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Background The etiology of gingival overgrowth due to cyclosporine A (CsA) is still unknown. The aim of this study was to determine the possible role of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) on extra-cellular matrix (ECM) homeostasis when treated with different levels of CsA and its difference between fetal and adult human gingival fibroblasts (HGFs). Methods Each group of cells (adult and fetal) was cultured in 40 wells that consisted of four different CsA treatment concentrations. Every 10 wells were treated with 0, 50, 100, and 150 ng/mL of CsA which makes a total of 80 wells. Supernatants of every well were used to determine the concentration of MMPs and TIMPs using the Elisa kits from Boster, CA, USA. Results MMP-1 level increased with the treatment of CsA when treated with 50 and 150 ng/mL of CsA (p = 0.02 and p = 0.04) as TIMP-1 decreased (p < 0.0001) in adult group; while in the fetal group, TIMP-1 level increased with treatment of 150 ng/mL (p < 0.0001). MMP-2 level increased in both adult and fetal groups (p < 0.0001). MMP-3 level decreased in adult group (p < 0.0001) but went up in fetal HGFs (p = 0.01) when treated with 150 ng/mL CsA. TIMP-2 level increased in all wells significantly when treated with CsA (p < 0.0001). The study showed that CsA affects secretion of MMPs and TIMPs. MMP-1 increment and TIMP-1 decrement were observed, which indicate more degradation of ECM. This may be due to single donor use in this study. TIMP-2 and MMP-2 were both more active when treated with CsA which may be due to the gelatinase activity of them and that in CsA gingival overgrowth. There was more inflammation rather than fibrosis.

Objective and background: To report on a case of cyclosporine A-related gingival overgrowth (GO) treated by conventional scaling and Erbium:YAG laser that unexpectedly showed complete healing with normalization of the gingiva, making unnecessary further surgical treatment for gingival volume reduction. Since Erbium:YAG laser was approved in 1997 by the U.S. Food and Drug Administration for hard and soft tissue treatments in dentistry, several studies have been published to demonstrate its efficacy for bone cutting, plaque and subgingival calculus removal, and antiseptic effects both on soft and hard periodontal tissues. Methods: We report herewith the case of a patient undergoing cyclosporine A therapy, affected by GO who underwent scaling and full mouth disinfection with chlorhexidine 2% rinses, followed by Erbium:YAG laser treatment of gingival pseudopockets, without surgical removal of the overgrown gingiva. Results: Unexpectedly, complete healing of the periodontal tissues was observable after one single laser application and no adjunctive surgical procedure was necessary. Conclusions: Erbium:YAG laser could be considered a really effective option for the nonsurgical treatment of drug-induced GO, avoiding the surgical procedures and also promoting a fast healing and a patient compliance surely higher than conventional techniques.

Background/purpose: Cyclosporine A (CsA) has been used as an immunosuppressive agent with a side effect of gingival overgrowth. It has been known that CsA-induced epithelial-mesenchymal transition (EMT) in gingiva, but the molecular mechanism has not been fully unveiled. The purpose of the study is to investigate functional roles of microRNAs in gingival overgrowth., Methods: The effect of CsA on the expression of microRNA-200b (miR-200b) in normal human gingival fibroblasts (HGFs) was determined using qRT-PCR. Luciferase reporter assay and Western blot were utilized to examine the relationship between miR-200b and EMT inducer Slug. Cell proliferation was assessed by MTT assay., Results: CsA was found to downregulate the miR-200b transcript in HGFs in a dose-dependent manner. Luciferase reporter assay confirmed that Slug was a direct target of miR-200b, and the CsA-induced cell proliferation and Slug upregulation were inhibited by overexpression of miR-200b. Additionally, the silence of Slug reversed the increased proliferation of HGFs by miR-200b inhibitor., Conclusion: Repression of miR-200b after CsA administration led to an increase in Slug expression. Our results suggested that miR-200b was an upstream effector of the CsA-induced EMT and may act as a therapeutic target for CsA-induced gingival overgrowth., (Copyright © 2018. Published by Elsevier B.V.)

Background/purpose: Gingival overgrowth occurs as a side effect of systemic medication with immunosuppressant cyclosporine A (CsA). Slug, a master regulator of epithelial-mesenchymal transition, is dramatically upregulated in a variety of fibrotic diseases. The aim of this study is to investigate the role of epithelial-mesenchymal transition marker Slug in the pathogenesis of CsA-induced gingival overgrowth., Methods: Clinically healthy gingiva and CsA-induced gingival overgrowth specimens were analyzed by immunohistochemistry. The effect of CsA on normal human gingival fibroblasts (HGFs) was used to elucidate whether Slug expression could be affected by CsA by real-time reverse transcription-polymerase chain reaction and western blot. Cell proliferation in CsA-treated HGFs with Slug lentiviral-mediated shRNAi knockdown was evaluated by tetrazolium bromide reduction assay., Results: Slug expression was higher in CsA-induced gingival overgrowth specimens than in clinical healthy gingiva (p < 0.05). Slug expression was significantly higher in CsA-induced gingival overgrowth specimens with higher levels of inflammatory infiltrates (p < 0.05). CsA was found to increase Slug transcript and protein expression in HGFs in a dose-dependent manner (p < 0.05). In addition, knockdown of Slug significantly suppressed CsA-induced cell proliferation in HGFs (p < 0.05)., Conclusion: Taken together, upregulation of Slug in HGFs stimulated by CsA may play an important role in the pathogenesis of CsA-induced gingival overgrowth., (Copyright © 2016. Published by Elsevier B.V.)

Background/purpose: Cyclosporine A (CsA) is used as an immunosuppressive agent, and its prominent side effect is the induction of gingival overgrowth. Snail is a master regulator of epithelial-mesenchymal transition (EMT). EMT under pathological processes could lead to fibrotic changes. The purpose of this study was to investigate the role of Snail in the pathogenesis of CsA-induced gingival overgrowth., Methods: The effect of CsA on normal human gingival fibroblasts (HGFs) was used to elucidate whether Snail expression could be induced by CsA by using quantitative real-time reverse transcription-polymerase chain reaction and western blot. The cell proliferation rate in CsA-treated HGFs with Snail lentiviral-mediated short hairpin RNA interference (shRNAi) knockdown was evaluated by tetrazolium bromide reduction assay., Results: CsA increased the Snail transcript and Snail protein expression in HGFs in a dose-dependent manner (p < 0.05). In addition, downregulation of Snail by lentiviral infection significantly reduced CsA-stimulated cell proliferation in HGFs (p < 0.05)., Conclusion: CsA stimulated Snail expression and cell proliferation in HGFs, while silencing Snail could effectively reverse these phenomena. These results may provide new avenues for the design of novel antifibrotic therapies for CsA-induced gingival overgrowth through targeting Snail., (Copyright © 2015. Published by Elsevier B.V.)

