Effects of cyclosporin, phenytoin, and nifedipine on the synthesis and degradation of gingival collagen in tufted capuchin monkeys (Cebus apella): Histochemical and MMP-1 and -2 and collagen I gene expression analyses

Background: The purpose of this experimental study was to evaluate the collagen fiber distribution histologically after phenytoin, cyclosporin, or nifedipine therapy and to correlate it with collagen I and matrix metalloproteinase (MMP)-1 and -2 gene expression levels.Methods: Gingival samples from the canine area were obtained from 12 male monkeys (Cebus apella). The mesial part of each sample was assessed by reverse transcription-polymerase chain reaction, whereas the distal part was processed histologically for picrosirius red and hematoxylin and eosin stainings, as well as for collagen IV immunostaining. One week after the first biopsy, the animals were assigned to three groups that received daily oral dosages of cyclosporin, phenytoin, or nifedipine for 120 days. Additional gingival samples were obtained on days 52 and 120 of treatment from two animals from each group on the opposite sides from the first biopsies.Results: Picrosirius red staining showed a predominance of mature collagen fibers in the control group. Conversely, there was an enlargement of areas occupied by immature collagen fibers in all groups at days 52 and 120, which was not uniform over each section. There was a general trend to lower levels of MMP-1 gene expression on day 52 and increased levels on day 120. Phenytoin led to increased levels of MMP-2 and collagen I gene expression on day 120, whereas the opposite was observed in the nifedipine group.Conclusion: Cyclosporin, phenytoin, and nifedipine led to phased and drug-related gene expression patterns, resulting in impaired collagen metabolism, despite the lack of prominent clinical signs.

Cyclosporin A-induced gingival overgrowth in renal transplant patients

Background: the incidence of gingival overgrowth (GO) associated with the use of cyclosporin A (CsA) is controversial. In the present study, we determined the incidence of GO in Brazilian renal transplant patients treated with CsA and the possible associations between periodontal and pharmacological variables.Methods: the test group consisted of 20 renal transplant patients, and the control group included 20 non-transplant patients. Periodontal conditions were evaluated based on the plaque index (PI), gingival index (GI), probing depth (PD), and the rate of gingival overgrowth, together with pharmacological variables (daily CsA dose and duration of treatment).Results: A significant difference in PI (P<0.0001) and PD (P<0.0001) was observed between groups, while GI (P=0.15) did not differ significantly. Using the Pearson correlation coefficient, a significant correlation was observed not only between GI (P<0.001; r=0.8141) and GO, but also for PD (P<0.001; r=0.866) and GO. The other correlations were not statistically significant.Conclusions: We conclude that GO induced by CsA may vary according to the individual sensitivity of each patient and may or may not be correlated with other local factors (periodontal variables).

Effect of cyclosporin A on alveolar bone homeostasis in a rat periodontitis model

Objectives: the administration of cyclosporin A has been associated with significant bone loss and increased bone remodeling. The present investigation was designed to evaluate the effects of cyclosporin A on alveolar bone of rats subjected to experimental periodontitis, using serum, stereometric and radiographic analysis.Methods: Twenty-four rats were divided into one of the following groups with six animals each: group I, control rats; group II, in which the animals received a cotton ligature around the lower first molars; group III, in which the rats received a cotton ligature around the lower first molars and were treated with 10 mg/(kg body weight day) of cyclosporin A; group IV, in which the rats were treated with 10 mg/(kg body weight day) of cyclosporin A. At the end of experimental period, at 30 days, animals were killed and the serum calcium and alkaline phosphatase levels were measured in all groups. The distance from the alveolar bone crest to the cemento-enamel junction was measured radiographically for each mesial surface of the lower first molars of each rat. After histological processing, the stereological parameters: volume densities of multinucleated osteoclasts (V-o), alveolar bone (V-b), marrow (V-m), and relation of eroded surface/bone surface (Es/Bs) were assessed at the mesial region of the alveolar bone.Results: Significant decreases in serum calcium were observed in those groups that received cyclosporin A therapy. No significant changes in serum alkaline phosphatase were observed. The therapy with cyclosporin A combined with the ligature placement decreased the V-b and increased the V-o, V-m and Es/Bs at the mesial surface of lower first molars. on the other hand, the radiographic data showed that cyclosporin A therapy diminished the alveolar bone loss at the mesial surface of the lower first molars.Conclusions: Therefore, within the limits of this study, we suggest that cyclosporin A at immunosuppressive levels can bring about an imbalance in the alveolar bone homeostasis in rats. However, in the presence of inflammatory stimulation, the inhibition of the immune system by cyclosporin A may decrease the initial periodontal breakdown.

