Cyclosporine-induced gingival overgrowth in beagle dogs

Development of gingival overgrowth during daily long-term cyclosporine A treatment was studied in 2-yr-old beagles. Gingival enlargement developed in five of 12 dogs (42%), primarily in the mandibular anterior area. The earliest gingival changes occurred by 3 wk as an increase in the size of the interdental papillae. The lesions progressively became more severe, in some cases obscuring portions of teeth by wk 6. The redundant tissue exhibited an increase in connective tissue components and an inflammatory infiltrate primarily of plasma cells. Severity of the overgrowth varied in responding animals; both incidence and severity were related to the CSA concentration in blood. The mean CSA blood levels of responders were significantly greater than nonresponders at wk 3, 6 and 10. Since beagles develop gingival overgrowth similar to humans, they provide an excellent model to investigate the roles of local and systemic factors in the induction of gingival overgrowth.     

Nitrendipine-induced gingival hyperplasia. First case report

Drug-induced gingival hyperplasia is well documented within the literature. It has been associated with phenytoin, cyclosporine, and calcium channel blocking agents. Nitrendipine is an experimental calcium channel blocking agent that also appears to cause the side effect of drug-induced gingival hyperplasia. The clinical and histologic presentation of this side effect and possible biochemical mechanisms of pathogenesis are discussed.     

Vigabatrin-induced gingival overgrowth

Abstract Vigabatrin is a relatively new medication used in the treatment of epilepsia. The present report concerns the use of vigabatrin by a 19-year-old woman. The patient manifested marked gingival overgrowth compatible clinically and histologically with the overgrowth induced by phenytoin, cyclosporine and calcium channel blockers. This is the 1st report of vigabatrin-induced gingival overgrowth. Clinicians should be aware of similar lesions in patients using new anticonvulsants.     

Amlodipine-induced gingival overgrowth

Abstract Amlodipine is a calcium channel blocker used in the management of angina and hypertension. We report 3 cases of gingival overgrowth in adult dentate patients associated with chronic usage of this drug. Gingival changes occurred within 3 months of dosage and appeared to be compounded by the patient's existing periodontal condition. In all 3 patients, there was sequestration of amlodipine in their crevicular fluid. The significance of this finding in relation to the pathogenesis of this unwanted effect remains to be elucidated.     

Cyclosporin-induced gingival overgrowth in children

Cyclosporin is a potent immunosuppressant drug commonly used to prevent organ transplant rejection. In recent years, there has been a widening of its therapeutic use and an increase in the number of patients undergoing transplantation. Gingival overgrowth is one of several oral side-effects of cyclosporin, with a quoted prevalence of between 8% and 100%. There is continued debate over the factors which modify the degree of overgrowth, including individual sensitivity, age, dose of drug, duration of drug therapy and the presence of dental plaque. The exact mechanism of gingival overgrowth is still being debated, but appears to be caused by a combination of the proliferation of fibroblasts within the gingival tissue, an increase in the deposition of collagen and extracellular matrix, and a decrease in phagocytosis with a net gain in gingival tissue mass. A number of treatment options are utilized in the treatment of gingival overgrowth, including CO2 laser surgery, improved oral hygiene, the use of antibiotics such as metronidazole and azithromycin, and surgical intervention. In the clinical application of cyclosporin, there is little correlation between cyclosporin dose, serum trough levels and total exposure to the drug, making it difficult to achieve the desired therapeutic response. These problems were previously further complicated by the variability of absorption of the drug via the gastrointestinal tract. The original cyclosporin formulation, Sandimmune, was replaced by a new formulation, Neoral, which has a more reliable absorption, and gives a closer correlation between trough concentration levels and individual bioavailability. There is a conflict of opinion over whether or not the side-effect profile of Neoral varies from its precursor Sandimmune. It has yet to be seen whether the increased bioavailability of Neoral will result in an increased severity and prevalence of gingival overgrowth. An alternative immunosuppressant drug, tacrolimus, which is a macrolide antibiotic with a different side-effect profile, has emerged as a substitute for cyclosporin in organ transplantation. However, there have been conflicting reports of its side-effects and its capacity to cause gingival overgrowth.     