Background: Interleukin (IL)-6 family of cytokines, including IL-6, oncostatin M (OSM), leukemia inhibitory factor (LIF), and IL-11, have fibrogenic features. The current study determines gingival crevicular fluid (GCF) levels of fibrosis-related IL-6-type cytokines in cyclosporine A (CsA)-induced gingival overgrowth (GO)., Methods: Eighty non-smokers were included (40 CsA-medicated renal transplant patients with GO [GO+; n = 20] or without GO [GO-; n = 20], 20 individuals with gingivitis, and 20 healthy participants). Probing depth and plaque, papilla bleeding, and hyperplastic index scores were recorded. GCF samples were obtained from the mesio-buccal aspects of two teeth. GCF IL-6, IL-1β, OSM, LIF, and IL-11 levels were analyzed by enzyme-linked immunosorbent assay., Results: The GO+ and GO- groups had higher IL-6 total amounts than the healthy group (P <0.008). IL-1β total amounts in the GO+ group were significantly higher than in both the healthy and GO- groups (P <0.008). OSM total amount was elevated in the GO+ and GO- groups compared with both the gingivitis and healthy groups (P <0.008). All groups had similar LIF and IL-11 total amounts (P >0.008). Moderate positive correlations were detected among IL-6, IL-1β, OSM, and IL-11 total amount in GCF and clinical parameters (P <0.05)., Conclusions: IL-6 and OSM increases in GCF as a result of CsA usage or an immunosuppressed state irrespective of the severity of inflammation and the presence of GO. The IL-6 family of cytokines might not be directly involved in biologic mechanisms associated with CsA-induced GO. Lack of an association between assessed IL-6 cytokines and CsA-induced GO might indicate distinct effects of these cytokines on fibrotic changes of different tissues.

Objective: The aim of the present study was to investigate the effect of cyclosporine-A (CsA) medication on gingival crevicular fluid (GCF) LL-37, human neutrophil peptide (HNP)1-3 and adrenomedullin (ADM) levels., Design: CsA-treated renal transplant recipients with GO (CsA GO+) and without GO (CsA GO-), tacrolimus-medicated renal transplant recipients (n = 20/group), systemically healthy subjects with gingivitis (n = 21) and individuals free of periodontal and systemic diseases (n = 20) were included in the present study. Periodontal parameters were recorded and GCF samples were obtained from the study participants. GCF LL-37, HNP1-3 and ADM levels were analyzed by enzyme-linked immunosorbent assay., Results: GCF LL-37 total amount was higher at GO+ sites than the other study sites (p < 0.05). Total amount of GCF HNP1-3 was higher in immunosuppressive treatment groups than healthy and gingivitis groups, regardless of GO presence (p < 0.05). GCF ADM total amount was similar in all study groups. GCF volume, papillary bleeding index and hyperplastic index (p < 0.05) were significantly correlated with GCF LL-37 total amounts (p < 0.05), but not with GCF HNP1-3 and ADM total amount at GO+ sites (p > 0.05)., Conclusion: Neutrophil infiltration due to extended inflammation might have increased GCF LL-37 levels at GO+ sites and contributed to the pathogenesis of CsA-induced GO., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background and Objective: Cyclosporine A (CsA) is an immunosuppressive agent administered to transplant patients. A well-known reported oral side effect of CsA consumption is gingival overgrowth (GO). Changes in the expression of integrins occurring in the gingiva following CsA treatment have been reported but these reports are mainly concerned with the connective tissue of the gingiva. In this study we targeted the alterations in the oral epithelium using KB cells, an oral epithelial cell line., Methods: Cultured oral epithelial cells were treated with increasing concentrations of CsA (0.1, 1 and 10 µg/mL) and the molecular changes involving antioxidant enzymes [glutathione peroxidase (GPx) and glutathione reductase (GR)] and the level of reactive oxygen species (ROS) were measured. Quantitative real-time PCR was used to assess the expression of selected integrins (α2, α5 and β1)., Results: At CsA concentration above 0.1 µg/mL GPx demonstrated an increase in activity while GR activity and the level of reduced glutathione were diminished (p < 0.05). α5 and β1 integrin were downregulated at all treatment concentrations of CsA while α2 integrin presented this effect at concentrations above 1 µg/mL (p < 0.05)., Conclusion: The results suggest a possible role for oxidative stress and the altered expression of integrins in the pathology of CsA-induced gingival overgrowth.

Background/purpose: The prominent side effect of the immunosuppressive drug cyclosporine A (CsA) is gingival overgrowth. Hypoxia-inducible factor (HIF)-1α regulates a wide variety of profibrogenic genes, which are closely associated with tissue fibrosis. The aim of this study was to compare HIF-1α expression in normal gingival tissues and CsA-induced gingival overgrowth specimens and further explore the potential mechanisms that may lead to induction of HIF-1α expression., Methods: Fifteen CsA-induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry. Western blot was used to investigate the effects of CsA on the expression of HIF-1α in cultured human gingival fibroblasts. The effects of CsA on plasminogen activator inhibitor (PAI)-1 expression were evaluated in environmental hypoxia., Results: HIF-1α staining in gingival tissue was stronger in CsA-induced gingival overgrowth group than normal gingival group (p < 0.05). The expression of HIF-1α was significantly higher in CsA-induced gingival overgrowth specimens with higher levels of inflammatory infiltrates (p = 0.041). CsA was found to upregulate HIF-1α protein in a dose-dependent manner (p < 0.05). Hypoxia increased CsA-induced PAI-1 protein expression than normoxic conditions (p < 0.05)., Conclusion: These results suggest that HIF-1α expression is significantly upregulated in CsA-induced gingival overgrowth specimens. The activation of HIF-1α may promote fibrogenesis by an increase of PAI-1 expression and a subsequent elevation of extracellular matrix production in gingival tissues., (Copyright © 2012. Published by Elsevier B.V.)

Background and Objective: Gingival overgrowth is a prominent side effect of cyclosporine (CsA) therapy in renal transplant patients. Although the exact mechanism by which this drug induces gingival overgrowth is uncertain, marked variations in individual susceptibility to this drug suggest a genetic predisposition. Studies have shown that genetic variation (polymorphism) in the trinucleotide cytosine-adenine- guanine (CAG) sequence in exon 1 of the androgen receptor (AR) gene is related to altered activity of the AR as a transcription factor. However, the relationship between the length of the CAG repeat and gingival overgrowth has not yet been studied. The present study was carried out to determine whether there is an association between CsA-induced gingival overgrowth and the length of the CAG repeats in the AR gene., Material and Methods: Genomic DNA samples were prepared from the blood of 50 renal transplant patients with CsA-induced gingival overgrowth and from the blood of 100 renal transplant patients on CsA with no gingival overgrowth., Results: The difference in allele distribution among the subjects with gingival overgrowth and control samples was statistically significant (p = 0.001)., Conclusion: The findings suggest a link between CsA7induced gingival overgrowth and a smaller size of CAG repeat in the AR gene., (© 2013 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd.)

