Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.

BACKGROUND: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. METHODS: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months). CONCLUSIONS: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.

Cholestatic liver dysfunction after long-term phenytoin therapy.

Cholestatic jaundice developed in a 64-year-old woman who had received phenytoin sodium for more than 40 years. Discontinuation of phenytoin therapy resulted in resolution of the hepatic abnormalities, which recurred on rechallenge, strongly suggesting a causal relation to the drug. Phenytoin therapy was discontinued again, with complete resolution of the hepatic abnormalities. The liver biopsy specimen obtained during therapy showed cholestasis compatible with obstruction of the biliary tree, although an obstructive process was never demonstrated. The biochemical abnormalities and histologic features observed most likely represent an unusual response to phenytoin therapy.

Pulmonary embolism in patients with acute leukemia and severe thrombocytopenia.

While pulmonary thromboembolism has been reported in patients with acute leukemia complicated by severe thrombocytopenia, it has been studied infrequently and its pathogenesis remains imprecisely understood. Findings of 80 consecutive autopsies of patients with acute leukemia showed that three had pulmonary thromboembolism. All three patients had been severely thrombocytopenic and had received numerous platelet transfusions. Serial sections of thrombi were evaluated with electron microscopy. In no instance were platelet aggregates detected. However, Candida organisms were prominent in thrombotic specimens from each patient. These findings suggest that thromboembolism in such patients may involve occult fungal infection. Because pulmonary thromboembolism can complicate the course of acute leukemia and severe thrombocytopenia, it should be considered when clinical data suggest its occurrence.

Function and morphology of platelets produced for transfusion by intermittent-flow centrifugation plateletpheresis or combined platelet-leukapheresis.

The effects on platelet function of intermittent-flow centrifugation pheresis were measured employing platelets collected from ten donors by combined platelet-leukapheresis with hydroxyethyl starch (LP) and from ten by plateletpheresis (PP) by similar techniques except without starch. Greater numbers of platelets were produced by LP than by PP. Aggregation of platelets collected by both LP and PP was normal (did not differ from prepheresis baseline) to collagen and to 10(-5)M adenosine diphosphate (ADP). Slight impairment to aggregation with 2 X 10(-6)M ADP and 5.5 X 10(-5)M epinephrine occurred with both techniques. These abnormalities, however, were significantly less severe in platelets collected by LP. Platelet morphology by electron microscopy was nearly normal, although glycogen granules were absent in LP platelets. Thus, hydroxyethyl starch, at doses currently used during a single LP, does not enhance abnormalities of platelet aggregation over those expected to result from PP alone. Actually, LP platelets function better in vitro than those collected by PP. Large numbers of platelets can be harvested by LP, and their use as a component that is comparable to PP platelets may mean improved efficiency and reduced costs for pheresis centers.

Laser microscope irradiation of Physarum polycephalum: dynamic and ultrastructural effects.

Streaming plasmodia of Physarum polycephalum were irradiated with a microscope-mounted ruby laser and the resulting changes were recorded by cinemicrography or streak photographs. Some lesions were processed for electron microscopy. By varying the incident energy, three levels of response were detected. Two transient responses, a gelation briefly blocking streams and a more severe gelation with contraction, changed movement patterns but not organelle ultrastructure. At higher energies, a permanently coagulated lesion was rapidly segregated from normal and transiently altered cytoplasm by formation of new membranes. Within the coagulum, pigment granules were destroyed, membranes were disrupted, and cytoplasm was flocculent. Nuclei and mitochondria were compact in the center and swollen in a peripheral space left by contraction of the coagulum. These changes are probably caused by heat produced by the interaction between the laser beam and the pigment granules of the plasmodium. Many of the changes seem to be secondary responses that follow the primary capture of energy during irradiation.