Antioxidants protect against gingival overgrowth induced by cyclosporine A.

OBJECTIVE: We investigated the importance of reactive oxygen species (ROS) on developing gingival overgrowth (GO) and then introduced the antioxidant strategy to prevent, or even reduce GO. BACKGROUND: Gingival overgrowth is a common side effect of the patients receiving cyclosporine A (CsA), an immune suppressant. Although it has been broadly investigated, the exact pathogenesis of the induced GO is still uncertain. METHODS: We cultured human primary gingival fibroblasts and used animal model of GO to investigate the ameliorative effects of antioxidants on CsA-induced GO. To examine the CsA-induced oxidative stress, associated genes and protein expression, and the overgrown gingiva of rats by using immunocytochemistry, confocal laser scanning microscopy, real-time PCR, ELISA, gelatin zymography, gingival morphological, and immunohistochemical analysis. RESULTS: We found for the first time that ROS was responsible for the CsA-induced oxidative stress and TGF-ß1 expression in human primary gingival fibroblasts, as well as the GO of rats. The antioxidants (oxidative scavenger of vitamin E and an antioxidative enzyme inducer of hemin) ameliorated CsA-induced pathological and morphological alterations of GO without affected the CsA-suppressed il-2 expression in rats. CsA-induced oxidative stress, HO-1, TGF-ß1, and type II EMT were also rescued by antioxidants treatment. CONCLUSIONS: We concluded that CsA repetitively stimulating the production of ROS is the cause of CsA-GO which is ameliorated by treating antioxidants, including vitamin E and sulforaphane. Furthermore, the immunosuppressive effect of CsA is not interfered by antioxidant treatments in rats. This finding may thus help the clinician devise better prevention strategies in patients susceptible to GO.

Closed vs open surgical exposure of palatally displaced canines: surgery time, postoperative complications, and patients' perceptions: a multicentre, randomized, controlled trial.

Background: Closed and open surgical techniques are two different main approaches to surgical exposure of palatally displaced canines (PDCs). Because there is insufficient evidence to support one technique over the other, there is a need for randomized controlled trials. Objectives: To compare surgery time, complications and patients' perceptions between closed and open surgical techniques in PDCs. Trial design: The trial was a multicentre, randomized, controlled trial with two parallel groups randomly allocated in a 1:1 ratio. Material and methods: Study participants were 119 consecutive patients from 3 orthodontic centres, with PDCs planned for surgical exposure, randomly allocated according to a computer-generated randomization list, using concealed allocation. Full-thickness mucoperiosteal flap was raised, and bone covering the canine was removed in both interventions. In closed exposure, an attachment with a chain was bonded to the canine and the flap was sutured back with the chain penetrating the mucosa. In open exposure, a window of tissue around the tooth was removed and glass ionomer cement placed on the canine crown, to prevent gingival overgrowth during spontaneous eruption. Patient perceptions were assessed with two questionnaires, for the evening on the day of operation and 7 days post-surgery. Blinding: It was not possible to blind either patients or care providers to the interventions. The outcome assessors were blinded and were unaware of patients' intervention group. Results: Seventy-five girls and 44 boys, mean age 13.4 years (SD 1.46) participated in the study and got either of the interventions (closed exposure, n = 60; open exposure, n = 59). Surgery time did not differ significantly between the interventions. Complications though were more severe in bilateral cases and the patients experienced more pain and impairment in the open group. Conclusion: There were no statistically significant differences regarding surgery time between the groups. Postoperative complications were similar between the groups in unilateral PDCs, but more common in the open group in bilateral cases. More patients in the open group experienced pain and impairment compared to the closed group. Trial registration: Trial registration: ClinicalTrials.gov, ID: NCT02186548 and Researchweb.org, ID: 127201.

Impact of three different mouthwashes on the incidence of gingival overgrowth induced by cyclosporine-A: a randomized controlled experimental animal study.

OBJECTIVE: This study aimed to evaluate the effects of three different mouthwashes on the incidence of cyclosporine-A-induced gingival overgrowth. STUDY DESIGN: One hundred albino rats were divided into five equal groups. Group I rats received no treatment. Group II rats were administered cyclosporine-A. Group III, IV, and V rats were handled as group II and concomitantly treated with chlorhexidine gluconate, cetylpyridinium chloride, and essential oil mouthwashes, respectively. Ten rats from each group were euthanized after the first week of treatment, and the remaining rats were euthanized after the second week of treatment. The obtained specimens were stained with hematoxylin and eosin, Masson's trichrome, and tumor growth factor beta (TGF-ß), matrix metalloproteinase 1 (MMP-1), and interleukin 6 (IL-6) immunohistochemical stains. RESULTS: The histologic findings at the end of the first and second weeks revealed marked increases in gingival overgrowth for groups II and IV in comparison with groups III and V. Increased epithelial thickness and collagen accumulation were prominent in groups II and IV compared with the other groups. Groups II and IV revealed the highest immunoreactivities for TGF-ß and for IL-6. Groups I, III, and V revealed the highest level of MMP-1 expression. CONCLUSIONS: Essential oils and chlorhexidine gluconate mouthwashes significantly reduced the incidence of gingival overgrowth compared with cetylpyridinium chloride.

