The pharmacokinetics and safety of porfimer after repeated administration 30-45 days apart to patients undergoing photodynamic therapy.

BACKGROUND: Porfimer is an intravenous (i.v.) injectable photosensitizing agent used in the photodynamic treatment of tumours and of high-grade dysplasia in Barrett's oesophagus. AIM: To assess the pharmacokinetics as well as the safety profiles of porfimer after a first and a second dose administered 30-45 days apart in patients undergoing photodynamic therapy. METHODS: Nineteen patients (16 with cholangiocarcinoma) were enrolled. Porfimer sodium was administered by i.v. injection over 3-5 min. Blood samples were collected prior to starting i.v. drug injection and postdose at different time points after the first and second administrations. RESULTS: Porfimer exposure values after the second administration were statistically higher than those observed after the first administration, suggesting a slight accumulation of porfimer following repeated administration. The apparent mean elimination half-life of porfimer increased from 410 h after the first administration to 725 h after the second administration. The safety profiles of porfimer after a first and a second administration were similar and did not raise additional concern. Eight patients experienced nine serious adverse events. Only photosensitivity was deemed study-drug related. CONCLUSION: Porfimer appears to display a safe and tolerable profile when used in patients requiring a second photodynamic therapy within 45 days.

The effects of incorporation of bromodeoxyuridine into mammalian DNA on the migration patterns of DNA fragments subjected to pulsed-field gel electrophoresis after X irradiation or cutting with a restriction enzyme.

Incorporation of bromodeoxyuridine (BrdU) into DNA in both Chinese hamster ovary (CHO) cells and human melanoma (U1) cells reduced the rate of DNA migration in transverse alternating-field electrophoresis (TAFE) agarose gel optimized for separating molecules larger than 2 Mb. This "BrdU migration effect" was independent of the method of damaging the DNA; i.e., the effect was observed after irradiation of the cells or treatment of the plugs containing DNA with the restriction enzyme, Mlu-1, and similar results were found for CHO and U1 cells. However, when the amount of cutting of DNA was estimated from the amount of DNA migrating from the plugs, a difference between U1 cells and CHO cells was observed in that incorporation of BrdU enhanced the cutting of DNA by either irradiation or Mlu-1 digestion for U1 cells but not for CHO cells. Therefore, the "BrdU migration effect" could not be attributed to an increase in large molecules because of reduced cutting of the BrdU-labeled DNA. The decrease in migration rate during pulsed-field gel electrophoresis when BrdU replaces thymidine in the DNA is hypothesized to result from the increase in negative charge on BrdU-labeled DNA. An increase in electron charge density is expected to increase the reorientation time of BrdU-labeled DNA fragments during each voltage pulse due to an increase in the elongation length of the DNA caused by an increase in electronegativity.

The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure.

Hypocalcemia, hyperphosphatemia, and resistance to the action of PTH are well characterized features in the setting of advanced chronic renal failure (CRF). Although the underlying mechanisms are ill-understood, clinical and experimental evidence points to both PTH receptor down-regulation and post-receptor abnormalities in their pathogenesis. In the present study we have examined the effect of advanced CRF in rats on the renal expression of PTH/PTHrP receptor (PTH-R). CRF was created by a standard two-step operation (5/6 nephrectomy). Four weeks thereafter, 19 uremic rats were compared with 23 sham-operated rats. Uremic rats had higher mean (+/- SD) plasma creatinine levels than control rats, 164 +/- 107 microM versus 43 +/- 5 microM, respectively. They also had higher plasma phosphorus and iPTH levels, 4.70 +/- 1.71 mM versus 2.59 +/- 0.37 mM and 561 +/- 336 versus 27 +/- 18 pg/ml, respectively. Mean plasma total calcium and blood ionized calcium were significantly lower in uremic than in control rats, 2.13 +/- 0.06 mM versus 2.61 +/- 0.10 mM and 1.07 +/- 0.11 versus 1.31 +/- 0.06 mM, respectively. Mean plasma calcitriol concentration was also significantly lower in uremic than in control rats, 39.8 +/- 14.6 and 80.4 +/- 15.2 pg/ml, respectively. Nine out of the 19 rats were examined for renal PTH-R gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)