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Notes: Summary The distribution and excretion of radioactivity from [14C]-fotemustine was examined in mice with melanomas at different stages of development to determine whether the disease state substantially alters the disposition of the drug and its metabolites. Normal BDF1 mice and mice that had been subcutaneously grafted with B16 melanoma either 1, 3, 7, 14 or 21 days previously were used. The animals were killed at either 5 min, or at 3, 24 or 96 h after receiving an intravenous dose of [14C]-fotemustine (20 mg/kg) and were examined either by whole-body autoradiography or by liquid scintillation counting of excreta and tissues of interest. The majority of the [14C]-fotemustine dose was excreted in the urine, with similar amounts being measured in both non-tumourous animals (61.6%±13.1%) and tumourous mice grafted 14 days previously (67.2%±5.7%). Small amounts of radioactivity, again similar in both non-tumourous and tumourous mice, were recovered in the faeces (5.4%±5.6% and 3.6%±1.8%, respectively) and as carbon dioxide (7%±3.5% and 6.4%±1%, respectively), with minimal amounts being expired as chloroethanol (〈1%). When mice were examined 5 min after dosing, there was extensive tissue distribution accounting for 75%±10% of the dose. The highest concentrations determined by both whole-body autoradiography and liquid scintillation counting were measured in the excretory organs, with 33 and 28 μgEq/g being found in the liver and kidney, respectively. High levels were also seen in the lung and plasma (19.8 and 19.5 μgEq/g, respectively). Analysis of variance indicated that groups of tissues, such as the excretory organs, blood and plasma or the pigmented tissues, showed distinct but inconsistent patterns. Only tumours at 14 and 21 days of development were suitable for examination, and these showed levels of 12.1 μgEq/g; however, the tumourto-plasma ratio increased from between approx. 0.5 and 0.6 at 5 min to approx. 2 at 96 h after dosing, suggesting retention within the melanoma, whereas the ratio for the femur remained at approx. 1. Whole-body autoradiography showed that the distribution in the tumour was not uniform, but rather was concentrated in the peripheral area (presumably viable cells) as opposed to the central necrotic region. Thus, the high and sustained concentration of radioactivity found in the active cells of the melanoma may provide an explanation for the high efficacy of the drug.

Notes: Abstract In a model of bronchopulmonary aspergillosis terbinafine did not improve survival of experimental animals in doses up to 80 mg/kg/day despite adequate lung concentrations. Pretreatment and aerosolization of the compound were also ineffective. Terbinafine was markedly less active in vitro when serum was used instead of Yeast-Nitrogen-Glucose-broth. It is concluded that a lack of bioavailability in the presence of serum may explain the lack of activity of terbinafine in experimental aspergillosis.

Notes: Abstract The in vitro activity of cilofungin (LY121019), a new semi-synthetic antifungal agent was evaluated. Potent activity was seen againstCandida albicans andCandida tropicalis, with almost identical MIC and MFC results, whereas no activity was seen against any isolates ofCandida parapsilosis or threeAspergillus spp. However, MICs were dependent on medium and test conditions chosen. It is concluded that cilofungin has good activity against some medically important yeasts in vitro, and that its in vitro activity depends on the method used.