[show abstract] [hide abstract]
ABSTRACT: Lanthanum (La) carbonate is a new treatment for hyperphosphatemia. We tested the effects of oral La carbonate and aluminum hydroxide, respectively, on tissue accumulation and liver function in rats with chronic renal failure (CRF).
Adult male non-CRF and CRF rats were randomly assigned to 3 groups receiving either standard diet (St.D), or the same diet supplemented with 3% La carbonate (non-CRF La vs. CRF La) or 3% aluminum hydroxide (non-CRF Al vs. CRF Al).
After 12 weeks, serum phosphorus was decreased in both CRF La and Al groups. Urinary La and Al excretion was increased in these two groups, and so was liver and bone La content, and liver Al content. Both total body and liver weight were decreased in CRF La and CRF Al rats. Liver cell proliferation was decreased in these groups, while plasma total alkaline phosphatases and alanine aminotransferase were increased. Hepatic total cytochrome p450 content was reduced in CRF La, but not in CRF Al rats.
Long-term oral La overload in rats with CRF was associated with a decrease in liver (and total body) weight and mild alterations of liver function, as was Al overload, possibly as a consequence of trace element accumulation.
Nephron Experimental Nephrology 01/2010; 115(4):e112-21. · 2.01 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Photodynamic therapy (PDT) involves a non invasive treatment of small and superficial cancers using a photosensitive drug and light to kill tumoral cells. 5,10,15-meso-tri-(meta-O-beta-D-glucosyloxyphenyl)-20-phenylporphyrin [m-TPP(glu)3] is a new photosensitizer (PS) with more enhanced photocytotoxicity relative to 5,10,15,20-meso-tetra-(meta-hydroxyphenyl) chlorin [m-THPC] (Foscan). It was injected intravenously once to healthy rats at three different doses (0.25, 0.5 and 1 mg kg(-1)) and compared to m-THPC (0.3 mg kg(-1)). Pharmacokinetic parameters for both photosensitizers were derived from plasma concentration-time data using a non-compartmental analysis and a two-compartment pharmacokinetic model. m-TPP(glu)3 is more rapidly eliminated throughout the organism than m-THPC. Its mean plasma clearance is 19 mL h(-1) kg(-1) (6 mL h(-1) kg(-1) for m-THPC), and its mean residence time is 5h (20 h for m-THPC). The area under curve (AUC) and initial mean serum concentration (C0) were found to be proportional to the dose. As for Foscan, no metabolite of m-TPP(glu)3 was detected in plasma. The biodistribution study demonstrates that the most significant amount of m-TPP(glu)3 was concentrated in organs such as lung, liver and spleen which are rich in reticulo-endothelial cells. Maximum concentrations were reached in organs 14 h after IV administration. At 48 h, the photosensitizer was essentially eliminated from all organs. Because of its shorter elimination time, m-TPP(glu)3 is more attractive than m-THPC as a PDT agent since secondary side effects of shorter duration could be expected.
Journal of Photochemistry and Photobiology B Biology 11/2006; 85(1):56-64. · 3.11 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Lanthanum (La) carbonate has recently been proposed as an alternative, calcium- and aluminum-free phosphate binder for the treatment of hyperphosphatemia of chronic renal failure (CRF). However, the extent to which CRF enhances tissue La accumulation induced by oral La overload above that observed under conditions of normal renal function remains a matter of debate. In the present study, we examined this issue in two different rat models of CRF.
In a first series of experiments, adult male Sprague-Dawley rats received either a diet to which 0.3% adenine (wt% in feed) was added to induce CRF ("chemical CRF,"N= 20), or a diet free of adenine (control, N= 16). In a second series of experiments, adult male Sprague-Dawley rats underwent 5/6 nephrectomy in a two-step procedure ("surgical CRF,"N= 24). Half of all CRF and control rats were exposed to dietary La (3% lanthanum carbonate, wt% in feed) for four weeks (La[+] rats), whereas the other half received a placebo (La[-] rats).
At the end of this time period, creatinine clearance was 1.51 +/- 0.15 (mean +/- SEM) and 1.45 +/- 0.11 mL/min in La[-] control and La[+] control rats, and declined to 0.22 +/- 0.03 and 0.31 +/- 0.03 mL/min in La[+]-adenine-CRF and La[+]-Nx-CRF rats, respectively. Urinary La excretion was 0.025 +/- 0.010 microg/24 hr in La[-] control rats. It increased to 4.9 +/- 1.2, 17 +/- 3.8, and 77 +/- 18 microg/24 hr in La[+] control, La[+]-adenine-CRF, and La[+]-Nx-CRF rats, respectively. However, only the last value was significantly different from control value. Tissue La concentration was increased in La[+] control rats compared with La[-] control rats. More importantly, tissue La concentration was strikingly higher in La[+]-CRF rats than in La[+] control rats. Thus, liver La (ng/g dry wt) was 1173 +/- 148 in La[+]-adenine-CRF and 1742 +/- 158 in La[+]-Nx-CRF rats, respectively, compared with 385 +/- 29 in La[+] control rats (P < 0.001), and 7.0 +/- 1.4 in La[-] control rats; similarly, bone La was 230 +/- 14 and 288 +/- 26 compared with 81 +/- 8, respectively (P < 0.001), versus 27 +/- 4 in La[-] control rats. Comparable differences were observed in the kidney, skeletal muscle, myocardium, lung, and brain, although to different extents in La[+]-adenine-CRF compared with La[+]-Nx-CRF rats. Finally, liver and kidney weight was significantly reduced in La[+]-adenine-CRF rats compared with La[-]-adenine-CRF rats.
The oral administration of lanthanum carbonate to normal rats leads to a more than 10-fold increase of tissue La content in at least some organs, including the liver, lung, and kidney. This increase is further enhanced by the uremic state, per se. Plasma levels are a poor indicator of tissue burden. Given the dramatic tissue levels obtained with this rare earth metal given by the oral route, particularly in liver for absolute values, it is probable that the stimulation by CRF is at least partially explained by an increase in intestinal La absorption. The absorptive pathways involved in intestinal La absorption require further study, including possibly enhancing conditions.
Kidney International 03/2005; 67(3):1062-9. · 7.92 Impact Factor