Influence of cyclosporin A on quality of bone around integrated dental implants: a radiographic study in rabbits

To evaluate the influence of cyclosporin A (CsA) administration on bone around integrated dental implants assessed by a bone quality index and by quantitative subtraction radiography.A total of 36 machine surface commercial implants were placed in 18 adult rabbits. After a 3-month healing period without any disturbance, the animals were randomly divided into three groups of six animals each. Group A was sacrificed at this time. CsA was injected subcutaneously in an immunosuppressive dose of 10 mg/kg/day in a test group (Group T), and a Group B served as a control, receiving only vehicle. After 3 months of cyclosporin administration, the animals of both Groups B and T were sacrificed. Radiographs were obtained at implant surgery and at the day of sacrifice with a CMOS sensor. Bone quality around the implants was compared between the groups using a bone quality index and quantitative subtraction radiography.The bone analysis showed that in Group T, the bone quality changed dramatically from a dense cortical to a loose trabecular bone structure (P < 0.0001, chi(2) test) while in Groups A and B there were no significant differences. Quantitative digital subtraction radiography showed significantly (P < 0.05) lower gray shade values (radiographic density) in a region of bone formation around the implants in Group T (118 +/- 12) than in Groups A (161 +/- 6) and B (186 +/- 10).Within the limits of this study, CsA administration has a negative effect on the quality of bone around integrated dental implant.

Intermittent Therapy with 1,25 Vitamin D and Calcitonin Prevents Cyclosporin-Induced Alveolar Bone Loss in Rats

Bone loss associated with cyclosporin A (CsA) therapy can result in serious morbidity to patients. Intermittent administration of 1,25 Vitamin D and calcitonin reduces osteopenia in a murine model of postmenopausal osteoporosis. The purpose of this study was to evaluate the effects of this therapeutic approach on CsA-induced alveolar bone loss in rats. Forty male Wistar rats were allocated to four experimental groups according to the treatment received during 8 weeks: (1) CsA (10 mg/kg/day, s.c.); (2) 1,25 Vitamin D (2 mu g/kg, p.o.; in weeks 1, 3, 5, and 7) plus calcitonin (2 mu g/kg, i.p.; in weeks 2, 4, 6, and 8); (3) CsA concurrently with intermittent 1,25 Vitamin D and calcitonin administration; and (4) the control treatment group (vehicle). At the end of the 8-week treatment period, serum concentrations of bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase (TRAP-5b), osteocalcin, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) were measured and an analysis of bone volume, bone surface, number of osteoblasts, and osteoclasts was performed. CsA administration resulted in significant alveolar bone resorption, as assessed by a lower bone volume and an increased number of osteoclasts, and increased serum bone-specific alkaline phosphatase, TRAP-5b, IL-1 beta, IL-6, and TNF-alpha concentrations. The intermittent administration of calcitriol and calcitonin prevented the CsA-induced osteopenic changes and the increased serum concentrations of TRAP-5b and inflammatory cytokines. Intermittent calcitriol/calcitonin therapy prevents CsA-induced alveolar bone loss in rats and normalizes the production of associated inflammatory mediators.

Cyclosporin A causes impairment of the ventral prostate tissue structure of Wistar rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The influence of chlorhexidine on the severity of cyclosporin A-induced gingival overgrowth

THE INFLUENCE OF CHEMICAL PLAQUE CONTROL, using topically applied 0.12% chlorhexidine, on the severity of cyclosporin A (CsA)-induced gingival overgrowth (GO) was evaluated. Forty Holtzman rats were divided into four groups: 1) control; 2) cyclosporin A: a 10mg/kg/day subcutaneous dose of CsA; 3) chlorhexidine: 0.12% chlorhexidine (CHX) was applied to the buccal surface of the right mandibular molars; and 4) cyclosporin A/chlorhexidine: a combination of the treatment described for cyclosporin A and chlorhexidine groups. The animals were fed a high sucrose diet during the experiment and were sacrificed after 14 and 21 days. The histometric analysis revealed a significant increase in buccal gingival area in the cyclosporin A group compared to other groups (P < 0.01) after 21 days. The epithelium thickness of the buccal gingiva was significantly increased in the cyclosporin A group, compared to the control group (P < 0.05). The cyclosporin A/chlorhexidine group exhibited statistically significantly lower gingival overgrowth than the cyclosporin A group. These findings, if replicated in human studies, suggest that topically applied 0.12% chlorhexidine may be a valuable measure in the management of cyclosporin-induced gingival overgrowth.

