ponazuril and toltrazuril

Triazines are relatively new antiprotozoal drugs that have successfully controlled coccidiosis and equine protozoal myeloencephalitis. These drugs have favorably treated other protozoal diseases such as neosporosis and toxoplasmosis. In this article, we discuss the pharmacological characteristics of five triazines, toltrazuril, ponazuril, clazuril, diclazuril, and nitromezuril which are used in veterinary medicine to control protozoal diseases which include coccidiosis, equine protozoal myeloencephalitis, neosporosis, and toxoplasmosis.

Topics: Acetonitriles; Animals; Antiprotozoal Agents; Coccidiosis; Encephalomyelitis, Equine; Horses; Nitriles; Protozoan Infections, Animal; Toxoplasmosis, Animal; Triazines

Co-amorphous supersaturated drug delivery systems are emerging as an alternative strategy to improve the water solubility of BCS II drugs. Typically, the supersaturation and stability of co-amorphous systems largely depend on the type of employed co-former. This study aims to assess the potential for active metabolites of drugs as co-former in drug-drug co-amorphous formulations. Toltrazuril (Tol) was chosen as the model drug, to which ponazuril (Pon) was added as co-former. Considering the importance of intermolecular interactions in co-amorphous systems, we performed highlighted investigations including molecular dynamics simulation and quantum mechanics calculations. The results indicated that Tol and Pon molecules were connected by N-H···O = C hydrogen bonds in the form of a complementary pairing of amide groups. Further, the solubility/dissolution and solid-state stability of the co-amorphous system were investigated. We found that co-amorphous Tol-Pon was stable for at least one month at 40 °C/75% RH, while amorphous materials underwent recrystallization within 10 days. Moreover, both drugs in the co-amorphous system exhibited enhanced "spring parachute effect" during the dissolution process. This could be attributed to the noticeably increased solid-state stabilization as well as inhibition of Pon on the crystallization of Tol from a supersaturated state. In general, our study provides some useful information and molecular insights to guide the development of drug-active metabolite-based co-amorphous formulations.

Topics: Drug Stability; Pharmaceutical Preparations; Solubility; Triazines

Mice infected with tachyzoites of Neospora caninum (syn.: Hammondia heydorni) must be pretreated with cortisone in order to show disease symptoms. This indicates the status of an opportunistic agent of disease. Toltrazuril was an effective curative agent.

Topics: Animals; Coccidiosis; Coccidiostats; Cortisone; Mice; Neospora; Triazines

Rhesus monkey kidney cell cultures were used to propagate tachyzoites of the NC-1 strain of Neospora caninum (syn. Hammondia heydorni). The infected cell cultures were incubated for 4-12 h in media containing 0, 1, 10 or 100 microg/ml of either toltrazuril or ponazuril. The effects were studied by light and electron microscopy. Drug dosages of at least 30 microg/ml were needed to eliminate the parasites. Ponazuril was found (with respect to the reduction of the number of parasites) to be less effective at dosages of 30 microg/ml compared to toltrazuril. However, the damage to the tachyzoites being incubated in 30 microg toltrazuril or ponazuril seen by electron microscopy was so significant that it was surely lethal. The initial damage occurred within the apicoplast and the tubular mitochondrion in all cases,thus destroying two of the most important cell organelles.

Topics: Animals; Cell Line; Coccidiostats; Culture Media; Macaca mulatta; Microscopy; Microscopy, Electron; Mitochondria; Neospora; Organelles; Triazines

The production of an antibody to detect toltrazuril or its metabolite ponazuril is complicated due to structural constraints of conjugating these coccidiostats to a carrier protein. Therefore a search was carried out for a compound that shared a common substructure to use as an antigen mimic. The chosen compound, trifluoraminoether, was conjugated to two carrier proteins (HSA and BTG) and used in the immunisation of six rabbits. Two immunogen doses (1 mg and 0.1 mg) were also used. All six rabbits produced an immunological response to the hapten regardless of the carrier protein or immunogen dose used. The most sensitive polyclonal antibody produced, designated R609, was subsequently characterised. This antiserum exhibited an IC50 of 18 ng ml(-1) using a competitive ELISA format. Cross reactivity studies show that this serum is specific for toltrazuril and its metabolites (toltrazuril sulfoxide and toltrazuril sulfone) but does not cross-react with other coccidiostats such as halofuginone, nitroimidazoles or nicarbazin. This is the first reported production of an antibody capable of specifically binding toltrazuril and ponazuril.

Topics: Animals; Antibodies; Benzene Derivatives; Coccidiostats; Ethers; Haptens; Immunization; Molecular Mimicry; Rabbits; Triazines

Neosporosis is a disease affecting predominantly fetal development in cattle and dog hosts; and it may cause neuromuscular disfunction in infected newborn calves and pups. Predispositions--including, e.g. transient immunosuppression during pregnancy--may result in an increased dissemination of the parasite within the host or its offspring. Chemotherapeutic treatment of neosporosis may be an issue, provided that an appropriate drug is made available. In this respect, we describe the use of a mouse model for the evaluation of toltrazuril and ponazuril medication as a means of preventing parasite dissemination and subsequent formation of cerebral lesions. Toltrazuril- and ponazuril-treated mice were experimentally infected intraperitoneally (i.p.) with 2 x 10(6) Neospora caninum tachyzoites. The infection was monitored at three levels: clinically, by assessing symptoms, histologically, by assessing the occurrence of cerebral lesions and parasites by immunohistochemistry, and on the molecular level, by detection of parasite DNA using PCR. Chemotherapy using either toltrazuril or ponazuril, both applied in a drinking-water formulation (20 mg toltrazuril or ponazuril kg(-1) body weight day(-1)) completely prevented the formation of cerebral lesions in all treated animals, as assessed by immunohistochemistry. PCR analyses of these treated animals showed that DNA-detectability was reduced by 91% and 90% upon toltrazuril and ponazuril medication, respectively.

Topics: Animals; Antibodies, Protozoan; Coccidiosis; Coccidiostats; Female; Mice; Mice, Inbred C57BL; Neospora; Triazines