Effects of combined oral treatments with cyclosporine A and nifedipine or diltiazem on drug-induced gingival overgrowth in rats

Background: Cyclosporine A (CsA) and calcium channel blockers induce gingiv al overgrowth in humans and animals. Recently, nifedipine and diltiazem hav e often been used to control CsA-related hypertension in organ transplant p atients. The purpose of this study was to examine the effects of a combined oral treatment of CsA and nifedipine or diltiazem on the severity of gingi val overgrowth in rats. Methods: Fifteen-day-old Fischer rats were treated orally with single or co mbined applications of CsA, nifedipine, and/or diltiazem for 40 days; and i nduced gingival overgrowth, rat growth, and blood drug levels were compared among the different experimental groups. The experiment consisted of 6 gro ups: one control group (group A) and 5 test groups treated with CsA (group B), nifedipine (group C), and diltiazem (group D), as well as those concurr ently treated with CsA and nifedipine (group E), and CsA and diltiazem (gro up F). Gingival overgrowth was determined by measuring the depth of the gin gival sulcus. Results: The mandibular buccal gingival sulcus depth of group A was 365 +/- 41.2 mum. Among the test groups, the most remarkable gingival overgrowth w as seen in group E (1,020 +/- 63.3 mum), followed by group F (895 +/- 43.8 mum), group B (870 +/- 48.3 mum), group C (525 +/- 116 mum), and then group D (505 +/- 83.2 mum). Rat body weight gain was reduced significantly by or al CsA treatment. Neither nifedipine nor diltiazem suppressed rat growth wh en used independently; however, rat growth reduced by CsA was further suppr essed by a combined use of diltiazem, but not nifedipine. CsA blood levels were reduced by concurrent oral treatment with nifedipine or diltiazem alon g with the blood levels of those calcium channel blockers when treatment wa s in combination with CsA. Conclusions: These results suggest that gingival overgrowth is induced in r ats as a side effect of CsA, nifedipine, or diltiazem, and the combined use of these drugs influences rat growth, blood drug levels, and the severity of gingival overgrowth.