Combined effects of cyclosporin and nifedipine on gingival overgrowth in rats is not age dependent

BACKGROUND: Cyclosporin A and nifedipine cause gingival overgrowth in rat, and the combined use of these drugs increases the overgrowth severity. OBJECTIVE: The purpose of this study was to compare gingival overgrowth of rats of differents ages treated with cyclosporin A and nifedipine alone or given concurrently. MATERIALS AND METHODS: Rats 15, 30, 60 and 90 d old were treated with 10 mg/kg body weight of cyclosporin A and/or 50 mg/kg body weight of nifedipine in the chow. RESULTS: Young rats showed evident gingival overgrowth with nifedipine, cyclosporin A, and cyclosporin A and nifedipine given concurrently. Adult rats did not show significant gingival alterations when treated with cyclosporin A and nifedipine alone. Nevertheless evident gingival overgrowth with alterations of the epithelium and connective tissue were observed when treated simultaneously with cyclosporin A and nifedipine. CONCLUSION: These results suggest that the combined effects of cyclosporin A and nifedipine on gingival overgrowth in rat is not age dependent.     

Gingival overgrowth induced by nifedipine and cyclosporin

Abstract. In this study, we developed a quantitative method with digital image analysis to evaluate the degree of gingival overgrowth (GO), and compared GO in kidney transplant patients treated with cyclosporin A (CsA) ( n =21) or CsA+ nifedipine ( n = 8) and a group of healthy controls ( n = 30). The method was reproducible and reliable. Our findings showed significant differences in papillary and gingival surface between controls and transplant patients treated with GO inducers. Gingival overgrowth index also differed significantly between controls and each patient group ( p < 0.01, Kruskal-Wallis test). The administration of the calcium channel blocker nifedipine potentiated the adverse effect of CsA: comparison of the morphometric findings revealed significant differences between patients treated with CsA alone and CsA+ nifedipine in papillary area, dental area, and GO index ( p < 0.01, Mann-Whitney U -test). We conclude that the method of image analysis we developed is useful in assessing the degree of GO.     

Morphometric evaluation of gingival overgrowth and regression caused by cyclosporin in rats

Cyclosporin A is a selective immunosuppressant, used in organ transplants to prevent graft rejection. Cyclosporin A can cause various side effects including gingival overgrowth. The aim of this work was to evaluate gingival overgrowth of rats treated daily with 10 mg/kg bodyweight of cyclosporin A for 60 days, as well as the regression after the interruption of treatment. All rats treated with cyclosporin A developed gingival overgrowth, with increased thickness of the epithelium, height and width of the connective tissue. The density of fibroblasts and collagen fibers also increased. Five to 90 days after the interruption of treatment with cyclosporin A, there was a progressive reduction of the gingival volume and of collagen fibers and fibroblast densities. The reduction was more pronounced in the initial periods and after 90 days did not return to the normal values.     

The prevalence and severity of cyclosporin and nifedipine-induced gingival overgrowth

Abstract The gingival health of 32 renal transplant patients who were medicated with cyclosporin was compared with a similar cohort of 23 renal transplant patients medicated with both cyclosporin and nifedipine. Both groups of patients had been taking the above medication for at least 3 months. Plaque scores, gingival inflammation and probing depths were similar for both groups. Patients medicated with the combination of nifedipine and cyclosporin had a significantly higher gingival overgrowth score (p= <0.046) when compared with the group receiving cyclosporin alone. The incidence of clinically significant overgrowth (i.e., overgrowth >30% which would require surgical intervention) was similar in both groups. Gingival overgrowth was not related to cyclosporin dosage. It is concluded that patients taking cyclosporin or cyclosporin and nifedipine experience gingival overgrowth and that the severity of the overgrowth is greater in patients taking the combined therapy. The levels of plaque and gingival inflammation appear to be associated with this phenomenon.     

