Diclazuril, a new anticoccidial drug, was tested in poultry against six Eimeria species either in single species infections in dose titration studies or in mixed species infections in floor pen trials. The dose titration studies in cockerels indicated that diclazuril at dosages of 10, 5, 1, and .5 ppm was highly active against all major pathogenic species: E. tenella, E. acervulina, E. necatrix, E. brunetti, E. maxima, and E. mitis and effective in terms of weight gain and suppression of mortality, dropping scores, and oocyst counts. In two floor pen trials diclazuril was fed for 6 wk to broiler chickens experimentally infected either with E. tenella and E. acervulina or with E. necatrix and E. brunetti. Dose levels of 10, 5, and 1 ppm suppressed mortality and lesion scores. Even at 1 ppm the mean terminal body weight, feed conversion, and productivity index of treated birds were comparable to results for the uninfected, unmediated controls. In these pilot studies, involving 1,020 Hisex and 1,000 Hubbard broiler chickens, it has been demonstrated that diclazuril at the dose level of 1 ppm in the diet is an excellent anticoccidial without any adverse effects.

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For the development of new systemically acting, oral antifungal azoles, it is of key importance to compare them with ketoconazole, the first available drug in this therapeutic class.Ketoconazole is a major breakthrough although hepatic side-effects as well as interactions with mammalian steroids might rarely occur during prolonged treatment. The prediction of these side-effects is difficult but the potential to interact with mammalian cytochrome P-450 enzymes is considered to be important. Therefore, for the selection of itraconazole a multidisciplinary approach was applied to study this potential. The present paper deals with the toxicological profile of itraconazole and its safety evaluation. In addition, a further comparison with ketoconazole and also with fluconazole is provided, in so far sufficient information is available.For the liver as a potential target organ, the available data indicate that itraconazole is not a predictable hepatotoxic drug in man. The major endocrine targets for overdosing with antifungal azoles are the adrenal cortex and the gonads. Endocrine studies show that itraconazole is not bearing a potential to interfere with steroid hormones in patients, which is a major improvement when compared to ketoconazole. In rats, elevation of serum cholesterol is observed especially after chronic exposure to itraconazole. This species-specific phenomenon leads at toxic dose levels to secondary events, especially in the long-term toxicity studies. In man, including those with existing hypercholesterolemia, serum cholesterol is not adversely affected by itraconazole.In pregnant rats, ketoconazole was shown to be teratogenic at high, toxic doses. The same observation has been made for itraconazole and this also might be true for fluconazole. On the other hand, all three azoles are not teratogenic in the rabbit species. Studies with itraconazole in adrenalectomized rats and in rats given exogenous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are important mediators for teratogenicity. Since itraconazole does not affect adrenal function in patients, the teratogenic risk is estimated to be low.

A single 5-mg/kg oral dose of diclazuril affected both the asexual and sexual development of Eimeria tenella in experimentally inoculated chickens. In second-generation schizonts, early growth and nuclear divisions progressed normally, but a marked inhibition of merozoite formation was observed. Exogenesis of merozoites was largely prevented, whereas production of micronemes, amylopectin granules, and dense bodies and the formation of rhoptries, conoid, and pellicle continued. All these subcellular organelles accumulated, together with differentiated nuclei, within the main cytoplasmic mass. In the end, complete necrosis of the schizonts occurred. In macrogamonts, dilation of the rough endoplasmic reticulum around type II wall-forming bodies, fusion of type II wall-forming body contents, disturbance of the normal parallel arrangement of rough endoplasmic reticulum, and disruption of row formation of amylopectin granules became evident. In the microgamonts, normal evagination of microgametes was prevented; the flagellar complex formed within the main cytoplasmic mass and the differentiated nuclei remained present within the parasite body. The macro- and microgamonts also ended up in a stage of complete necrosis. These data indicate that diclazuril treatment primarily affects the normal differentiation of the respective endogenous stages during parasite development. This leads to complete degeneration of schizonts and gamonts indicating the lethal effect of this new anticoccidial compound.