The influence of cyclosporin a on mechanical retention of dental implants previously integrated to the bone: A study in rabbits

Background: Immunosuppressive agents may induce severe changes on bone metabolism and may impair the osseointegration process during the implant healing. No data are available concerning the influence of cyclosporin A on dental implants previously integrated to the bone. The aim of this study was to evaluate the influence of cyclosporin A administration on the mechanical retention of bone previously integrated to dental implants.Methods: Eighteen female New Zealand rabbits were submitted to an implant surgery. Each animal received one commercial dental implant of 10 x 3.75 mm. After 12 weeks of an undisturbed healing period, six animals were randomly sacrificed and the removal torque test was performed (group A). In addition, six animals were submitted to a daily injection of cyclosporin A in a dosage of 10 mg/kg (group C), and six animals received saline solution as a control (group B). After 12 weeks of cyclosporin A administration, groups B and C were sacrificed and submitted to a removal torque test in which higher values can be interpreted as higher mechanical bone retention to the implant surface or higher osseointegration.Results: the removal torque results were 30.5 (+/- 9.8) Ncm for group A, 50.17 (+/- 17.5) Ncm for group B, and 26 (+/- 7.8) Ncm for group C. The statistical analysis showed significant differences between groups A and B (P < 0.05) and groups B and C (P < 0.01).Conclusion: Cyclosporin A administration may impair the mechanical retention of dental implants previously integrated to the bone.

Oral health in renal transplant recipients administered cyclosporin A or tacrolimus

OBJECTIVE: the aim of this study was to determine the oral status of renal transplant recipients receiving cyclosporin A (CsA) or tacrolimus (FK-506) as immunosuppressant.SUBJECTS AND METHODS: A total of 88 renal transplant recipients receiving CsA (63 men and 25 women, mean age 51.4 years) and 67 receiving FK-506 (57 men and 10 women, mean age 33.5 years) were included in the study. Donor type, histocompatibility, cold ischemia time and prior delayed graft function were similar between the two groups. Demographics and pharmacological data were recorded for all subjects.RESULTS: the results demonstrated that CsA caused a greater number of oral diseases. A greater number of gingival overgrowth was present in patients treated with CsA. However, the combined use with calcium channel blockers increased the gingival overgrowth number. The occurrence of candida in saliva was observed in 80 renal recipients treated with CsA and 20 treated with FK-506. The presence of squamous oral carcinoma (n = 3) and herpes simplex (n = 10) was observed in patients treated with CsA. These alterations were not observed in renal recipients treated with FK-506.CONCLUSIONS: Renal recipients constitute a high-risk group for oral diseases, as they are immunocompromised. However, the FK-506 regime appears to ameliorate this effect, compared with CsA. Adequate pre- and post-transplant oral health care is recommended for these subjects, irrespective of the time interval for which the drug is administered.

Conversion of immunosuppressive monotherapy from cyclosporin A to tacrolimus reverses bone loss in rats

Tacrolimus is used for transplant patients with refractory graft rejection and those with intolerance to cyclosporin (CsA), without the disfiguring adverse effects frequently attributed to CsA therapy. Since we have shown that CsA-associated bone loss can also affect alveolar bone, the purpose of this study was to evaluate the effects of conversion of monotherapy from CsA to tacrolimus on alveolar bone loss in rats. Groups of rats were treated with either CsA (10 mg/kg/day, s.c.), tacrolimus (I mg/kg/day, s.c.), or drug vehicle for 60 and 120 days, and an additional group received CsA for 60 days followed by conversion to tacrolimus for a further 60-day period. Bone-specific alkaline phosphatase (BALP), tartrate-resistent acid phosphatase (TRAP-5b), calcium (Ca2+), interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) concentrations were evaluated in the serum. Analyses of bone volume, bone surface, number of osteblasts, and osteoclasts were performed. Treatment with CsA for either 60 or 120 days was associated with bone resorption, represented by lower bone volume and increased number of osteoclasts; serum BALP, TRAP-5b, IL-1 beta, IL-6, and TNF-alpha were also higher in these animals. After conversion from CsA to tacrolimus, all the altered serum markers returned to control values in addition to a significant increase of bone volume and a lower number of osteoclasts. This study shows that conversion from CsA to tacrolimus therapy leads to a reversal of the CsA-induced bone loss, which can probably be mediated by downregulation of IL-1 beta, IL-6, and TNF-alpha production.