Background and Objective: Systemic macrolide antibiotic administration has been shown to result in the elimination or reduction cyclosporine A-induced gingival overgrowth. Roxithromycin (ROX) is known to have anti-inflammatory, immunomodulatory and tissue reparative effects. This study was to evaluate the effect of adjunctive ROX therapy on cyclosporine A-induced gingival overgrowth and interleukin (IL)-1β, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) levels in gingival crevicular fluid of renal transplant patients., Material and Methods: Thirty-one patients with clinically significant overgrowth and 16 periodontally healthy subjects were included in this randomized, double-blind, placebo-controlled, parallel-arm study. Patients received scaling and root planing (SRP) at baseline and randomized to take either ROX or placebo for 5 d. The clinical parameters, including plaque index, papillary bleeding index, probing depth and gingival overgrowth scores, were recorded. The amounts of IL-1β, TGF-β1 and VEGF in gingival crevicular fluid were detected by ELISA. Periodontal parameters as well as gingival crevicular fluid biomarker levels were evaluated at baseline and at 1 and 4 wk post-therapy., Results: Following SRP plus ROX and SRP plus placebo therapy, significant improvements in clinical periodontal parameters of both study groups were observed (p < 0.025). In the ROX group, adjunctive ROX therapy resulted in a greater gingival overgrowth scores reduction compared with those in the placebo group at 4 wk (p < 0.017). Initial amounts of IL-1β, TGF-β1 and VEGF for both the ROX and placebo groups were significantly higher than those for healthy subjects (p < 0.017), with no statistical difference between the two study groups. At 1 and 4 wk post-therapy, significant decreases in the amounts of IL-1β, TGF-β1 and VEGF were observed in both study groups when compared with baseline (p < 0.025), but there was no difference in the levels of IL-1β and VEGF between the two study groups. The amount of decrease in TGF-β1 levels for the ROX group was statistically significant compared to that for the placebo group at 4 wk after treatment (p < 0.017)., Conclusion: Our study indicated that combination of ROX with non-surgical therapy improves gingival overgrowth status and decreases gingival crevicular fluid TGF-β1 levels in patients with severe gingival overgrowth. The reduction of gingival crevicular fluid TGF-β1 following ROX therapy suggests an anti-inflammatory/immunomodulatory effect of ROX on the treatment of cyclosporine A-induced gingival overgrowth., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The use of cyclosporine A (CsA) induces hyperplasia of the gingival epithelium in a site-specific response manner, but the molecular mechanism via which the lesion occurs is unclear. The present research aims to investigate the site-specific effect of CsA on the apoptosis of gingival epithelium associated with gingival hyperplasia., Methods: Forty Wistar rats were divided into CsA-treated and non-treated groups. Paraffin-embedded sections of mandibular first molars were selected for hematoxylin and eosin staining, immunohistochemistry analyses of bcl-2 and caspase-3, and the staining of terminal deoxynucleotidyl transfer-mediated dUTP nick-end labeling (TUNEL). The area of the whole gingival epithelium and the length of rete pegs were measured, and the number of bcl-2- and caspase-3-positive cells in the longest rete peg were counted. The analysis of variance for factorial designs and Fisher least significant difference test for post hoc analysis were used to determine the significance levels., Results: In CsA-treated rats, bcl-2 expression was significantly upregulated, whereas caspase-3 expression was downregulated, along with a reduced number of TUNEL-positive cells. The site-specific distribution of bcl-2 was consistent with the site-specific hyperplasia of the gingival epithelium in CsA-treated rats., Conclusions: CsA inhibited gingival epithelial apoptosis via the mitochondrial pathway and common pathway. The antiapoptotic protein bcl-2 might play a critical role in the pathogenesis of the site-specific hyperplasia of gingival epithelium induced by CsA. There were mechanistic differences in the regulation of apoptosis for cells in the attached gingival epithelium, free gingival epithelium, and junctional epithelium.

Background: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients., Methods: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models., Results: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension., Conclusion: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

Objective: Immunosuppressive drugs may induce an increase of the gingival connective tissue in the extracellular matrix. The aim of this study was to assess the effectiveness of nonsurgical periodontal treatment in reducing gingival overgrowth (GO) in transplant patients taking cyclosporin A (CsA) or tacrolimus (Tcr). Method and Materials: An observational cohort study employing 68 transplant patients with diagnosis of GO, 51 taking CsA and 17 in therapy with Tcr, was performed at the Periodontal Unit of the School of Dental Sciences (University of Trieste, Italy). Percentages of plaque index (PI), bleeding on probing (BoP), sites with probing depth (PD) > 3 mm, and hypertrophy index (HI) were registered at baseline, 90 days, 180 days, and at 1 year after nonsurgical periodontal therapy. Furthermore, HI at baseline and after 1 year was investigated by multiple linear regression. Results: Both groups have significantly improved their clinical parameters: CsA group: PIbaseline = 41.67%; PIyear = 33%; BoPbaseline = 13.88%; BoPyear = 6.94%; PD > 3 mmbaseline = 18.6%; PD > 3 mmyear = 12.96%; HIbaseline = 22%; HIyear = 10%; Tcr group: PIbaseline = 40.73%; PIyear = 38.54%; BoPbaseline = 20.78%; BoPyear = 12.5%; PD > 3 mmbaseline = 21.53%; PD > 3 mmyear = 13.19%; HIbaseline = 12%; HIyear = 6.5%. Age showed a statistical negative correlation with HI at baseline (P < .05), while PD > 3 mm was positively correlated to the baseline HI (P < .001). Only HI at baseline showed a statistically significant negative relation with HI at 1 year (P < .001). Conclusion: After nonsurgical periodontal therapy no patients needed additional periodontal surgery. Nonsurgical periodontal treatment itself represents an efficacious therapy in transplant patients treated with CsA and Tcr. [ABSTRACT FROM AUTHOR]

Cyclosporine A, an extremely effective immunosuppressant, is also associated with various untoward effects, including gingival overgrowth. Despite intense clinical and laboratory investigation, the cellular-molecular mechanism through which cyclosporine A simultaneously acts as a selective immunosuppressant while it elicits a connective tissue reaction in the gingiva remains poorly understood. In recent years, cellular and molecular biologic techniques have elucidated a variety of growth factors that control connective tissue homeostasis. Two growth factors known to be major elements in wound repair and connective tissue of these factors may be responsible for promoting fibroblastic proliferation and fibroblastic production of extracellular matrix constituents in overgrown gingival tissues. Expression of these factors has recently been shown to be upregulated in these tissues. The results of these recent studies may provide a foundation for understanding the molecular mechanism involved in the pathogenesis of cyclosporine A-induced gingival overgrowth. (Quintessence Int 1999;30:775-783) [ABSTRACT FROM AUTHOR]

Objective Gingival overgrowth is a side effect associated with some distinct classes of drugs, such as anticonvulsants, immunosuppressants, and calcium channel blockers. One of the main drugs associated with gingival overgrowth is the antiepileptic phenytoin, which affects gingival tissues by altering extracellular matrix metabolism. It has been shown that mutation of human SOS1 gene is responsible for a rare hereditary gingival fibromatosis type 1, a benign gingival overgrowth. The aim of the present study is to evaluate the possible contribution of SOS1 mutation to gingival overgrowth-related phenotype. Design We selected and screened for mutations a group of 24 epileptic patients who experienced significant gingival overgrowth following phenytoin therapy. Mutation scanning was carried out by denaturing high-performance liquid chromatography analysis of the entire coding region of the SOS1 gene. Novel identified variants were analyzed in-silico by using Alamut Visual mutation interpretation software, and comparison with normal control group was done. Results Mutation scanning of the entire coding sequence of SOS1 gene identified seven intronic variants and one new exonic substitution (c.138G > A). The seven common intronic variants were not considered to be of pathogenic importance. The exonic substitution c.138G > A was found to be absent in 100 ethnically matched normal control chromosomes, but was not expected to have functional significance based on prediction bioinformatics tools. Conclusions This study represents the first mutation analysis of the SOS1 gene in phenytoin-induced gingival overgrowth epileptic patients. Present results suggest that obvious pathogenic mutations in the SOS1 gene do not represent a common mechanism underlying phenytoin-induced gingival overgrowth in epileptic patients; other mechanisms are likely to be involved in the pathogenesis of this drug-induced phenotype. [ABSTRACT FROM AUTHOR]