Prevention of phenytoin-induced gingival overgrowth by lovastatin in mice.

Drug-induced gingival overgrowth is caused by the antiseizure medication phenytoin, calcium channel blockers, and ciclosporin. Characteristics of these drug-induced gingival overgrowth lesions differ. We evaluate the ability of a mouse model to mimic human phenytoin-induced gingival overgrowth and assess the ability of a drug to prevent its development. Lovastatin was chosen based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition. Data indicate that anterior gingival tissue overgrowth occurred in phenytoin-treated mice based on gross tissue observations and histomorphometry of tissue sections. Molecular markers of epithelial plasticity and fibrosis were regulated by phenytoin in gingival epithelial tissues and in connective tissues similar to that seen in humans. Lovastatin attenuated epithelial gingival tissue growth in phenytoin-treated mice and altered the expressions of markers for epithelial to mesenchymal transition. Data indicate that phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that lovastatin normalizes the tissue morphology and the expression of the molecular markers studied. Data are consistent with characterization of phenytoin-induced human gingival overgrowth in vivo and in vitro characteristics of cultured human gingival epithelial and connective tissue cells. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required.

Regression of Calcium Channel Blocker--Induced Gingival Enlargement in the Absence of Periodontal Therapy.

AIM: To illustrate the negative effect of calcium channel blocker (CCB) drugs on the gingival tissues and the reversibility of these lesions. CASE DESCRIPTION: The authors examined a forty-eight year-old male patient with drug-induced gingival enlargement associated with diltiazem, a CCB drug. Prior to initiating the proposed periodontal treatment, the patient was advised to consult his physician, for a possible switch to a different anti-hypertensive drug. The patient returned to the clinic three months later with a significant regression of the gingival overgrowth, which was induced by the patient ceasing the prescribed regimen without medical consultation or periodontal intervention. CONCLUSION: Although CCBs are effective cardiovascular drugs, they can negatively impact the oral health by promoting gingival overgrowth in some patients. Substitution of these drugs is strongly recommended prior to any periodontal intervention in order to improve prognosis and prevent recurrence, and should be done only by the medical providers.

Effect of periodontal treatment in renal transplant recipients.

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.

Less morbidity with flapless implant.

UNLABELLED: Flapless implant placement requires punch removal of the gingiva without flap reflection, suggesting this technique will be less invasive, and with less tissue destruction, than comparable alternative techniques. METHODS: Eleven implants were placed with flapless (FL) technique and 11 implants were placed with full-thickness flap (FT) technique in split mouth technique. FL technique was done with dermal tissue puncture, while FT was performed with crestal incision, including the papillae. Patients were followed-up postoperatively for clinical and morbidity evaluation in both groups. RESULTS: There was no pain, and there were only mild signs of inflammation, at the sites of flapless implant placement in the 11 patients studied. In contrast, there were complaints of mild to moderate pain and signs of inflammation at the site of full-thickness flap implant placement in the 11 patients studied. In addition, there was gingival overgrowth over the healing cap noted in this group. CONCLUSIONS: FL technique may be recommended for the apprehensive or hyperalgesic patient because of the absence of pain it conveys, as well as the decreased postoperative swelling. Periosteal disruption is responsible for the patient's morbidity postoperatively.

Sonic tooth brushing reduces gingival overgrowth in renal transplant recipients.

Cyclosporine (CSA) is a commonly used immunosuppressive medication in pediatric transplantation. Drug-induced gingival overgrowth (DIGO) is a frequent side effect associated with CSA use and can impair the patient's ability to achieve good oral hygiene. This study tested the hypothesis that sonic tooth brushing and oral hygiene instruction can reduce the occurrence or severity of DIGO in CSA-treated pediatric renal transplant recipients. Twenty-three pediatric renal transplant patients with DIGO were randomly allocated to treatment or control groups. The treatment group received oral hygiene instruction and use of a sonic toothbrush, while the control group continued their usual home care with manual brushes. Dental impressions and photographs of all subjects were taken at baseline and every 3 months for a year. The casts and photographs were evaluated by a dental panel to compare the DIGO levels from baseline until the end of the study. After 12 months the control group had significantly more severe DIGO than did the sonic tooth brushing and oral hygiene instruction group (OR=4.5, 95%CI=1.2-16.0, P=0.03). Of the risk factors considered, only male gender was significantly associated with worse outcome (OR=6.1, 95%CI=2.3-16.1, P=0.03). The use of a powered toothbrush, together with oral hygiene instruction, may be an important component of health maintenance for pediatric transplant patients on CSA.

Periodontal and soft tissue prevention strategies for the adolescent dental patient.