环孢菌素A导致牙龈过度生长机理的研究近况

牙龈过度生长是环孢菌素A的重要的不良反应之一,其病理特征是牙龈组织上皮层的增厚和胞外基质的蓄积,但其确切的病理机制仍不清楚。该文就环孢菌素A导致的牙龈过度生长的病因及病理机制的研究现状做一综述。     

Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus

BACKGROUND: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA). Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement. AIMS: The purpose of the present study was to monitor the gingival response of 4 renal transplant patients (RTPs), with clinically significant CsA-induced gingival overgrowth, after their immunosuppressive therapy was switched to tacrolimus. METHODS: Intra-oral photographs and alginate impressions were taken both prior to the drug conversion and again, 6 to 9 months later. Gingival overgrowth scores were determined, from plaster models on both these occasions. RESULTS: All of the RTPs experienced significant resolution of their gingival enlargement within the time period studied; however, only one had complete regression. CONCLUSION: It is concluded that conversion of RTPs with gingival overgrowth from CsA to tacrolimus may provide an effective management strategy for this clinical problem.     

Expression of fibronectin-binding integrins in gingival epithelium in drug-induced gingival overgrowth

BACKGROUND AND OBJECTIVE: Gingival overgrowth is a side-effect of nifedipine and cyclosporin medications. Integrins are transmembrane glycoproteins that mediate cell adhesion, regulate cell proliferation and participate in the regulation of tissue fibrosis. The aim of this study was to investigate whether expression of epithelial cell integrins is linked to the development of drug-induced gingival overgrowth. MATERIAL AND METHODS: Human gingival biopsies of patients taking nifedipine, cyclosporin, or a combination of both medications, were used. Expression of the alpha5beta1, alphavbeta1 and alphavbeta6 integrins, and of cellular extra domain A of fibronectin, was localized in frozen sections using immunohistochemistry. RESULTS: The activated conformation of the beta1, alpha5beta1 and alphavbeta6 integrins were more frequently expressed in distinct locations in the oral epithelium in the combined drug group. Cellular extra domain A of fibronectin, a ligand for both alpha5beta1 and alphavbeta6 integrins, was expressed within the connective tissue of all groups. It was also expressed around the basal keratinocytes of the control, nifedipine and cyclosporin-induced gingival overgrowth groups, but not in the combined medication group. No relationship between the presence of inflammation and integrin expression was found. CONCLUSION: The results indicate that expression of certain integrins is up-regulated in the epithelium of drug-induced gingival overgrowth where they could participate in controlling the formation of elongated rete ridges and tissue fibrosis.     

The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth

BACKGROUND/AIMS: To investigate whether the choice of calcium channel blocker, used in conjunction with cyclosporin A, affected the prevalence of gingival overgrowth. METHOD: A cohort of 135 renal transplant recipients who had been medicated with cyclosporin A in combination with either nifedipine (89) or amlodipine (46) since transplant, took part in the study. The inclusion criteria were that eligible subjects had been in receipt of a kidney transplant for at least 12 months, had at least 10 teeth and had not received specialist periodontal treatment. The age, gender, current drug regimen and dosage were recorded for each participant and alginate impressions taken of both arches. The presence and severity of gingival overgrowth were scored from plaster models. RESULTS: A higher proportion (72%) of the amlodipine group were categorised as having gingival overgrowth compared with only 53% of the nifedipine group, chi square=4.5, p<0.05. Logistic regression analysis was used to explore the relationship between the presence or absence of gingival overgrowth (dependent variable) and age, gender, time since transplant, dose of cyclosporin A, centre in which the patient was treated, and the calcium channel blocker used (independent variables). Independent predictors of gingival overgrowth in this multivariate analysis were whether the individual was treated with amlodipine or nifedipine (p=0.01) and whether the individual was young or old (p=0.01). Within the multivariate analysis, the odds ratio for amlodipine to be associated with gingival overgrowth compared with nifedipine was 3.0 (confidence interval 1.3-6.9). CONCLUSIONS: The prevalence of gingival overgrowth in renal transplant recipients maintained on cyclosporin A and nifedipine is lower than those treated with cyclosporin A and amlodipine.     

Stereologic study of cyclosporin A-induced gingival overgrowth in renal transplant patients

Gingival biopsies were taken from 13 renal transplant patients (mean age 26.5 yr), 11 of whom exhibited cyclosporin A (CsA)-inditced gingival overgrowth. Control material was obtained from seven volunteers (mean age 28 yr). Gingival tissue components were analyzed by quantitative microscopy (stereology) on 5-(μm-thick sections of interdental papillae. The volume density (Vv) of different tissue components and the surface density of epithelial ridges were calculated by conventional point and intersection counting. The study showed that the volume density of oral epithelium and the surface density of the epithelial ridges in the CsA-induced gingival overgrowth were significantly increased compared to normal gingival tissue. The connective tissue of the lesion exhibited a significant increase in volume density of cells, blood vessels and non-collagenous matrix with a corresponding decrease in the collagenous matrix. These results indicate that CsA-induced gingival overgrowth represents a tissue with an altered composition characterized by increased thickness of oral epithelium and relatively-increased amount of cells, vessels, non-collagenous matrix and decreased collagenous matrix in the connective tissue.     

