NMDA receptor antagonist felbamate reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat.

Increased levels of glutamate and aspartate have been detected after subarachnoid hemorrhage (SAH) that correlate with neurological status. The NMDA receptor antagonist felbamate (FBM; 2-phenyl-1,3-propanediol dicarbamate) is an anti-epileptic drug that elicits neuroprotective effects in different experimental models of hypoxia-ischemia. The aim of this dose-response study was to evaluate the effect of FBM after experimental SAH in rats on (1) behavioral deficits (employing a battery of assessment tasks days 1-5 post-injury) and (2) blood-brain barrier (BBB) permeability changes (quantifying microvascular alterations according to the extravasation of protein-bound Evans Blue by a spectrophotofluorimetric technique 2 days post-injury). Animals were injected with 400 muL of autologous blood into the cisterna magna. Within 5 min, rats received daily oral administration of FBM (15, 30, or 45 mg/kg) for 2 or 5 days. Results were compared with sham-injured controls treated with oral saline or FBM (15, 30, or 45 mg/kg). FBM administration significantly ameliorated SAH-related changes in Beam Balance scores on days 1 and 2 and Beam Balance time on days 1-3, Beam Walking performance on days 1 and 2, and Body Weight on days 3-5. FBM also decreased BBB permeability changes in frontal, temporal, parietal, occipital, and cerebellar cortices; subcortical and cerebellar gray matter; and brainstem. This study demonstrates that, in terms of behavioral and microvascular effects, FBM is beneficial in a dose-dependent manner after experimental SAH in rats. These results reinforce the concept that NMDA excitotoxicity is involved in the cerebral dysfunction that follows SAH.

Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer.

This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m2 on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15-17, or to receive paclitaxel 100 mg/m2 alone on days 1, 8, and 15. Objective response was defined as a > oe = 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/ estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/ estramustine are recommended.