Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.     

Unusual venous thrombosis associated with protein C deficiency

A patient in whom massive puerperal thrombophlebitis developed had protein C deficiency. In patients who initially have thrombosis that is unusual either in its nature or extent, investigation may, as in this case, reveal the presence of a hypercoagulable state.     

Aorto-caval fistula: a clinical spectrum

Ten cases of aortocaval fistula (ACF) associated with abdominal aortic aneurysm (AAA) were reviewed. In 5 cases the ACF became apparent after evacuation of the thrombus; only 5 patients presented with features of patent ACF. Four patients in addition presented with extra-caval rupture of the aneurysm. Based on these variables, a classification relating ACF and AAA was developed. In this series all patients were male with a mean aneurysm size of 8.5 cm. All patients required bifurcation grafts for reconstruction. A multifactorial etiology related to enlargement and rupture of all aneurysms seems to apply to ACF. Eight of 10 patients survived. Awareness of this entity and proper preparation allow for successful outcome in the treatment of this condition.     

The value of uterine artery Doppler in the prediction of uteroplacental complications in multiparous women.

OBJECTIVE: To investigate the value of second-trimester uterine artery Doppler in the prediction of complications resulting from uteroplacental insufficiency in low- and high-risk multiparous women. METHODS: Color flow pulsed Doppler imaging of both uterine arteries at 20 weeks' gestation was performed on 628 multiparous women; 458 of them had no known risk factors and 170 had clinically identifiable high-risk factors at booking. An abnormal result was defined as bilateral notches and a mean resistance index (RI) >/= 0.55 (50th centile) or unilateral notches and a mean RI >/= 0.65 (80th centile). The main outcome measure was adverse pregnancy outcome defined as any case of pre-eclampsia, small-for-gestational age birth weight (< 5th centile), placental abruption, stillbirth or early neonatal death. RESULTS: There was an adverse outcome in 30 women (6.6%) in the low-risk group and 48 (28.2%) women in the high-risk group. In the high-risk group the sensitivity to predict adverse pregnancy outcome in screen-positive women was 81.4% for a specificity of 89.0%, a positive predictive value of 71.4% and a negative predictive value of 93.4%. Normal Doppler studies in the high-risk group conferred a risk of adverse perinatal outcome of 6.6%, similar to the risk of adverse outcome in the low-risk population (6.6%). In the low-risk group the sensitivity for an adverse outcome in screen-positive women was 33.3% for a specificity of 92.8% and a positive predictive value of 24.4%. CONCLUSION: In high-risk multiparous women, persistent bilateral notches with mean RI >/= 0.55 and unilateral notches with mean RI >/= 0.65 at 20 weeks' gestation identifies the vast majority of women who will subsequently develop complications secondary to uteroplacental insufficiency. Normal uterine artery Doppler studies in these women confers a risk of adverse outcome similar to that of women with an uncomplicated obstetric history. In low-risk women, the screening efficacy of uterine artery Doppler for adverse perinatal outcome is poor and does not justify routine screening.