8-Aminoquinolines as anticoccidials--II.

During a chemistry program aimed at finding a novel analogue of pentaquine with improved in vivo activity, a number of hypotheses concerning the way this drug acts in the chicken were investigated. Consideration of the products of monoamine oxidase metabolism of pentaquine suggested that pentaquine aldehyde is the likely active metabolite. Although isolation of this unstable compound was not possible, oxime and cyclic acetal and ketal derivatives were obtained and shown to possess in vitro anticoccidial activity.

Antagonistic effect of nucleic acid precursors on the anticoccidial activity of 6-azauracil.

The antagonistic phenomena to anticoccidial activities of 6-azauracil (AzU) induced by certain nucleic acid precursors were examined in battery experiments. Each nucleic acid precursor, orotate, orotidine, uracil, uridine, adenine and adenosine was mixed in feed in combination with effective levels of AzU. The test feed was provided through the test term to White Leghorn cockerels which were infected with Eimeria tenella, E. necatrix or E. acervulina. In vitro tests were also conducted for antagonistic phenomena similarly to in vivo test using E. tenella cultured in chick kidney (CK) cells. Orotate and uridine reduced dose-dependently the anticoccidial activity of AzU in E. tenella infection in chickens. Uracil and orotidine revealed similar effect. Adenine and adenosine did not show any antagonistic effect to AzU. In E. necatrix infection, orotate and uridine had a similar tendency to that of E. tenella, whereas uracil and orotidine was less pronounced. The activity of AzU against E. acervulina was also blocked by the treatment with uridine and orotate. AzU inhibited the schizont's development of E. tenella in the CK cells, and this effect was reduced by uridine, but not by orotate and orotidine. The antagonistic effect of the pyrimidine nucleic acid precursors on AzU activity suggested that the anticoccidial effect of AzU to E. tenella, E. necatrix and E. acervulina is derived from inhibition of the metabolism of pyrimidine nucleotide synthesis in these parasites.

Investigation for the characteristic anticoccidial activity of diclazuril in battery trials.

To clarify the character of the anticoccidial activity of diclazuril a series of battery trials was conducted. Diclazuril showed excellent anticoccidial activity in the infection of chickens with Eimeria tenella, E. necatrix or E. acervulina at the feeding level of 0.1 ppm. When diclazuril was administered in combination with a nucleic acid precursor, uracil, uridine, orotate or orotidine, the reduction of the activity of diclazuril to the infections induced by above species was not observed. While, bloody droppings with severe cecal lesions were resulted, when diclazuril was administered in combination with uridine 5(1)-diphosphoglucose (UDPG) or its N-acetyl amine (UDPGNAC) to chickens infected with E. tenella. While, body weight gain of the birds and oocyst output was not affected by these combination-treatment. Results demonstrated that the antagonistic effect of UDPG and UDPGNAC to diclazuril was partial. The possibility of the cross resistance between diclazuril and 6-azauracil (AzU) in E. tenella was investigated using two populations induced resistance to AzU or diclazuril. The results demonstrated that the cross resistance does not exist between AzU and diclazuril, indicating that the mode of action of each drug is different.

alpha-Difluoromethylornithine: a promising lead for preventive chemotherapy for coccidiosis.

alpha-Difluoromethylornithine (DFMO; RMI 71,782) given in drinking water in concentrations as low as 0.0625% inhibited infections of Eimeria tenella and minimized the development of lesions in chickens. It had approximately the same activity as a currently used anticoccidial drug, amprolium, and also had the advantage of being relatively nontoxic in chickens. Body weight gains were not reduced in chickens given 0.0635% DFMO or less for 14 days starting 8 days before they were inoculated with oocysts, but were reduced in chickens given drinking water containing 0.125 and 0.25% DFMO. The anticoccidial activity of DFMO was completely reversed by injection (intraabdominal) of putrescine hydrochloride (300 mg/kg of body weight/day), indicating that the drug may act by blocking putrescine biosynthesis. Inoculated chickens, in which coccidial lesion development was suppressed by DFMO, resisted subsequent challenge exposure with E tenella, as did nontreated infected control birds which had recovered from infection.