Cyclosporine and gingival overgrowth

A case of cyclosporine-induced gingival overgrowth is presented. Overgrown and inflamed gingivae were noted at several sites in the mouth of a patient taking cyclosporine following a renal transplant. These were associated with areas adjacent to heavy plaque and calculus deposits on the teeth. Histological examination of the overgrown tissues revealed fibro-epithelial changes characterized by elongated rete pegs, myxomatous degeneration of the connective tissue associated with dense infiltration of plasma cells and lymphocytes. The fibroblasts from normal and overgrown sites were studied in vitro. Fibroblasts from the overgrown tissue proliferated at a slower rate and produced slightly less protein than the cells from normal, healthy gingival sites. These features reflect a site-specific alteration in fibroblast activity and indicate that the lesion is related to local factors exacerbated by cyclosporine therapy.     

Medication induced gingival overgrowth

A number of idiopathic, pathological and pharmacological reactions may result in an overgrowth of the gingiva. This review concentrates on those overgrowths associated with various pharmacological agents. The pharmacokinetics and side effects of each drug associated with gingival overgrowth are discussed along with the clinical and histological features and treatment. By examining the possible pathogeneses for these overgrowths we propose a unifying hypothesis for the causation based around inhibition of apoptosis and decreased collagenase activity modulated by cytoplasmic calcium.     

Cyclosporine and gingival overgrowth

A case of cyclosporine-induced gingival overgrowth is presented. Overgrown and inflamed gingivae were noted at several sites in the mouth of a patient taking Cyclosporine following a renal transplant. These were associated with areas adjacent to heavy plaque and calculus deposits on the teeth. Histological examination of the overgrown tissues revealed fibro-epithelial changes characterized by elongated rete pegs, myxomatous degeneration of the connective tissue associated with dense infiltration of plasma cells and lymphocytes. The fibroblasts from normal and overgrown sites were studied in vitro. Fibroblasts from the overgrown tissue proliferated at a slower rate and produced slightly less protein than the cells from normal, healthy gingival sites. These features reflect a site-specific alteration in fibroblast activity and indicate that the lesion is related to local factors exacerbated by Cyclosporine therapy.     

Human gingival glycosaminoglycans in cyclosporin-induced overgrowth

Glycosaminoglycans in normal and cyclosporin‐induced gingival overgrowth were extracted by papain digestion and purified by Mono Q‐FPLC chromatography. The purified glycosaminoglycans were analyzed by agarose gel electrophoresis and by the pattern of degradation products formed by chondroitin lyases on HPLC chromatography. Our results on the glycosaminoglycan composition showed presence of chondroitin 4‐ and 6‐sulfate, dermatan sulfate, heparan sulfate and hyaluronic acid in both normal gingiva and cyclosporin‐induced gingival overgrowth. The total and relative amounts of glycosaminoglycans were similar between normal and overgrown gingiva. This suggests that the glycosaminoglycan composition is not changed in cyclosporin‐induced gingival overgrowth. Our present biochemical results conflict with histochemical and biosynthetic data previously reported by other groups. Those studies suggested that the affected tissues contained higher levels of glycosaminoglycans and that cyclosporin induced comparably high levels of these compounds in in vitro cultures of gingival fibroblasts. Therefore, these discrepant results suggest that a cyclosporin‐induced increase on gingival glycosaminoglycans still remains an open question. The implications of these conflicting results are discussed.     

Photographic scoring of gingival overgrowth

BACKGROUND: A wide range of methods have been employed to determine the severity of gingival overgrowth resulting in uncertainty regarding the prevalence of the side-effect. There is no simple, non-invasive, objective, blind method for assessing gingival overgrowth. AIM: This article aims to describe a method which is suitable for use in large-scale population studies. MATERIALS AND METHODS: Photographs were taken of the anterior, buccal gingivae and teeth of 925 patients medicated with calcium channel blockers. In addition, each patient was ascribed a clinical gingival overgrowth score. 100 patients had repeat photographs, and a further 10 patients had alginate impressions taken. The models were scored for severity of gingival overgrowth using a described technique. The slides were scored using a modification of this technique. RESULTS: When photographic and study model scores were compared, photographic scores were consistently higher, and as a result, a photographic score of 38.6% was considered to represent a significant overgrowth. There was good agreement between clinically determined scores and photographic scores (kappa=0.71). CONCLUSIONS: The results indicate that this method is suitable for large-scale population studies where it also has the advantage of providing a continuous scale of gingival changes for subsequent statistical analysis.     

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.     