Drug-induced gingival enlargement (GE) is a frequent adverse effect observed in patients treated with anticonvulsant, immunosuppressant, and some antihypertensive medications-the antiepileptic phenytoin being the main drug associated with GE due to its high incidence (around 50%). The molecular mechanisms behind drug-induced gingival overgrowth are still unknown. By reverse transcription polymerase chain reaction, we demonstrate that the calcium-permeable ion channels TRPA1, TRPV1, and its capsaicin-insensitive isoform TRPV1b are expressed in human gingival fibroblasts (HGFs), the most abundant cellular type in periodontal tissue. Cultured HGFs responded with intracellular calcium elevations to phenytoin and to the canonical TRPA1 agonist allyl isothiocyanate. Application of phenytoin activated a nonselective cationic current in HGFs with a typical signature for TRPA1 channels. Moreover, this activation was blocked by HC030031, a specific TRPA1 blocker. Similarly, the use of shRNAs against hTRPA1 in HGFs reduced TRPA1 expression and activation by phenytoin. In addition, we show that phenytoin increased intracellular calcium levels in cells transfected with mouse or human TRPA1 channels. Responses to phenytoin were not observed in untransfected cells or cells expressing TRPM8 or TRPV1. The activation of HGFs by phenytoin was markedly reduced in the presence of antioxidant vitamins: ascorbic acid, folic acid, and α-tocopherol. By performing cell proliferation assays, we found that phenytoin did not augment the proliferation rate of HGFs. In contrast, alcian blue and picrosirius red staining of long-term HGFs cultures indicated that phenytoin induces extracellular matrix accumulation of collagen. Collectively, these findings support an important role of TRPA1 channels in phenytoin-induced GE, provide insight into the pathophysiologic mechanism, and offer novel therapeutic opportunities for its treatment. [ABSTRACT FROM AUTHOR]

Background: Transglutaminase (TGM)-2 has been shown to contribute to fibrosis by extracellular matrix accumulation in some organs and is activated by intracellular reactive oxygen species. The aim of this study is to investigate levels of gingival crevicular fluid (GCF) and plasma TGM-2 and oxidative stress markers (OSMs) in cyclosporin A (CsA)-induced gingival overgrowth (GO).Methods: The study enrolled 20 healthy (H) individuals; 20 patients with gingivitis (G); 20 CsA-medicated patients with GO (CsA GO+); and 20 CsA-medicated patients without GO (CsA GO-). GCF and plasma levels of TGM-2 were analyzed by enzyme-linked immunosorbent assay. Spectrofluorometry was used to analyze thiobarbituric acid reactive substance (TBARS); ferric-reducing antioxidant power (FRAP); total oxidant status (TOS); and total antioxidant capacity (TAC).Results: GCF TGM-2 level was elevated in CsA GO+ compared with G (P = 0.048) and H (P = 0.001) groups. GCF TBARS level was elevated in CsA GO+ compared with other groups (CsA GO- group: P = 0.003; G group: P <0.001; and H group: P <0.001) and was higher in CsA GO- than in H (P = 0.048). GCF FRAP level was lower in CsA GO- than in H (P = 0.04). Both CsA GO+ and CsA GO- groups had lower GCF TOS levels than H (P <0.001 and P = 0.002) and G (P = 0.003 and P = 0.04). GCF TAC was higher in CsA GO+ than in H (P = 0.02). Plasma TGM-2 level was elevated in CsA GO+ compared with G (P = 0.048) and H (P = 0.002). Plasma FRAP level was higher in H and CsA GO- than in CsA GO+ (P = 0.008 and P = 0.02).Conclusions: CsA use significantly alters GCF and plasma levels of TGM-2 and OSMs. TGM-2 may contribute to CsA-induced GO in CsA-treated patients by changing GCF and plasma levels of OSMs. Further studies are needed to prove causality and its direction. [ABSTRACT FROM AUTHOR]

Background and Objective It has previously been shown that both cyclosporine A and tacrolimus cause gingival overgrowth in the rat. We proposed that sirolimus may play an important role in decreasing the severity of gingival overgrowth. Therefore, the aim of this study was to evaluate the gingival changes induced by immunosuppressants, in the presence and absence of sirolimus, using histopathology and stereological methods. Material and Methods Thirty-six male Sprague-Dawley rats were distributed into six treatment groups, each containing six rats, as follows: (i) cyclosporine A for 8 wk; (ii) tacrolimus for 8 wk; (iii) sirolimus for 8 wk; (iv) cyclosporine A + sirolimus for 8 wk; (v) tacrolimus + sirolimus for 8 wk; and (vi) distilled water for 8 wk. Histomorphometric analyses included measurements of epithelial thickness and connective tissue width and height. Stereological analyses included measurements of volumetric densities of fibroblasts (Vf), collagen fibers (Vcf) and blood vessels (Vbv). Results Connective tissue width and height were significantly increased in cyclosporine A, tacrolimus and cyclosporine A + sirolimus groups compared with the control group ( p < 0.05), and epithelial thickness was significantly increased in the cyclosporine A group and tacrolimus group compared with the control group ( p < 0.05). Vf was significantly increased in the cyclosporine A group and the tacrolimus group compared with the control group ( p < 0.05), whereas Vcf and Vbv were significantly increased in the cyclosporine A, tacrolimus and cyclosporine A + sirolimus groups compared with the control group ( p < 0.05). Conclusion The results of the study suggest that sirolimus seems not to be associated with gingival overgrowth, and combined usage of sirolimus and immunosuppressants decreases the severity of gingival overgrowth. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of periodontal treatment on gingival overgrowth in a group of renal transplant patients. Subjects and Methods: Twenty-five renal transplant recipients receiving immunosuppressive therapy with cyclosporine A (CsA) were randomly assigned to 2 groups. Group 1 (n = 15) included patients who had been specifically referred to a dental clinic to prevent gingival overgrowth and were given full periodontal therapy. Group 2 (n = 10) was comprised of patients who did not receive any professional periodontal cleaning. Patients from both groups were examined to determine their periodontal status before and after 3, 6 and 12 months in terms of their plaque index, gingival index and gingival overgrowth. During the examination, their overall health was stable. Results: For group 1, the scores were 1.89 (baseline), 0.98 (6 months) and 0.56 (12 months), and hence there were significant reductions (p = 0.0001). The gingival indices were 1.71 (baseline), 0.76 (6 months) and 0.35 (12 months), and the reductions were also significant (p = 0.0001). A significant association was observed between poor oral hygiene and the degree of gingival overgrowth. The 1-year post-treatment follow-up showed that patients in group 1 did not develop gingival overgrowth due to the use of CsA as group 2 did without prior periodontal therapy. Conclusion: Oral hygiene status was the most important variable related to the development and degree of gingival overgrowth due to the use of CsA. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction. Several factors can influence the gingival tissues such as disrupting tissue homeostasis and the occurrence of pathological conditions. The aim of our study was to investigate and compare the presence of apoptosis in patients undergoing immunosuppressive therapy, patients with periodontitis and healthy patients, as well as to achieve better understanding of the role of apotosis in the same processes. Methods. The first examined group consisted of 21 patients (10 males and 11 females; mean age 37.4± 10.2 years) with neither kidney diseases nor cyclosporine A (CsA) therapy, who had a verified periodontal disease. The second group consisted of 21 kidney-transplant patients (9 males and 12 females), with diagnosed gingival overgrowth (GO) undergoing continuous immunosuppressive therapy. The control group consisted of the same number of patients, clinically healthy subjects (15 males and 6 females; mean age 29 ± 4.0 years) with plaque-induced gingivitis. The following indexes were analyzed: plaque index (PI), index of gingival inflammation (GI) according to Loe-Silnes, and gingival overgrowth index (GOI) according to MacGaw, et al. The determination of CsA in blood was performed by a fluorescence polarised immunoassay (FPIA). The tissue samples were estimated by semi-quantitative analysis in order to determine the presence of apoptotic cells and imunohistochemical expression of the bcl-2 and p53 proteins. Results. In our study we found statistical differences in bcl-2 and apoptotic index, among the groups: the greatest expression of bcl-2 and apoptotic index was registered in the group treated with CsA, and the lowest expression was noted in the gingivitis group (p<0.01). There was a statistical significant positive correlation between bcl-2 and apoptotic index, PI, and GI index (p<0.05). There was no significant correlation between the blood concentration of CsA and apoptosis (p>0.05; r=0.187). Conclusions. Our findings suggest that increased apoptosis may have a role in the pathogenesis of CsA-induced gingival overgrowth in the cases of patients on high dose of CsA. [ABSTRACT FROM AUTHOR]

