Phase I and pharmacokinetics studies of prochlorperazine 2-h i.v. infusion as a doxorubicin-efflux blocker.

In an earlier phase I study, we reported that the maximal tolerated dose (MTD) of prochlorperazine (PCZ) given as a 15-min i.v. infusion was 75 mg/m2. The highest peak plasma PCZ concentration achieved was 1100 ng/ml. The present study was conducted to determine if PCZ levels high enough to block doxorubicin (DOX) efflux in vitro could be achieved and sustained in vivo by increasing the duration of i.v. infusion from 15 min to 2 h. The treatment schedule consisted of i.v. prehydration with at least 500 ml normal saline (NS) and administration of a fixed standard dose of 60 mg/m2 DOX as an i.v. bolus over 15 min followed by i.v. doses of 75, 105, 135, or 180 mg/m2 PCZ in 250 ml NS over 2 h. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose. Toxicities attributable to PCZ were sedation, dryness of mouth, anxiety, akathisia, hypotension, cramps, and confusion. The MTD of PCZ was 180 mg/m2. Large interpatient variation in peak PCZ plasma levels (91-3215 ng/ml) was seen, with the plasma half-life (t1/2 alpha) being approximately 57 min in patients given 135-180 mg/m2 PCZ. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) were 350.1 +/- 183.8 1/m2, 260.7 +/- 142.7 l m2 h-1 and 1539 +/- 922 ng ml h-1, respectively, in patients given 180 mg/m2 PCZ and the respective values for patients receiving 135 mg/m2 were 48.9 +/- 23.76 l/m2, 33.2 +/- 2.62 l m2 h-1, and 4117 +/- 302 ng ml h-1. High PCZ plasma levels (> 600 ng/ml) were sustained in all patients treated with 135 mg/m2 PCZ for up to 24 h. DOX plasma elimination was biphasic at 135 and 180 mg/m2 PCZ, and a > 10-ng/ml DOX plasma level was maintained for 24 h. Partial responses were seen in three of six patients with malignant mesothelioma, in two of ten patients with non-small-cell lung carcinoma, and in the single patient with hepatoma. Our data show that PCZ can be safely given as a 2-h infusion at 135 mg/m2 with clinically manageable toxicities. The antitumor activity of the combination of DOX and PCZ needs to be confirmed in phase II trials.

Levels of three hemostatic factors in relation to serum lipids. Monocyte procoagulant activity, tissue plasminogen activator, and type-1 plasminogen activator inhibitor.

To explore the relationship between blood lipid levels and a predisposition to thrombosis, levels of three hemostatic factors were measured in 41 human subjects and correlated with serum lipids. Procoagulant activity associated with peripheral blood monocytes isolated and purified after a 2-hour incubation in whole blood was not significantly related to lipid levels. However, activity in monocytes incubated with 100 ng/ml of bacterial endotoxin was significantly correlated with high density lipoprotein (HDL) cholesterol (r = 0.55, p less than 0.005), while net procoagulant activity (endotoxin-challenged minus basal) was significantly correlated with both HDL cholesterol (r = 0.61, p less than 0.005) and total cholesterol (r = 0.50, p less than 0.01). Plasma levels of the fibrinolytic factor, tissue plasminogen activator, were significantly correlated with total cholesterol (r = 0.41, p less than 0.01), while those of the type-1 plasminogen activator inhibitor were significantly correlated with both total cholesterol (r = 0.46, p less than 0.01) and total triglycerides (r = 0.31, p less than 0.05). The balance between the fibrinolytic factors was not significantly related to serum lipids. These results suggest that the expression of procoagulant activity by peripheral blood monocytes exposed to endotoxin may be enhanced in cases where HDL cholesterol levels are high. In addition, these results suggest that hypertriglyceridemia may be associated with a decreased fibrinolytic capacity due to elevated secretion of plasminogen activator inhibitor.