Gingival tissue proteoglycan and chondroitin-4-sulphate levels in cyclosporin A-induced gingival overgrowth and the effects of initial periodontal treatment

OBJECTIVES: Cyclosporin A (CsA) is a potent immunosuppressive drug used in organ transplant patients to prevent graft rejection. CsA-induced gingival overgrowth is one of the side effects of this drug and its pathogenesis is still unclear. The present study was planned to comparatively analyse total proteoglycan (PG) and chondroitin-4-sulphate (C4S) levels in CsA-induced overgrown gingival tissue samples obtained before and after initial periodontal treatment and to compare these findings with the situation in healthy gingiva. MATERIAL AND METHODS: Gingival tissue samples were obtained from nine patients with CsA-induced gingival overgrowth before and 4 weeks after initial periodontal treatment including oral hygiene instruction and scaling and also from 10 healthy control subjects. Total PG and C4S levels were determined by biochemical techniques. PG levels were analysed using modified Bitter and Muir method. C4S assay was carried out using chondroitin sulphate lyase AC and chondroitin-6 sulphate sulphohydrolase enzymes. The results were tested statistically using non-parametric tests. RESULTS: All clinical measurements in the CsA-induced gingival overgrowth group demonstrated significant reductions 4 weeks after initial periodontal treatment (p<0.05). There was no significant difference between the levels of baseline total PG in CsA-induced gingival overgrowth and healthy control groups (p>0.05). The gingival tissue levels of PG in CsA-induced gingival overgrowth group decreased significantly 4 weeks after treatment (p=0.043). Gingival tissue C4S levels in the overgrowth group were significantly higher than the healthy control group at baseline (p=0.000). C4S levels of the overgrowth group were significantly reduced after treatment (p=0.033), but these levels were still significantly higher than the healthy control group (p=0.000). CONCLUSION: The observed prominent increase in gingival tissue C4S levels may be interpreted as a sign of an increase in C4S synthesis in CsA-induced gingival overgrowth. Furthermore, remission of clinical inflammation by means of initial periodontal treatment had a positive effect on tissue levels of these extracellular matrix molecules.     

药物性牙龈肥大发病机制的研究进展

药物性牙龈肥大(DIGO)主要由长期服用苯妥英钠、环孢素A、硝苯地平引起,不仅影响牙面的清洁与美观和牙齿正常生理功能,而且可能造成患者心理上的障碍。然而,DIGO发病机制复杂,无法明确,导致治疗较为棘手。许多学者对其进行了多方面的研究,提出许多观点与假设,包括胶原生成与降解失衡机制、炎症等。该文从分子机制与药物具体机制两方面总结了近几年对DIGO发病的研究,并对DIGO未来的研究方向进行探讨,希望能够对DIGO的预防与临床治疗有所帮助。     

Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug-induced gingival overgrowth

The present study investigates the relationship between the pharmacokinetic variables of nifedipine with the incidence and severity of gingival overgrowth in 9 adult male patients medicated with the drug for at least 6 months. Five of the patients had experienced significant gingival changes and were thus designated "responders". The remaining four patients exhibited no gingival overgrowth, and thus acted as a control. A baseline periodontal examination (plaque scores, bleeding index and gingival overgrowth assessment) was carried out on each patient, and confined to the upper and lower anterior teeth. Serial blood and gingival crevicular fluid samples were collected over an eight-hour investigation period. Samples were analyzed for nifedipine by gas chromatography. No significant difference (p>0.05) was seen between responders and non-responders with regard to drug therapy, periodontal parameters or plasma pharmacokinetics of nifedipine. Nifedipine was detected in the gingival crevicular fluid of seven subjects (all responders, and two non-responders). The peak concentration of nifedipine in crevicular fluid was 15–90 fold greater than levels observed in plasma.     