Cyclosporine A, a drug that inhibits the immune response, has been widely used for over 30 years in immunosuppressive therapy protocols for patient-recipients of the transplanted organs. One of the commonly reported side effects of Cyclosporine A is gingival overgrowth, with varying degrees of severity, which may interfere with the aesthetics and normal functions of the oral cavity. Combination with other drugs that can recognize the gum tissue as a secondary target organ increases the risk of drug-induced gingival overgrowth. In cases where a lower dose of Cyclosporine A or conversion to another immunosuppressive agent (a drug not assigned to such a side effect) are not possible, the management of severe gingival overgrowth focuses on surgical excision of the excessively proliferated gingival tissue. We report the case of a young adult with moderate drug-induced gingival overgrowth, the beneficiary of a functional transplanted kidney about 9 years ago, treated with two immunosuppressives, who has undergone gingivectomy with electrocautery, as a necessary intervention to improve the oral hygiene and to avoid worsening of malfunctions in the oral cavity. [ABSTRACT FROM AUTHOR]

Background/Purpose: Gingival overgrowth can be induced in patients treated with cyclosporine-A (CsA), an immunosuppressant often used following organ transplantation. A pre-existing rat model designed to mimic CsA-induced gingival overgrowth in humans was used to test the effectiveness of frequent application of a chlorhexidine antiplaque solution in reducing the overgrowth. Methods: Four groups of rats were fed CsA. One group received chlorhexidine mouthwash twice a day, the second group received chlorhexidine mouthwash once a day, the third group received chlorhexidine mouthwash every other day, and the fourth group did not receive chlorhexidine mouthwash all. A fifth negative control group received only mineral oil. Overgrowth was determined by measuring the changes in the gingival probing depth and the keratinized gingival widthon molars. A gingival histological examination was performed. Results: Rats treated with mouthwash twice daily exhibited decreased probing depths and gingival widths without statistical significance. Histological examination revealed that CsA treatment caused gingival enlargement, whereas chlorhexidine treatment twice a day diminished the enlargement. Conclusion: These findings suggest that chlorhexidine mouthwash used twice daily may reduce the severity of CsA-induced gingival overgrowth. Further research is warranted to determine the optimal dose and treatment regimen. [Copyright &y& Elsevier]

Background Gingival overgrowth is an adverse drug reaction ( ADR) well known with phenytoin, cyclosporine or calcium channel blockers but can be related to other drugs. Aim We reviewed spontaneous notifications of drug-induced gingival overgrowth ( DIGO), in France. Material & methods We selected DIGO cases registered in the French Pharmacovigilance Database, between 1984 and 2010. Results We found 147 DIGO cases (0.04% of all cases), most of them (86.4%) 'non serious'. Patients were more frequently men (58.5%) and between 40 and 69 years (58.5%). Evolution was favourable in 47.5% of cases. The most frequently 'suspected' drugs were calcium channel blockers (30.6%) followed by immunosuppressants (15.2%) and anticonvulsants (10.1%). The DIGO was also reported with drugs for which the ADR was 'unlabelled' (mycophenolate mofetil, valproic acid, clarithromycin, ethynylestradiol, levonorgestrel, desogestrel, etc.). There were two peaks of occurrence (0-3 and >12 months) for immunosuppressants or calcium channel blockers and only one (>12 months) for anticonvulsants. Conclusion Gingival overgrowth is often a 'non serious' ADR but evolution was favourable in only half of cases. This ADR is 'labelled' for calcium channel blockers, cyclosporine and phenytoin but can also occur with other immunosuppressants or anticonvulsants, antibiotics, oral contraceptives, etc. [ABSTRACT FROM AUTHOR]

Cota LOM, Aquino DR, Franco GCN, Cortelli JR, Cortelli SC, Costa FO. Gingival overgrowth in subjects under immunosuppressive regimens based on cyclosporine, tacrolimus, or sirolimus. J Clin Periodontol 2010; 37: 894–902. doi: 10.1111/j.1600-051X.2010.01601.x. Aim: To assess the prevalence and variables associated with gingival overgrowth (GO) in renal transplant recipients medicated with cyclosporine (CsA), tacrolimus (Tcr), or sirolimus (Sir). Materials and Methods: One hundred and thirty-five eligible subjects were divided in CsA, Tcr, and Sir groups comprising 45 subjects each. GO was visually assessed and subjects were assigned as GO+ or GO− in a post hoc definition. Saliva samples were collected and the presence of periodontal pathogens was assessed through polymerase chain reaction. Variables of interest were compared between GO+ and GO− subjects through univariate and multivariate analysis. Results: Prevalence of GO was of 60.0% for CsA, 28.9% for Tcr, and 15.6% for Sir groups. Within the CsA group, GO was associated with papillary bleeding index ( p=0.001); within the Tcr group, GO was associated with CsA previous use ( p=0.013), and calcium channel blockers (CCB) use ( p=0.003); within the Sir group, GO was associated with papillary bleeding index ( p=0.018), and CCB use ( p=0.020). A higher frequency of Tannerella forsythia was observed among GO+ subjects medicated with Tcr. Conclusion: Pharmacological and periodontal variables were associated with GO in different immunosuppressive regimens. Integration between the medical and the dental team may be an important approach in the post-transplant maintenance routine. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Interleukin-6 (IL-6) may be involved in drug-induced gingival overgrowth (GO). The present study was conducted to assess the association between IL-6 (−174 G/C) gene polymorphism and GO in renal transplant recipients under cyclosporine (CsA), tacrolimus (Tcr), or sirolimus (Sir)-based regimens. Methods: Within an eligible population, 45 unrelated subjects were selected for each CsA, Tcr, and Sir group, totaling a sample of 135 subjects. GO was visually assessed and subjects were assigned as controls (non-responders) or cases (responders) in a post hoc definition. IL-6 gene polymorphism was assessed using the polymerase chain reaction amplification and digestion. The distribution of genotypes and allele frequencies in responders and non-responders were compared using the Chi-squared test. Results: The number of responders was 27 (60.0%), 13 (28.9%), and 7 (15.6%) in the CsA, Tcr, and Sir groups, respectively. No differences could be observed at frequencies of −174GG, −174CG, and −174CC genotypes when comparing responders to non-responders in the CsA, Tcr, and Sir groups. Similar to genotypes, allele frequencies showed no differences between responders and non-responders in all groups. Conclusions: No association between IL-6 (−174 G/C) gene polymorphism and gingival overgrowth was observed in renal transplant recipients under CsA, Tcr, or Sir-based immunosuppressive maintenance regimens. [Copyright &y& Elsevier]

