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 gingival overgrowth in humans and animals. Recently, nifedipine and diltiazem have often been used to control CsA-related hypertension in organ transplant patients. 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 gingival overgrowth in rats.


METHODS
Fifteen-day-old Fischer rats were treated orally with single or combined applications of CsA, nifedipine, and/or diltiazem for 40 days; and induced gingival overgrowth, rat growth, and blood drug levels were compared among the different experimental groups. The experiment consisted of 6 groups: 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 concurrently treated with CsA and nifedipine (group E), and CsA and diltiazem (group F). Gingival overgrowth was determined by measuring the depth of the gingival sulcus.


RESULTS
The mandibular buccal gingival sulcus depth of group A was 365 +/- 41.2 microm. Among the test groups, the most remarkable gingival overgrowth was seen in group E (1,020 +/- 63.3 microm), followed by group F (895 +/- 43.8 microm), group B (870 +/- 48.3 microm), group C (525 +/- 116 microm), and then group D (505 +/- 83.2 microm). Rat body weight gain was reduced significantly by oral CsA treatment. Neither nifedipine nor diltiazem suppressed rat growth when used independently; however, rat growth reduced by CsA was further suppressed by a combined use of diltiazem, but not nifedipine. CsA blood levels were reduced by concurrent oral treatment with nifedipine or diltiazem along with the blood levels of those calcium channel blockers when treatment was in combination with CsA.


CONCLUSIONS
These results suggest that gingival overgrowth is induced in rats 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.
Morisaki
I
I
Division of Special Care Dentistry, Osaka University Faculty of Dentistry, Japan. morisaki@dent.osaka-u.ac.jp
Fukui
N
N
Fujimori
Y
Y
Murakami
J
J
Daikoku
H
H
Amano
A
A
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D004110:Diltiazem / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D004338:Drug Combinations; D004347:Drug Interactions; D005881:Gingiva / Q000187:drug effects; D019214:Gingival Overgrowth / Q000139:chemically induced* / Q000145:classification; D006128:Growth / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344; D016037:Single-Blind Method
D002121:Calcium Channel Blockers; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D004110:Diltiazem; D009543:Nifedipine