药物性牙龈增生发病机制的研究进展

药物性牙龈增生是指服用抗癫痫药、钙通道阻滞剂和免疫抑制剂等某些特定药物引起的牙龈增生和体积增大,具有共同的病理组织学特点,其发病机制目前仍无定论。下面就药物性牙龈增生在胶原的合成与降解失衡、上皮细胞的增殖和程序性细胞死亡以及上皮下炎症浸润机制上取得的研究进展作一综述。     

Effectiveness of periodontal therapy on the severity of cyclosporin A-induced gingival overgrowth

AIM: The purpose of the present study was to evaluate the clinical effects of aetiological periodontal treatment in a group of transplant patients medicated with cyclosporin A (CsA) who exhibited severe gingival overgrowth. MATERIALS AND METHODS: Twenty-one patients received oral hygiene instructions, supra- and subgingival scaling and periodontal maintenance therapy and were monitored for 12 months. Full-mouth plaque score (FMPS), full-mouth bleeding score (FMBS), periodontal probing depth and degree of gingival overgrowth (Seymour index GO) were recorded at baseline, 6 and 12 months after treatment. RESULTS: Statistical evaluation revealed that all clinical variables significantly decreased compared with baseline. At baseline 18 out of 21 treated patients (85.71%) exhibited clinically significant overgrowth. Initial GO score of 2.38+/-1.92 in the anterior sextants and of 1.29+/-1.59 in the posterior segments were reduced to 0.56+/-0.83 and to 0.45+/-0.84 at 12 months (p<0.001). A difference of 1.82 and 0.84 in the severity of treated GO was accompanied by a 42% and 34% decrease in FMPS and FMBS, respectively. CONCLUSIONS: Aetiological periodontal treatment and regular maintenance therapy were effective in resolving the inflammation and in eliminating the need for surgical treatment in patients receiving CsA.     

Cyclosporin-A-induced gingival overgrowth in renal transplant children

Gingival overgrowth was assessed in renal transplant children, 19 boys and 13 girls, aged 2.5–18 yr, who had been on a cyclosporin-A (CsA)-based immunosuppressive regimen for at least 12 months. Data collected included number of posttransplant months, total CsA dose administered during the first 6 posttransplant months, oral dose and blood trough level of CsA on the day of examination, plaque accumulation (VPI%), gingival inflammation (GBI%), loss of attachment, and gingival overgrowth. Thirteen percent of the children exhibited gingival overgrowth characterized by one or more units with increased sulcus probing depth (≥4 mm), i.e. pseudopockets. The total amount of CsA administered during the first 6 posttransplant months was significantly higher in the children with gingival overgrowth than in those without. The study indicates that the development of CsA-induced gingival overgrowth is positively related to the total dose of the drug administered to the children during the first 6 posttransplant months.     

Nifedipine-induced gingival overgrowth in the presence or absence of gingival inflammation in rats

One adverse effect of nifedipine, a long-acting vasodilator, is gingival overgrowth. Preexisting gingival inflammation and/or dental plaque has been suggested to be responsible for the progression of this side effect, but the precise mechanism is uncertain because of a lack of suitable animal models. A study was therefore done to establish an experimental model of gingival overgrowth in rats and to investigate the possible involvement of gingival inflammation and/or dental plaque in its development. Specific pathogen-free Fischer rats (male, 14 days old) were used . Gingival inflammation and dental plaque accumulation were induced by infection with Streptococccus mutans MT8148R. The nifedipine-treated rats (experimental group) were fed a caries-inducing diet contai ning nifedipine either with or without infection, while the nifedipine-untreated rats (control group) were fed the same diet, similarly with or with out the infection. Marked gingival overgrowth was induced in the mandibular molar region of nifedipine-treated rats regardless of S. mutans infection, although the infection resulted in a further increase in the degree of gingival overgrowth. Histological examination of the gingival overgrowth revealed the presence of redundant subepithelial connective tissue in the treated rats, and inflammatory cell infiltration was apparent only in the tissue of the S. mutans-infected rats regardless of the nifedipine administration. These findings suggest that nifedipine induces gingival overgrowth in rats either in the presence or absence of gingival inflammatio n and/or dental plaque, although these factors can augment the effect of the drug. Our experimental system seems to be a useful model for studying the mechanism of this side effect.