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AbstractThe aim of the present work was to evaluate the effect of bendazac lysine on the human lens epithelial cell line HLE-B3 adhesion to polymethylmethacrylate (PMMA) intraocular lenses (IOLs). After adherence to IOLs, cells were incubated in the presence of the drug for 24 h. The number of cells contained in a 6-mm2 area was then counted with an inverted phase microscope and adherent cells were distinguished from detached floating cells by focusing through the medium. Results obtained show that bendazac is able to induce a linear dose-dependent inhibition of HLE-B3 adhesiveness to PMMA IOLs. In particular, treatment with bendazac 33, 100 and 300 μM resulted in a 15, 32 and 54% inhibition, respectively. Statistical analysis shows that this effect is significant at 100 μM (p < 0.05) and 300 μM (p < 0.01). The analysis of the effects of bendazac on the viability and on the proliferative capacity of HLE-B3 cells did not show any drug-related toxicity up to the concentration of 400 μM. The present study demonstrates that bendazac lysine is able to inhibit adhesion of lens epithelial cells to PMMA IOLs and suggests the potential beneficial use of this drug in preventing secondary cataract development.Copyright © 2004 S. Karger AG, Basel

The activity of a novel calcitonin SB 205614 was compared with salmon calcitonin (sCT) and (Asu1,7)-eel calcitonin (ELC) in six different models of osteoclastic bone resorption in vitro and in vivo. SB 205614 is an ELC analogue that has an acetylenic bridge instead of the natural disulphide bridge, rendering the molecule more stable biologically than sCT and equally stable to ELC. Our aim was to determine whether this structural change compromised biologic activity, and if not, whether the increased stability could be used to exploit novel modes of administration. In the in vitro assays of pit formation by disaggregated rat osteoclasts on cortical bone slices (DROcA) and PTH stimulation of 45Ca-release from prelabeled fetal rat bone, no significant differences in activity were observed between the three calcitonins. In the DROcA, IC50s of 0.003, 0.015 and 0.064 pg/ml for sCT, ELC, and SB 205614, respectively, were determined, with total or near complete inhibition observed at 1 pg/ml (0.3 pM). In the assay of PTH-stimulation of 45Ca release, IC50s were measured of 5.5, 4.8, and 12.9 pM for sCT, ELC, and SB 205614, respectively; in every case maximal inhibition (ca. 80%) was observed at 30 and 100 pM. The internationally approved U.S. Pharmacopoeia bioassay of hypocalcemia in the rat following intravenous (IV) administration indicated that SB 205614 had a greater potency than ELC or sCT. More important, a full dose-hypocalcemic response curve demonstrated significantly increased potency compared to sCT or ELC, as the doses causing 15% lowering of serum calcium (approximately 50% of the maximum effect) were 33.9, 25.2, and 12.9 mg/kg for sCT, ELC, and SB 205614, respectively. As a preliminary means of investigating alternative delivery forms of calcitonin, the time course of the hypocalcemic effect was investigated in the rat and rabbit following IV administration, and was compared with that following intranasal (IN) administration (rat and rabbit), and following intracolonic administration (rat only). Maximal effects were similar, whereas in general the hypocalcemic effect of SB 205614 was of a longer duration than the other two calcitonins; this was reflected in a larger area over the curve (AOC). However, following IN administration in the rabbit, where an aerosol delivery device similar to that used in the clinic was used to administer the calcitonins, SB 205614 (100 IU/kg) induced a highly significant two-fold increase in the AOC compared to ELC or sCT. The calcitonins were also compared in assays designed to measure therapeutic efficacy in the rat. In the prevention of retinoid-induced hypercalcemia, no significant differences were observed between the calcitonins. IC50s were obtained of 3.0, 2.9, and 4.8 IU/kg for sCT, ELC, and SB 205614, respectively. In the model of osteoporosis (induced by a combination of immobilisation and ovariectomy), the three calcitonins all showed a similar dose-dependent protection against femoral trabecular bone loss, which was significant at 15 IU/kg. These experiments in the rat suggested that following administration of equipotent doses intramuscularly, there were no significant differences between the activity of the calcitonins, although only SB 205614 significantly increased bone density in the tibia compared to operated animals at both 2.5 and 15 IU/kg. Thus, SB 205614, a novel structural analogue of ELC, is a highly potent calcitonin, which has some significant advantages over ELC and sCT, and thus may be more effective in the development of IN treatment of diseases involving elevated osteoclastic bone resorption, such as osteoporosis.