The pharmacokinetics of gefitinib and its metabolites in rat and dog were investigated in preclinical studies conducted to support the safety evaluation and clinical development of gefitinib, the first EGFR tyrosine kinase inhibitor approved for the treatment of non-small-cell lung cancer. Following intravenous dosing (5 mg kg(-1), gefitinib plasma half-life was 3-6h in rats and dogs, although studies using a more sensitive HPLC-MS assay produced longer estimates of half-life (7-14h). In these studies, plasma clearance was high (male rat: 25 ml min(-1) kg(-1); female rat: 16 ml min(-1) kg(-1); male dog: 16 ml min(-1) kg(-1)), as was the volume of distribution (8.0-10.41 kg(-1) in rat; 6.31 kg(-1) in dog), and exposure in female rats was double that in males. Following administration of [14C]-gefitinib, concentrations of radioactivity in plasma exceeded gefitinib throughout the profile, indicating the presence of circulating metabolites in both rat and dog. An HPLC-MS assay was developed to measure concentrations of gefitinib and five potential metabolites in plasma. All five metabolites were detected in the rat, but at levels much lower than gefitinib. In the dog, exposure to gefitinib and M523595 was similar, with much lower concentrations of M537194 and only trace levels of the other metabolites. This profile of metabolites is similar to that observed in man.
The peripheral parasitaemia of the Trypanosoma rotatorium complex in the bullfrog (Rana catesbeiana) is markedly affected by temperature. Over the long term, high temperatures are always coincident with high peripheral parasitaemia and vice versa; over the short term, increases in temperature bring about a corresponding increase in parasite level, and vice versa. A distinct diurnal cyclicity in parasitaemic level is found for one morph (type D) at elevated temperatures (26 °C); no such cyclicity was apparent at low temperatures (10 °C). Other morphs did not display any cyclicity at either temperature. It is proposed that the control of peripheral parasitaemia is due to changes in the level of metabolic activity of the host.Natural selection will favor any behavioral or growth pattern among trypanosomes which results in an increased peripheral parasitaemia at times and under conditions of optimal host–vector contact. The present results suggest an optimal host–vector contact for basking frogs. The possibility of an insect vector is discussed.
The construction of a flow-through system of compartmentalized cages for frogs is described. These cages utilize readily accessible allld relatively inexpensive materials, and can be built with ease. They are suitable for use in any laboratory with a table top abutting on a sink, ao.d are adaptable. Also described are techniques for the year-round retention of large numbers of frogs using large holding tanks. Methods for feeding adult and larval Amphibia, and techniques for marking and blood sampling, are also given. Mortality is extremely low.
The extent of the peripheral parasitaemia of the Trypanosoma rotatorium complex in bullfrogs (Rana catesbeiana Shaw) is subject to fluctuations depending on the metabolic state of the host. Electrical stimulation causes a significant increase in the peripheral haemoflagellate levels. Moreover, injections of adrenalin chloride solution result in a similar response, while injections of acetylcholine and hypertensin do not. Adrenalin may act directly on the trypanosomes or indirectly via the host through such phenomena as elevated glucose levels. Blood pressure does not appear to be a factor.
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