Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT).

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m(-2). The half-lives of both MAG-CPT and released CPT were prolonged (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

Protection of cattle against heartwater in Botswana: comparative efficacy of different methods against natural and blood-derived challenges.

Five groups of Tswana-cross castrated male cattle between 20 and 30 months of age (a total of 158 animals) were transported from a ranch in a heartwater-free area of south Botswana to a feedlot near Gaborone in the east of Botswana where heartwater is endemic. On arrival, one group was vaccinated intravenously with the Onderstepoort sheep blood heartwater vaccine, one group was vaccinated intravenously with the new Onderstepoort tick-derived heartwater vaccine and a third group was vaccinated subcutaneously with this tick-derived vaccine. Vaccine reactions were blocked with long acting oxytetracycline on the first day of fever. A fourth group had a series of injections of long acting oxytetracycline on days 0, 7, 14 and 21 after arrival, and a fifth served as untreated controls. The animals remained at the feedlot for 65 days during which time they faced a low level of challenge by Amblyomma hebraeum ticks. None contracted heartwater and so they were then challenged, together with a further group of control cattle, with a dose of the sheep blood vaccine. Some animals in all groups had severe heartwater reactions and died despite therapy, but 76.7 per cent, 64.5 per cent and 74.3 per cent of the cattle in the blood vaccine, intravenous tick vaccine and long acting oxytetracycline groups respectively were resistant to challenge, compared with 48.3 per cent of the subcutaneous tick vaccine group and 36.4 per cent of the controls. It was concluded that intravenous vaccination of susceptible adult cattle with either the blood or the tick-derived vaccine needs careful monitoring in the month after vaccination and does not necessarily result in immune animals.(ABSTRACT TRUNCATED AT 250 WORDS)