Introduction. Oral hygiene in kidney transplant recipients contributes to maintenance of the transplanted organ and its function. Thus, an investigation of oral lesions could be counted as a notable work. These patients have the potential to be involved with lesions developed as a result of the administration of immunosuppressive drugs. The aim of this study was to investigate oral lesions in a group of kidney transplant recipients. Materials and Methods. The present study was a cross-sectional research on 100 patients with a kidney transplant for at least 3 months. Oral mucosa was assessed clinically for any lesion. Additional data on systemic diseases, transplant duration, and medications were recorded. Results. Twenty-four percent of the patients had at least 1 oral lesion. The most common lesion was oral candidiasis in 16% of the participants (13 cases of acute pseudomembranous and 3 cases of chronic oral candidiasis). Gingival enlargement was seen in 7% of the kidney transplant recipients, and 2% had a coated tongue. Conclusions. Elimination of oral fungal lesions in kidney transplant recipients is highly recommended. We hope this study can shed light on this particular aspect of healthcare in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Cyclosporin A (CyA) induces gingival overgrowth via its stimulatory effects on expression of transforming growth factor-beta1 (TGF-β1) and collagen. It is not known whether CyA has a direct effect on gingival fibroblasts or induces its effect indirectly via stimulation of myofibroblast transdifferentiation. The present study was undertaken to examine the in vivo and in vitro effect of CyA on myofibroblast transdifferentiation. Rats were treated for 60 days with a daily subcutaneous injection of CyA, and the gingival overgrowth tissue was analyzed by immunohistochemistry. In vitro, fibroblasts from normal gingiva (NG) were cultured in the presence of different concentrations of CyA, and subjected to semi-quantitative reverse transcriptase-polymerase chain reaction and western blot. Although CyA treatment stimulated TGF-β1 expression by NG fibroblasts, it lacked to induce expression and production of isoform a of smooth muscle actin (α-SMA), the specific myofibroblast marker. The expression levels of connective tissue growth factor (CTGF), which has been considered a key molecule to promote the transdifferentiation of myofibroblasts via TGF-β1 activation, were unaffected by CyA. Our results demonstrate that CyA-induced gingival overgrowth is not associated with activation of myofibroblast transdifferentiation, since CyA is not capable to increase CTGF expression. [ABSTRACT FROM AUTHOR]

Drozdzik A, Kurzawski M, Lener A, Kozak M, Banach J, Drozdzik M. Matrix metalloproteinase-3 gene polymorphism in renal transplant patients with gingival overgrowth. J Periodont Res 2009; doi: 10.1111/j.1600-0765.2009.01221.x. © 2009 The Authors. Journal compilation © 2009 Blackwell Munksgaard Background and Objective: Gingival enlargement frequently occurs in transplant patients receiving immunosuppressive drugs. It was hypothesized that gingival enlargement associated with cyclosporine use results from reduced degradation of extracellular matrix in the gingiva. Matrix metalloproteinase-3 (MMP-3) is involved in biodegradation of the extracellular matrix, and its inhibition may contribute to an abnormal accumulation of fibronectin and proteoglycans, which are MMP-3 substrates. The aim of this study was to investigate whether an association exists between MMP-3 genotypes and gingival enlargement in kidney transplant patients medicated with cyclosporine A. Material and Methods: Sixty-four unrelated kidney transplant patients suffering from gingival overgrowth, as well as 111 control transplant patients without gingival overgrowth, were enrolled in the study. Gingival overgrowth was assessed 6 mo after transplantation. During the post-transplant period all patients were given cyclosporine A as a principal immunosuppressive agent. MMP-3 polymorphism was determined using a PCR restriction fragment length polymorphism assay. Results: In kidney transplant patients suffering from gingival overgrowth the mean gingival overgrowth score was 1.35 ± 0.57, whereas in control subjects the mean gingival overgrowth score was 0.0. The distribution of MMP-3-1178A/*dupA alleles among all kidney transplant patients, as well as in the two study subgroups, did not differ significantly from Hardy–Weinberg equilibrium. The frequency of the MMP-3-1171*A/*A genotype (28.1% for gingival overgrowth vs. 26.1% for controls) and of the MMP-3-1171*dupA/*dupA genotype (32.8% for gingival overgrowth vs. 22.5% for controls) was similar for both study groups. The risk of gingival overgrowth was lowest among patients carrying the MMP-3-1171*A/*dupA genotype (odds ratio 0.52), but this did not differ markedly from the other genotypes. Conclusion: No association between MMP-3 gene polymorphism and gingival overgrowth was revealed in kidney transplant patients administered cyclosporine A. [ABSTRACT FROM AUTHOR]

Purpose: Tacrolimus, in contrast to cyclosporine, has not been found to be associated with gingival enlargement (GE) among adult transplant recipients. The purpose of this study was to explore the prevalence of GE in relation to tacrolimus and cyclosporine-based immunosuppressive regimens among pediatric solid-organ transplant recipients, controlling for the use of calcium channel blockers (CCB) and the presence of supragingival plaque. Methods: A standardized questionnaire was administered and a comprehensive oral examination was performed among pediatric renal and liver transplant recipients who were at least 6 months post-transplant. Results: The prevalence of GE among 133 participants was 26%. with the highest incidence among subjects receiving cyclosporine and CCB (60%) and the lowest among those receiving tacrolimus without CCB (13%). A multivariate model showed that the odds of having GE were 5 times higher among children receiving cyclosporine than in those not receiving this medication, and 4 times higher among boys than girls. Supragingival plaque and the use of CCB, however, were not found to be associated with GE. Conclusion: This study revealed that tacrolimus was not associated with gingival enlargement while cyclosporine remains a risk factor for the development of this condition in pediatric renal and liver transplant recipients. [ABSTRACT FROM AUTHOR]

Unsightly gingival enlargement is a frequent side effect in organ transplant recipients under immunosuppressive therapy with cyclosporin A (CsA). The purpose of this article was to report the treatment management of cyclosporin A-induced gingival overgrowth in a 9-year-old renal transplant recipient. Surgical reduction of the overgrown gingival tissue associated with an intensive biofilm control program and conversion from CsA to tacrolimus provided good clinical outcome with improvement of mastication, feeding, and phonetics. Gingival overgrowth stabilized with the change of medication. After approximately 3 months of follow-up, a regression of gingival enlargement was observed. [ABSTRACT FROM AUTHOR]

Aims: The relationship between gingival overgrowth (GO) induced by cyclosporine A (CsA) and transforming growth factor- β1 (TGF- β1) remains unclear. The aims of the present study were to evaluate TGF- β1 gene expression under different immunosuppressive treatments and its association with TGF- β1 gene functional polymorphism and GO in renal transplant recipients. Material and Methods: The study included 98 CsA-treated renal transplant recipients (with and without GO) and 44 tacrolimus-treated transplant patients (without GO). TGF- β1 mRNA expression was measured using a real-time quantitative polymerase chain reaction assay. The levels were correlated with TGF- β1 gene polymorphisms at codons 10 and 25, with different immunosuppressive treatment and GO. Results: The level of TGF- β1 gene expression was insignificantly lower in the CsA-treated group compared with the tacrolimus group, and significantly lower in the group with GO compared with patients without GO. In tacrolimus- and CsA-treated patients, but not in patients with GO, the level of TGF- β1 gene expression was associated with functional phenotypes of TGF- β1. The incidence, degree and extent of GO were higher in recipients with lower TGF- β1 gene expression. Conclusions: Lower level TGF- β1 gene expression, not functional polymorphism, in patients treated with CsA may be considered to be a risk factor for GO. [ABSTRACT FROM AUTHOR]

