The feasibility of using microcapsules containing a b o n e f o r m a t i o n s t i m u l a n t , ( 2 R , 4 S ) -( − ) -N -( 4diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2carboxamide (TAK-778) to enhance fracture repair was assessed in rats with streptozotocin-induced diabetes. The release profile of the microcapsules was designed to mimic a dosing regimen of multiple injections of TAK-778 solution. The solution was injected locally every third day from day 0 (the day of operation) to day 27 according to several dosing regimens, and fracture repair was assessed at day 28. The production of callus was most prominent when TAK-778 solution was injected so that 50-75% of the total dose (5 mg TAK-778/site) was administered during the first half of the treatment period. Thus, injectable microcapsules of 30 m in mean diameter were prepared in order to release TAK-778 over 4 weeks using a biodegradable polymer, poly(d,l-lactic/glycolic) acid, with a copolymer ratio of 85:15 (mol/ mol) and an average molecular weight of 14,000. A single local injection of the microcapsules markedly enhanced fracture repair, which resulted in recovery of destructive bending strength of the bone at day 28. Histologically, the injection of TAK-778 microcapsules stimulated both fibrous and cartilaginous proliferation and periosteal ossification in the callus at day 7; bony bridge formation was observed at day 28. At day 56, the callus was remodeled and cortical bony union was evidenced in the microcapsule-treated fractures compared with the controls, which showed only fibrous union.
The dose-dependent uptake of fractionated 3H-heparin in the subpopulations of liver cells, parenchymal and non-parenchymal cells, was characterized in rats in vivo. Following the intravenous administration of fractionated 3H-heparin, the radioactivity in plasma was eliminated according to the first order kinetics at each dose. However, the elimination rate constant decreased with dose over the dose range of 0.3 to 100 U/kg, suggesting nonlinear elimination. In accordance with the delay in the plasma elimination, the uptake rate constant of radioactivity by parenchymal as well as non-parenchymal cells of liver, the major distribution organ, also decreased. Although heparin has long been considered to be taken up by a reticuloendothelial system (RES) such as non-parenchymal cells in the liver, the uptake of fractionated 3H-heparin by parenchymal cells was found to be comparable with that by non-parenchymal cells at the lowest dose of 0.3 U/kg, and even larger than that by non-parenchymal cells at the highest dose of 100 U/kg. The uptake clearances of fractionated 3H-heparin at the dose of 0.3 U/kg were 86.4 and 504 ml/10(8) cells/d, respectively, for parenchymal and non-parenchymal cells. These values were much larger than those reported for polyvinylpyrrolidone, which has been suggested to be taken up by fluid phase endocytosis. Thus, the present study revealed the significant contribution of parenchymal cells in the hepatic uptake of fractionated 3H-heparin. The dose-dependent uptake with high clearance values in both parenchymal and non-parenchymal cells provides an in vivo suggestion of the specialized transport of fractionated heparin in these two subpopulations of liver cells.
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