramycin at 2 and 3 ppm. Equally effective, but characterized by lower production indices, were: clopidol + methylbenzoquate (216.7 ppm), lasalocid (90, 125 ppm) and monensin (20 ppm). Robenidine was very effective against intestinal coccidia at the dose of 66 ppm, however it had weak effect on E. stiedai's infection. Narasin and maduramycin (4.5 ppm) had toxic effect on animals. A field trial (anticoccidials applied for 6 weeks in does and their progeny) confirmed high effectiveness of salinomycin (25 ppm), maduramycin (1.5 ppm) and monensin (20 ppm).
Ten Eimeria field isolates from North Germany were studied in battery tests for sensitivity to selected anticoccidials. A high percentage of the Eimeria field isolates (9 out of 10) showed resistance to anticoccidials, mostly multiple resistance. Partial or complete resistance to maduramicin was found in 7 field isolates, to monensin in 6, to salinomycin in 5, to nicarbazin in 8, to halofuginone in 7, to robenidine and toltrazuril in 1, and to diclazuril in 2 field isolates. Multiple resistance had developed in 7 of the 10 isolates. Cross-resistance between maduramicin, monensin, and salinomycin occurred in 5 Eimeria isolates. One isolate showed cross-resistance between diclazuril and toltrazuril. From the resistant isolates 15 pure E. acerculina and 5 pure E. brunetti strains were obtained by single oocyst infections. Seven of the E. acerculina and 4 of the E. brunetti strains showed resistance or partial resistance that was also present in the original isolate. Ten of 11 resistant strains were multiply resistant.
The anticoccidial action of 6 drugs was studied by treating cell cultures with drug for 24 h after inoculation of the cultures with sporozoites of Eimeria tenella. A monitoring technique was used to confirm that the drug was being removed. Only monensin was shown to be coccidiocidal. Amprolium, lasalocid, methyl benzoquate, nicarbazin and robenidine were coccidiostatic at their minimum effective doses. Misleading coccidiocidal effects were observed when higher concentrations of methyl benzoquate, nicarbazin or robenidene were used.
Features of the anticoccidial activity of nicarbazin, amprolium, zoalene, sulphadimidine, diaveridine, Darvisul, spiramycin, chloramphenicol and oxytetracycline have been re-investigated both in vivo and in cell culture using Eimeria tenella. Of the drugs studied, only spiramycin was appreciably coccidiocidal, although nicarbazin and amprolium showed possibly slower coccidiocidal activity. In order to show activity against a particular stage in the life-cycle, higher concentrations of drug than those usually recommended for field usage had in most cases to be used. Under these conditions, parasites were usually inhibited as multinucleate 1st generation schizonts. With delayed medication, effects against 2nd generation parasites were in most cases found, and in many cases, although the parasites never matured to give viable merozoites, the large degenerating forms produced were able to cause extensive tissue destruction and haemorrhage. Methodology in this type of study is discussed in relation to more active and more recent anticoccidials, and some further experiments with robenidine reported.
Coccidia were isolated from litter samples collected in poultry houses in Georgia and other southeastern states and from intestinal scrapings from chickens submitted to diagnostic laboratories. The most common species of coccidia encountered were E. tenella, E. acervulina, and E. maxima. Each of the 41 isolates was tested for sensitivity to eight commercial anticoccidial drugs. Most of the isolates were resistant to some of the drugs judged by the parameters of percent weight gain, percent lesion score reduction, and a sensitivity index score. There was a high frequency of resistance to clopidol, amprolium/ethopabate, nequinate, zoalene, and sulfaquinoxaline. A very small percentage of the isolates tested were resistant to nicarbazin, robenidine, or halofuginone.
A floor-pen trial was conducted to investigate the effects of different shuttle programs upon the growth of broilers to 8 wk of age. Nicarbazin, halofuginone, and robenidine, when included in the starter feed for 3 wk, were effective in preventing lesions due to Eimeria. The effects of medication upon performance were apparent, medicated groups gaining more weight by 6 wk and having a lower feed conversion at 6, 7, and 8 wk than the unmedicated controls. There were no significant differences in body weight at 6, 7, or 8 wk or feed conversion at 6 or 7 wk among the medicated groups, whether medication was withdrawn for 7 or 14 days. A decrease in the number of small and medium oocysts in the litter was observed as the trial progressed. Few large oocysts (Eimeria maxima) were seen in the medicated groups. Numbers of oocysts did not increase following withdrawal of medication. Birds from all medicated groups were challenged at 6 wk with oocysts of Eimeria acervulina, Eimeria maxima, or Eimeria tenella. Weight gains were similar to that of the unchallenged controls, indicating that they had acquired immunity to these species of Eimeria.
