[Show abstract][Hide abstract] ABSTRACT: Central nervous system (brain or leptomeningeal) metastases (BLm) are considered rare in castration-resistant prostate cancer (CRPC) patients. Now that docetaxel has become the reference drug for first-line treatment of CRPC, patients whose disease is not controlled by hormonal manipulations may live much longer than before and have higher risk of developing BLm. We retrospectively reviewed the records of all patients with CRPC attending our centres from 2002 to 2010, and identified all of those who were diagnosed as having BLm and received (or were considered to have been eligible to receive) docetaxel-based treatment. We identified 31 cases of BLm (22 brain metastases and 9 leptomeningeal metastases) with an incidence of 3.3%. BLm-free survival was 43.5 months, and survival after BLm discovery was 4 months. With six patients surviving for more than 1 year after developing BLm, the projected 1-year BL-S rate was 25.8%. The findings of our study may be relevant in clinical practice as they indicate that incidence of BLm in CRPC patients in the docetaxel era seems to be higher than in historical reports, meaning that special attention should be paid to the appearance of neurological symptoms in long-term CRPC survivors because they may be related to BLm.
Journal of Neuro-Oncology 03/2012; 107(1):191-6. DOI:10.1007/s11060-011-0734-y · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dural metastasis is rare. In most reported cases, brain CT scan findings are mistaken for subdural hematoma or meningioma. We present here a 72-year-old male with a history of headache and progressive mental status changes. Brain CT scans suggested chronic subdural hematoma. However, the only surgical findings were diffuse thickening of the dura and sclerosis of the temporal bone. Histopathology revealed metastatic prostatic carcinoma. As the surgical approach and prognosis of chronic subdural hematoma and metastatic tumors are completely different, the differential diagnosis of these diseases is very important. A contrast-enhanced brain CT scan is recommended for patients who could possibly have dural metastases.
[Show abstract][Hide abstract] ABSTRACT: TXD258, a new taxoid antitumor agent, is a poor substrate for the P-glycoprotein (P-gp) in Caco-2 cells. In this study, we investigated the amount of drug accumulating in the brains of rats and mice under a variety of conditions (dose and infusion time, species and plasma concentration) using conventional in vivo pharmacokinetic techniques and in situ brain perfusion.
Mice were infused with radiolabeled TXD258 at 15, 30, 45 and 90 mg m−2 for 45 s or 1 h and rats were infused with 15 and 60 mg m−2 over 2.3 min. The radioactivity in the plasma and brains was measured. The brain concentrations of TXD258 in mice and rats were maximal from 2 min to 1 h postinfusion and radioactivity was still detectable at 168 h. While the plasma concentration of TXD258 increased linearly in mice with the infused dose, the brain content increased more than proportionally with the dose between 15 and 90 mg m−2. This nonlinear uptake of TXD258 also occurred in the plasma and brain of the rat.
These findings suggest that the protein-mediated efflux across the blood–brain barrier (BBB) becomes saturated. In situ brain perfusion studies confirmed that TXD258 is a P-gp substrate at the BBB of mice and rats. The P-gp of both species was saturated at the half-inhibitory concentration (∼13 μM) produced by i.v. infusion.
Thus, the observed nonlinear accumulation of TXD258 in the brain seems to occur by saturation of the P-gp at the rodent BBB. This saturation could have several advantages, such as overcoming a P-gp-mediated efflux, but the nonlinear pharmacokinetics could increase the risk of toxicity.
British Journal of Pharmacology (2003) 138, 1367–1375. doi:10.1038/sj.bjp.0705150
British Journal of Pharmacology 05/2003; 138(7):1367-75. DOI:10.1038/sj.bjp.0705150 · 4.84 Impact Factor
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