A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with Ki values of 28, 14, 17 and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg and volume of distribution was 0.6 ± 0.2 L/kg.
Several multi-stage infusion regimens and a computer controlled exponentially decreasing infusion regimen were evaluated in twelve patients undergoing head and neck surgery or neurosurgery. Thiopentone dosage was based on the mean of pharmacokinetic parameter values from the literature and adjusted for each patient's lean body mass in order to rapidly achieve a predetermined plasma thiopentone concentration of 15 or 20 micrograms/ml in the period following the initial bolus dose to induce anaesthesia. Anaesthesia was satisfactory in all cases. Plasma thiopentone concentrations were maintained between 10-20 micrograms/ml during infusion in the five patients who received either a four or five stage infusion and in the six patients who received the exponential infusion, but not in the single patient who received a two-stage infusion. The mean recovery time was 111 min. The plasma concentrations of total and unbound thiopentone at awakening showed little intersubject variability, despite considerable differences in total dose and duration of infusion, suggesting the absence of acute tolerance to the drug. Plasma clearance of total thiopentone correlated strongly with calculated lean body mass and to a lesser extent with total body weight suggesting that lean body mass, in particular, should be an accurate predictor of thiopentone maintenance dose requirements. This study shows that it is feasible to use thiopentone as a primary anaesthetic agent during surgery by administering the drug either as an exponentially decreasing infusion or as an infusion comprising 4 or 5 stepwise decreasing rates.
SummaryThe plasma concentrations and elimination ha!fZf'e of pentobarbitone were determined in 14 Thiopentone, widely used as an anaesthetic induction agent, is metabolised in the body to a variety of metabolites including pentobarbitone, which is formed by desulphuration and accounts for 2 4 per cent of the thiopentone dose administered.' Although pentobarbitone is pharmacologically active, it has been suggested that the significance of this metabolic pathway is only of relevance in patients where large doses of thiopentone are used for cerebral resuscitation.2 Stanski et aL3 studied thiopentone pharmacokinetics in patients receiving continuous infusions for up to 2 4 days for cerebral resuscitation. They found that thiopentone exhibited MichaelisMenten (nonlinear) kinetics and that plasma pentobarbitone concentrations were approximately 10 per cent of thiopentone concentrations at the end of the infusion. However, it is possible that the formation of pentobarbitone could have been saturated a t the high plasma thiopentone concentrations (about 70 pg/ml) ~b s e r v e d ,~ and that the ratio of pentobarbitone to thiopentone concentrations could be higher at lower plasma thiopentone concentrations.
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