Background: Tacrolimus, an immunosuppressive drug used in organ transplantation, has been reported not to induce gingival overgrowth. However, prevalence studies are limited, and the methods used for assessing gingival overgrowth varies among studies. Objective: The purpose of this study was to evaluate the effects of up to 240 days of tacrolimus therapy on gingival tissues of rats. Materials and methods: Rats were treated for 60, 120, 180 and 240 days with daily subcutaneous injections of 1 mg/kg body weight of tacrolimus. After histological processing, the oral and connective tissue, volume densities of fibroblasts ( Vf), collagen fibers ( Vcf) and other structures ( Vo) were assessed in the region of the lower first molar. Results: After 60 and 120 days of treatment with tacrolimus, gingival overgrowth was not observed. The gingival epithelium, connective tissue, as well as the values for Vf, Vcf, and Vo were similar to those of the control rats ( P > 0.05). After 180 and 240 days of the treatment, gingival overgrowth was associated with a significant increase in the gingival epithelium and connective tissue as well as an increase in the Vf and Vcf ( P < 0.05). Conclusions: Within the limits of the experimental study, it may be concluded that the deleterious side effects of tacrolimus on the gingival tissues of rats may be time-related. [ABSTRACT FROM AUTHOR]

Background: Gingival enlargement frequently occurs in transplant patients receiving immunosuppressive drugs. It was hypothesized that gingival enlargement associated with cyclosporin use results from increases in the number of fibroblasts and the volume of extracellular matrix. SPARC (secreted protein, acidic, and rich in cysteine) regulates cell--matrix interactions, binding to structural matrix proteins, and is induced by cyclosporin A (CsA). The aim of the study was to determine whether there is an association between SPARC genotypes and gingival enlargement in kidney transplant patients given CsA. Methods: Sixty-two unrelated kidney transplant patients with gingival overgrowth and 124 control transplant patients without overgrowth were enrolled into the study. Gingival overgrowth was assessed at 6 months after transplantation. All patients were given CsA as a principal immunosuppressive agent during the post-transplant period. SPARC polymorphism was determined using polymerase chain reaction-restriction fragments length polymorphism assay. Results: In kidney transplant patients with gingival overgrowth, the mean score of gingival overgrowth was 1.42 ± 0.63, whereas in control subjects it was 0. The distribution of SPARC 998C>G alleles among all kidney transplant patients, as well as in the two study subgroups, did not differ significantly from Hardy-Weinberg equilibrium. The frequencies of the 998G allele (24.2% versus 18.5%) and of 998G allele carriers (40.3% versus 33.1 %) among individuals with gingival overgrowth was higher compared to the control group, but the differences did not reach the statistical difference. The risk for gingival overgrowth was highest among patients carrying the 998GG genotype (OR 2.25), but it did not differ significantly from the risks associated with the other genotypes. Conclusion: No association between SPARC gene polymorphism and gingival overgrowth was revealed in kidney transplant patients who were administered CsA. [ABSTRACT FROM AUTHOR]

Background and Objective: Cyclosporin A is used as an immunosuppressive agent and its prominent side-effect is the induction of fibrous gingival overgrowth. The progression of fibrous gingival overgrowth results from the accumulation of extracellular matrix. Type I plasminogen activator inhibitor (PAI-1) acts as the inhibitor of extracellular matrix degradation and is involved in some fibrotic diseases. However, little is known about the correlation between PAI-1 and cyclosporin A-induced gingival overgrowth. The aim of this study was to investigate the effects of cyclosporin A on the expression of PAI-1 mRNA and protein in human gingival fibroblasts human gingival fibroblasts in vitro and to compare PAI-1 expression in normal healthy gingival tissues and cyclosporin A-induced gingival overgrowth specimens in vivo. Material and Methods: Quantitative reverse transcription–polymerase chain reaction and western blot assay were used to investigate the effects on human gingival fibroblasts exposed to cyclosporin A. In addition, 10 cyclosporin A-induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry. Results: Investigations of the time dependence of PAI-1 mRNA expression in human gingival fibroblasts treated with 200 ng/ml of cyclosporin A revealed a rapid accumulation of the transcript: a significant signal was first detectable after 1 h of exposure and the signal remained elevated throughout the 24-h incubation period ( p < 0.05). Cyclosporin A was also found to up-regulate PAI-1 protein in a time-dependent manner ( p < 0.05). The PAI-1 staining in gingival tissue was stronger in the cyclosporin A-induced gingival overgrowth group than in the normal gingival group ( p < 0.05). In the cyclosporin A-induced gingival overgrowth group, intensive staining for PAI-1 expression was observed mainly in the cytoplasm of fibroblasts, endothelial cells and inflammatory cells. Conclusion: These findings suggest that the up-regulation of PAI-1 may play an important part in the molecular pathogenesis of cyclosporin A-induced gingival overgrowth. [ABSTRACT FROM AUTHOR]

Thomason JM, Seymour RA, Ellis JS: Risk factors for gingival overgrowth in patients medicated with ciclosporin in the absence of calcium channel blockers. J Clin Periodontol 2005; 32: 273–279. doi: 10.1111/j.1600-051X.2005.00657.x.© Blackwell Munksgaard, 2005.This study investigates the effect of a range of potential risk factors on the severity of gingival overgrowth in transplant patients medicated with ciclosporin in the absence of any calcium channel blockers.One hundred dentate solid organ transplants medicated with ciclosporin (but not calcium channel blockers or phenytoin) were recruited for the study. Demographic, pharmacological and periodontal data were recorded and gingival overgrowth assessed from stone models.Univariate analysis identified the duration of transplant, papilla bleeding index, creatinine serum concentration, azathioprine and prednisolone dosage as risk factors for overgrowth severity. Multivariate modelling, excluding the periodontal parameters, gave a predictive model that included dosages of ciclosporin, azathioprine, prednisolone and weight (p<0.0001, adjusted-R2=19%). Adding the periodontal variables strengthened the model (p<0.0001, adjusted-R2=34.5%).The explanatory models in this study contain a number of variables that moderate inflammation (azathioprine and prednisolone) or are markers of it (papilla bleeding index). Dosage of each of the three immunosuppressants was identified as a risk factor for the severity of gingival change. This observation appears to have been masked by the effects of the calcium channel blockers in earlier studies. [ABSTRACT FROM AUTHOR]

Yamaguchi M, Naruishi K, Yamada-Naruishi H, Omori K, Nishimura F, Takashiba S. Long-term cyclosporin A exposure suppresses cathepsin-B and -L activity in gingival fibroblasts. J Periodont Res 2004; doi: 10.1111/j.1600-0765.2004.00746.x© Blackwell Munksgaard 2004 Gingival overgrowth is a common side-effect following administration of cyclosporin A. We reported previously that lysosomal protease cathepsin-L activity, but not cathepsin-B, was significantly suppressed by short-term cyclosporin A exposure in human gingival fibroblasts. Although this suppression may lead to decreased degradation of gingival connective tissue, a net increase in matrix proteins, and gingival overgrowth, the effects of cyclosporin A need to be more elucidated , considering the long-term use for patients following organ transplantation. The aim of the present study was to evaluate the effects of clinically relevant doses of cyclosporin A on cultured human gingival fibroblasts. We evaluated the effects of long-term cyclosporin A exposure on cell proliferation, mRNA expression of various proteases and both cathepsin-B and -L activity in human gingival fibroblasts. Human gingival fibroblasts were isolated from three donors' healthy gingiva and cultured from five to eight passages with or without 200 ng/ml of cyclosporin A. Proliferative activity of cyclosporin A-treated cells was examined using MTT assay. Total RNA and cellular proteins were collected for semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and for measurement of the cathepsin-B and -L activity. Long-term cyclosporin A exposure had no effects on cell proliferation. Accumulation of cathepsin-B, -H and -L mRNA was markedly suppressed by long-term cyclosporin A exposure, whereas accumulation of another lysosomal enzyme N-acetyl-β- d-glucosaminidase mRNA, which is involved in remodeling of gingival epithelium, was not apparently impaired in cyclosporin A-treated cells. Accumulation of matrix metalloprotease-1 (MMP-1) and tissue inhibitor of matrix metalloprotease-1 (TIMP-1) mRNA, which are involved in remodeling of extracellular matrix, also was not impaired. In addition, we demonstrated that long-term cyclosporin A exposure significantly suppressed not only the activity of the active form of cathepsin-(B + L) compared to the activity in non-treated cells ( p = 0.0458), but also the activity of the active form of cathepsin-B ( p < 0.0001) in human gingival fibroblasts. The decreased ability of protein degradation by not only cathepsin-L but also cathepsin-B is, at least, one of the several factors developing the cyclosporin A-induced gingival overgrowth. [ABSTRACT FROM AUTHOR]

