Investigations into the use of continuous low-level medication for the control of helminths in the ruminant
The work presented in this thesis is concerned with the chemotherapy of parasite infestations in the ruminant with the anthelmintic thiophanate [diethyl 4,4'-o-phenylene bis (3-thioallophanate)]. A new concept of administration was investigated, namely continuous low-level anthelmintic medication. Two aspects were studied which divide conveniently into two sections. In Section 1, following preliminary trials undertaken to assess the low-level anthelmintic activity of thiophanate, the effects are assessed when this drug is administered continually directly into the rumen of parasitised sheep. Thiophanate was infused at dosages between 3.0 and 5.0 mg per kg bodyweight over various periods of medication against various developmental stages of gastro-intestinal parasites. The daily drug release rate. required to inhibit egg hatch and eliminate the worm burden is established. A minimum daily release rate of 3.0 mg per kg bodyweight was shown to be required to completely inhibit egg hatch and 4.5 mg per kg for effective vermicidal activity. In similar experiments, the anthelmintic activities of levamisole (s-(-)-2,3,5,6-tetrahydro-6-phenylimidazo (2,1-b) thiazole), febantel (N-(2-(2,3-bis-(methoxycarbonyl)-guanidino)-5-(phenyl-thio)-phenyl)-2-methoxy-acetamide) and briefly oxfendazole (5-(phenylsulfinyl)-IH-benzimidazol-2yl) carbamate) were also examined. In Section 2, the development of an intra-ruminal bolus incorporating thiophanate and designed to release drug at a predetermined rate over an extended period of time is described. Experiments were carried out in sheep to assess the bolus density required for retention within the reticulo-rumen (monitored by direct bolus recovery), to compare various density factors (iron powder, iron bar core, iron shot and sand) and to assess the average drug release rate from different matrix formulations (based on fatty acids, palmitic acid and paraffin wax) when the boluses were dosed singly or in pairs. The development of a stable "carrier" on which to load a suitable matrix is also described, the majority of the experiments undertaken utilising this "carrier". The effect on the drug release rate of incorporating various "leaching aids" (digestible materials, wetting and soluble agents) into the matrix is examined and preliminary anthelmintic trials undertaken in experimentally infected lambs. The required drug release is achieved when the boluses are administered in pairs. The anthelmintic activity is confirmed. Possible matrices suitable for use as a single bolus administration were produced. The advantages of this form of anthelmintic medication over the single therapeutic dose are discussed along with some indications for further studies that emerged.