Cyclosporin-a-induced gingival overgrowth in heart transplant patients

Abstract The incidence of gingival overgrowth secondary to the administration of cyclosporine A (CsA) is widely reported in renal transplant recipients, while there is no information about periodontal conditions in heart transplant patients. In the present cross-sectional investigation the relationship between clinical periodontal conditions and pharmacological profiles of CsA was determined in 39 patients (31 male and 8 female, aged 18–63 years, mean 45.6±15.2 years) who possessed their 6 upper and 6 lower anterior teeth. All patients had been on a CsA-based immunosoppression regimen for at least 6 months (6–101. mean 39.3±30.1). 2 periodontal parameters (recorded on the 12 anterior teeth only) relating to gingival overgrowth were considered: hyperplastic index and % of sites with probing depth >3 mm. These parameters were always recorded by the same observer at first appointment and 2 months after an oral hygiene programme. Both non parametric statistical analysis (Kruskal-Wallis one-way analysis by rank. Wilcoxon signed rank-test and Mann Whitney U-test) and parametric analysis (stepwise multiple regression analysis, one-sample and two-sample t-test) were used to investigate the relationship between the periodontal parameters (dependent variables) and a series of independent variables: age. sex. plaque index (PI), gingival index (GI), CsA dose, CsA blood level, duration of therapy (months since allograft). Results failed to demonstrate any significant correlation between gingival overgrowth and age, sex, CsA dose or CsA blood level, PI. A positive significant correlation was found between periodontal conditions and GI and a significant inverse correlation between periodontal conditions and duration of therapy, suggesting that the relation between CsA therapy and gingival overgrowth in heart-transplant patients could be time-related and the negative influence of the drug on the periodontal status could spontaneously decrease over time.     

Altered collagen metabolism in nifedipine-induced gingival overgrowth

Fibroblasts from nifedipine-induced fibrotic gingiva (NFG) have been characterized with respect to several cellular functions which could contribute to the characteristic clinical overgrowth of the gingiva: collagen synthesis and breakdown, glycosaminoglycan production, fibronectin synthesis, and proliferation. Histologic examination of NFG tissue revealed a hyperplastic epithelium with elongated, branched rete pegs. The connective tissue consisted of densely-packed collagen fibers and numerous enlarged fibroblasts, as well as regions of thinner, disorganized collagen fibers in the vicinity of scattered inflammatory and mast cells. Results of in vitro experiments showed that the fibroblast strains from the fibrotic gingiva (NFG) produced significantly greater amounts of collagen and lower levels of collagenase activity when compared to age- and sex-matched normal human gingival fibroblast strains. The NFG fibroblasts did not produce significantly greater amounts of fibronectin, and their level of glycosaminoglycan production was less than that of the normal fibroblasts. The NFG fibroblasts did not proliferate significantly more rapidly than the normal fibroblast strains. These findings therefore show that there are defects in the regulation of collagen production by NFG fibroblasts in vitro , and suggest that these alterations in collagen metabolism contribute to the over-deposition of collagen in this tissue, rahter than hyperproliferation of the fibroblasts or through the production of increased amounts of fibronectin and glycosaminoglycans.     

Proteoglycans and glycosaminoglycans in phenytion-induced gingival overgrowth

Proteoglycans and glycosaminoglycans in normal gingival and phenytoin-induced gingival overgrowth were studied by gel electrophoresis and HPLC methods after extration with guanidinium hydrochloride and subsequent cesium chloride gradient centrifugation. The results showed that normal gingival. The relative collagen content was decreased in the phenytoin lesion. These results are in agreement with our revious stereological study, which reported an accumulation of the non-collagenous matrix chondroitin sulfates Containing non-sulfated, 4-sulfated and 6-sulfated disaccharide units, dermatan sulfate, hyaluronic acid and presumably also heparan sulfate in both normal gingival. and phenyton-induced gingival overgrowth. The increased amounts of PGs seen in the PHT lesion were associated with an increase mainly in chondroitinase sensitive glycosaminoglycans of high molecular weight and with a relative increase in iduroinc acid content. This study is consistent with the view that the PHT-lesion represents a tissue with an altered composition of the connective tissue.     

Phenytoin induced gingival overgrowth in institutionalized epileptics

In a cross-sectional, epidemiological study of phenytoin induced gingival overgrowth in 77 institutionalized persons with epilepsy, the severity of the gum lesions was quantified by means of a precise new technique. Lesion severity was then compared statistically to other clinical and laboratory parameters. Positive correlations were detected between overgrowth severity and gingival inflammation, probing depths, calculus accumulation, plaque score and the measurement gingival margin to mucogingival junction (GM-MGJ). No correlation was observed between lesion severity and patients age, daily drug dosage, plasma or saliva phenytoin level, or salivary concentration of the major phenytoin metabolite.     

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.