Drozdzik M, Mysliwiec K, Lewinska-Chelstowska M, Banach J, Drozdzik A, Grabarek J: P-glycoprotein drug transporter MDR1 gene polymorphism in renal transplant patients with and without gingival overgrowth. J Clin Periodontol 2004; doi: 10.1111/j.1600-051X.2004.00554.x. © Blackwell Munksgaard, 2004. To determine whether there is association between genotypes of drug transporter multidrug resistant (MDR)1 gene coding drug transporter P-glycoprotein and gingival overgrowth in kidney transplant patients. Fifty-four unrelated kidney transplant patients suffering from gingival overgrowth as well 120 control transplant patients without overgrowth were enrolled into the study. Gingival overgrowth was assessed by two independent periodontal specialists at 6 months after transplantation. During the post-transplant period all patients were given medication, which included cyclosporine A, diltiazem or verapamil, prednisone, azathioprine. MDR1 C3435T polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism assay. In kidney transplant patients suffering from gingival overgrowth mean score of gingival overgrowth was 1.43±0.63, whereas in control subjects was 0.0. Patients with gingival overgrowth induced by immunosuppressive medication were characterized by similar distribution of MDR1 genotypes. There were no significant differences of 3435CC, 20.4% and 22.5%, 3435CT, 61.1% and 54.2% and 3435TT, 18.5% and 23.3% genotypes (frequencies) between patients with and without gingival overgrowth. The risk of gingival overgrowth was the highest among patients carrying 3435CT genotype (OD 1.33), but did not differ markedly from the other genotypes, i.e. 3435CC (OD 0.88) and 3435TT (OD 0.75). Likewise to genotypes, distribution of alleles was similar in patients with gingival overgrowth and healthy gingiva. The wild-type allele 3435C was found in 50.9% and 49.6% of subjects whereas the mutated allele 3435T was revealed in 49.1% and 50.4% of patients with and without gingival overgrowth, respectively. The evaluated risk of gingival overgrowth in patients with 3435C allele was 1.06 versus 0.95 in those with healthy gingiva. The medication regimen administered in both groups of the study was comparable. Immunohistochemical studies revealed expression of P-glycoprotein in ducts of the salivary gland. No association between the MDR1 gene polymorphism and gingival overgrowth was revealed in kidney transplant patients administered cyclosporine A as a principal immunosuppressive agent. Further studies are needed to elucidate the role of P-glycoprotein in drug transport in salivary glands. [ABSTRACT FROM AUTHOR]

Spolidorio LC, Spolidorio DM, Holzhausen M. Effects of long-term cyclosporin therapy on the periodontium of rats. J Periodont Res 2004; doi: 10.1111/j.1600-0765.2004.00734.x © Blackwell Munksgaard, 2004 The treatment of cyclosporin A triggers an early bone loss and gingival overgrowth. There is a lack of studies exploring the effects of long-term cyclosporin A therapy on alveolar bone homeostasis and gingival tissue. The purpose of this study was to evaluate the effects of long-term therapy with cyclosporin A on the gingival tissue and on the alveolar bone metabolism in rats. Rats were treated for 60, 120, 180 and 240 days with a daily subcutaneous injection of 10 mg/kg body weight of cyclosporin A. At the end of experimental periods, animals were killed and the serum calcium (Ca2+) and alkaline phosphatase levels were measured in all groups. After histological processing, the oral epithelium and the connective tissue, as well as volume densities of alveolar bone ( Vb) and multinucleated osteoclasts ( Vo), were assessed at the region of the lower first molars. Significant increases in the serum alkaline phosphatase were observed in those groups that received cyclosporin A therapy. After 60 and 120 days of the treatment with cyclosporin A, evident gingival overgrowth associated with a significant increase of epithelium and connective tissue was observed, as well as a decrease of the densities of bone and an increase of densities of osteoclasts. After 180 and 240 days of the treatment, there was a reduction of the gingival overgrowth associated with significant decreases of epithelium and connective tissue, as well as an increase of bone densities and a decrease of osteoclasts. Within the limits of this experimental study, it can be concluded that the deleterious periodontal effects of cyclosporin A administration may be time-related side-effects. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy of metronidazole on cyclosporine-induced gingival overgrowth (GO), a prospective intra-subject double-blind longitudinal study was performed on six heart transplant patients with GO. All patients underwent scaling and root planing before any treatment. Metronidazole gel (Elyzol, Cabon) was then applied in two of the four anterior hemi-sextants of each subject, following a balanced random pre-programmed list, with a placebo gel being applied to the remaining two hemi-sextants. Plaque index (PI), bleeding on probing (BP) and probing depth (PD) were recorded for all teeth of the four anterior hemi-sextants before and at 1, 2, 3, and 4 months after gel application. A general linear model was fitted and ANOVA for repeated measurements with split-plot design and Chi-square analysis were used for statistical analysis. PD significantly decreased after 1 month following both treatments. Analogous results were obtained as regards PI and BP. No statistically significant difference was detected between results obtained with metronidazole and placebo. However, PD in the group of teeth treated with placebo significantly increased after 4 months, while PD values obtained from teeth treated with metronidazole remained statistically unchanged with respect to the 1st month. In conclusion, short-term results suggest that metronidazole and placebo are equally effective in reducing periodontal parameters and GO when associated with scaling and root planing. Long-term results, however, showed greater efficacy of metronidazole with respect to placebo in controlling cyclosporine-induced GO. [ABSTRACT FROM AUTHOR]

Cyclosporin A (CyA) is a potent immunosuppressor used in organ transplantation and in the management of various autoimmune diseases. Gingival overgrowth is one of the side-effects of the CyA-treatment, affecting the attached gingiva of 25-81% of treated patients. To investigate the production and activity of matrix metalloproteinases (MMPs) in the CyA-induced gingival overgrowth. 2 well-documented models were utilized: the in vivo CyA-induced rat gingival overgrowth and primary cultures of human gingival fibroblasts treated with CyA. Our results obtained from the Western blot assays demonstrated clearly that the production of MMP-1 and MMP-3 was significantly inhibited by CyA at similar concentrations found in the serum of patients undergoing CyA-treatment. Moreover, the gelatinolytic activity of MMP-2 was also reduced both in cultured fibroblasts and in the nit CyA-induced gingival overgrowth. Taken together, the data presented here suggest that these inhibitory effects may contribute to the extracellular matrix (ECM) components accumulation in the CyA-induced gingival overgrowth. [ABSTRACT FROM AUTHOR]