Thirty isolates of Eimeria tenella obtained from broiler and breeder farms were examined for their sensitivity to anticoccidial drugs. All were sensitive to robenidine, 28 were sensitive to methyl benzoquate, 25 to clopidol and 21 to nicarbazin. Most isolates were resistant or partly resistant to amprolium and dinitolmide.
Eimeria mivati was described as a new species of chicken coccidia in 1964 by Edgar and Seibold, but recently some British workers have relegated its status to that of a variety of Eimeria acervulina. Using strains supplied by Dr. Edgar, we have prepared lines of E. acervulina resistant to methyl benzoquate, sulfaquinoxaline and robenidine and a line of E. mivati resistant to methyl benzoquate. Genetic transfer of resistance between the various lines of E. acervulina to produce doubly-resistant coccidia has been demonstrated, but no such transfer could be obtained between E. mivati resistant to methyl benzoquate and the resistant lines of E. acervulina. Although some immunological relationship between E. acervulina and E. mivati has been demonstrated, we conclude that this failure of the 2 organisms to interbreed lends support to the status of E. mivati as a distinct species.
The activity of sulphaquinoxaline, robenidine, methyl benzoquate, clopidol and a mixture of methyl benzoquate and clopidol (Lerbek; Dow), was studied in rabbits infected with hepatic coccidiosis due to Eimeria stiedai. Growth inhibition, oocyst production and the activity in the serum of glutamate dehydrogenase and gamma glutamyltransferase were studied as indicators of parasite development. Only sulphaquinoxaline and Lerbek gave satisfactory control of this parasite. The latter formulation was more effective than either of its constituents used alone.
Anticoccidial drugs were added to diets formulated with a nutrient density of 1479 kcal/lb and 24% protein or with 80% of those energy and protein levels (low density) to determine whether rate of feed intake influences efficacy of drugs in broilers infected with coccidiosis. In four experiments with monensin, broilers receiving 60 or 100 ppm of monensin in the lower-density ration consumed more feed per unit of gain but gained less weight than those on the control diet. Coccidiosis (Eimeria tenella) was better controlled by 60 ppm of monensin in the low-density diet than in the high-density diet. There was some evidence of a similar efficacy-enhancing effect with nicarbazin, salinomycin, and lasalocid but not with robenidine. When drug intake was calculated as mg/kg of weight gain, there was a strikingly higher rate of intake of most drugs in the low-density diet, accounting for the apparent increase in activity. These results suggest that in countries where nutrient density of feeds varies significantly from those used in the United States, some compensation in levels of certain feed additives might be considered.
Infections of Eimeria tenella in chicken embryos were used to compare the anticoccidial activity of ten drugs. The minimal inhibitory concentration (MIC) and minimal toxic concentration (MTC) were affected by the time of inoculation into the embryos and by the chemical nature of the compounds. Some compounds (nicarbazin, amprolium) had no effect on the development of coccidia when they were injected into embryos after the day of infection. Drugs that act early in the life cycle of coccidia (robenidine, clopidol, decoquinate, diclazuril, halofuginone, monensin, salinomycin, and lasalocid) were active at 5-125 micrograms/embryo when they were injected on the day of infection. The ionophores and halofuginone were highly toxic to embryos; most synthetic compounds were nontoxic. The incubation of merozoites in drug suspensions prior to the infection of embryos did not result in embryo toxicity, but the resultant MICs were much higher than those obtained when drugs were injected directly into the embryos. Several products were essentially inactive. Neither nicarbazin nor amprolium prevented oocyst formation. The widely divergent endpoints for the MIC and MTC of anticoccidials in embryos seriously limits the application of this technique as a screen for anticoccidial drugs.
The short-term toxicity (EC50 respectively LC50 after 2 or 4 days) of 13 feed additives was determined to 4 freshwater organisms of different trophical levels: Chlorella pyrenoidosa, Daphnia magna, Lebistes reticulatus and Salmo gairdneri. The most toxic (LC(EC)50 less than 1 mg/1) were robenidine (to all tested organisms) and stenorol (to Daphnia); moderately toxic (1 less than LC(EC)50 less than 10 mg/1) was pyrimethamine. Amprolium, ethopabate, furazolidone and zoalene proved to be little toxic (LC(EC)50 greater than 10 mg/1); whereas buquinolate, carbadox, clopidol, decoquinate, grofas and sulfaquinoxaline were under the experimental conditions not toxic for the tested organisms.