1. The effects of two diphosphonates (compounds containing a P-C-P bond), disodium dichloromethanediphosphonate and disodium 1-hydroxyethane-1,1-diphosphonate, on the metabolism of cultured rat calvaria cells, rabbit ear cartilage cells and rat skin fibroblasts were investigated. 2. The diphosphonates had no effect on the growth of cartilage cells and on the exponential growth of the calvaria cells and the fibroblasts. However, dichloromethanediphosphonate stopped the growth of the calvaria cells and the fibroblasts after the beginning of confluence, whereas the untreated cells were still growing to a certain extent. This inhibition was dose-dependent. After the drug was withdrawn, the cells recovered slowly. 1-Hydroxyethane-1,1-diphosphonate had no detectable effect on the growth of any of the cell types studied. Both diphosphonates decreased the cloning efficiency of calvaria cells and fibroblasts. 3. The K+ content of cartilage, calvaria and skin cells was diminished only by the highest (0.25 mM) concentration of dichloromethanediphosphonate. 4. Radioactive dichloromethanediphosphonate and 1-hydroxyethane-1,1-diphosphonate were taken up linearly with time for at least 48 h by calvaria cells and fibroblasts. The diphosphonate concentration in the cells depended on its concentration in the medium. 5. Both diphosphonates, in a dose-dependent fashion, markedly inhibited glycolysis, dichloromethanediphosphonate being more effective than 1-hydroxyethane-1,1-diphosphonate, at drug doses that had no effect on cell growth or cellular K+ content. Calvaria cells were much more sensitive than cartilage cells. When cartilage cells were cultured in an N2 atmosphere, these effects on glucose and lactate metabolism disappeared. 6. As increased acid production appears to be associated with resorption of bone, this decrease in lactate may explain why diphosphonates are effective inhibitors of bone resorption in vivo.

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Cultures of rat gingival fibroblasts were exposed to various dilutions of lidocaine hydrochloride (Xylocaine), mepivacaine hydrochloride (Carbocaine), and prilocaine hydrochloride (Citanest). All three anesthetics produced cell-rounding and detachment from the substrate, which varied depending on the anesthetic, its concentration in the medium, and the duration of exposure (p less than 0.001). Effects were not pH-dependent in the range of 7.0-7.4 and were not modified by epinephrine in the concentration normally present in commercially prepared anesthetic solutions. Prilocaine produced morphological changes at a greater rate and at a lower concentration than did lidocaine or mepivacaine (p less than 0.001). The effects elicited by prilocaine were irreversible, since prolonged exposures to it resulted in various toxic effects: (1) detachment of the cells from the substrate, and (2) development of pyknotic nuclei and circumferential halos in cells that remained attached. The study strongly suggested that prilocaine has the potential to be more toxic to fibroblasts than either mepivacaine or lidocaine, a situation of potential clinical importance.

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