Recent research has refocused attention on the contribution of periodontal health to the general health of patients at various ages. This article describes changes in the periodontal tissues of adolescent dental patients related to hormonal fluctuations, lack of proper oral hygiene, and risk-taking behaviors. Attention is placed on the development and prevention of acute and chronic gingival conditions in addition to gingival tissue enlargement as one side effect of certain medications.

Inhibition of growth of human gingival fibroblasts by chimeric DNA-RNA hammerhead ribozyme targeting transforming growth factor-beta 1.

BACKGROUND: Transforming growth factor (TGF)-beta1 is involved in the pathogenesis of both drug-induced gingival overgrowth and hereditary gingival fibromatosis. Ribozymes enzymatically cleave target mRNAs and are expected to be utilized as the basis of novel nucleic acid-based therapies. We designed a chimeric DNA-RNA ribozyme targeting TGF-beta1 mRNA and examined its effect on growth of gingival fibroblasts in culture. METHODS: Chimeric DNA-RNA hammerhead ribozyme with sequence complementary to the loop structure of human TGF-beta1 mRNA was used. We evaluated transfer of the chimeric ribozyme by hemagglutinating virus of Japan (HVJ)-envelope into cultured human gingival fibroblasts in vitro and rat gingival tissues in vivo. We then examined effects of the chimeric ribozyme to TGF-beta1 on proliferation and DNA synthesis in human gingival fibroblasts. We also examined effects of the chimeric ribozyme to TGF-beta1 on expression of TGF-beta1, type IV collagens, and fibronectin mRNAs and expression of TGF-beta1 protein in human gingival fibroblasts. RESULTS: Chimeric ribozyme was sufficiently distributed into human fibroblasts in vitro and rat gingivae in vivo. Chimeric ribozyme to TGF-beta1 significantly inhibited expression of TGF-beta1, type IV collagen, and fibronectin mRNAs and TGF-beta1 protein in human gingival fibroblasts. Mismatch ribozyme had no effect on expression of these molecules. Chimeric ribozyme to TGF-beta1 also significantly inhibited proliferation and DNA synthesis in gingival fibroblasts. CONCLUSION: Chimeric DNA-RNA ribozyme targeting TGF-beta1 may be a useful gene therapy agent for treatment of gingival hyperplasia.

Enhancement of nifedipine-induced gingival overgrowth by concomitant ketoconazole in rats.

Nifedipine (NIF), a calcium channel blocker, is well known to induce gingival overgrowth (GO) as an adverse effect, and ketoconazole (KTZ), an azole antifungal agent, has been implicated in various drug interactions. We here examined the effects of concomitant KTZ on NIF-induced GO in a rat model. Fifteen-day-old male Fischer rats were fed chow with NIF, KTZ, or both. After 41 days, gingival conditions were evaluated and the concentration of NIF in serum was measured. Rats fed with NIF alone had induced GO and suppressed growth, while those given KTZ alone did not. Compared to the administration of NIF alone, concomitant KTZ significantly increased the severity of GO and the concentration of NIF in serum. These results suggest that concomitant KTZ increases the serum concentration of NIF and enhances the severity of GO.

Verapamil induced gingival enlargement in cluster headache.

Verapamil is an effective prophylactic treatment for cluster headaches and, therefore, is widely used. This report describes four patients with cluster headache who developed gingival enlargement after initiating treatment with verapamil. In two patients, it was possible to control this side effect adequately by optimising oral hygiene and dental plaque control. In the other two patients, lowering of the verapamil dose, in addition to optimal oral hygiene and dental plaque control, was necessary; in one patient verapamil had to be stopped completely to reverse the gingival enlargement. Doctors treating cluster headache with verapamil need to be aware of this side effect, especially as it may be preventable with good dental hygiene and dental plaque control, is reversible with reduction or cessation of verapamil, and can lead to dental loss.

Folic acid and phenytoin induced gingival overgrowth--is there a preventive effect.

The role of folic acid (5mg/day) in combination with oral hygiene measures (group II) vis-a-vis oral hygiene measures alone (group I) in prevention of phenytoin-induced gingival overgrowth was investigated in a one-year follow-up study on sixty, 8-13-year-old epileptic children receiving phenytoin. The allocation of the children to the two groups was done alternately. In these children, at baseline, plaque (Silness & Löe), gingivitis (Löe & Silness) and probing depths of gingival sulcus were recorded. These parameters were re-evaluated at 3-monthly intervals when gingival overgrowth was also recorded (Modified Harris & Ewalt Index). It was seen that, after a period of one year, gingival overgrowth occurred in 60 and 50 percent children of groups I & II respectively and its development, too, was delayed in group II. More cases (93 percent) in group II exhibited minimal overgrowth as against 78 percent in group I. The study concluded that systemic folic acid prescribed along with phenytoin delays the onset and reduces the incidence and severity of gingival overgrowth induced by phenytoin.

Inhibition of cyclosporin A-induced gingival overgrowth by azithromycin through phagocytosis: an in vivo and in vitro study.

BACKGROUND: The objective of the present study was to investigate the effect of cyclosporin A (CsA) and azithromycin (AZI) on collagen metabolism in the gingiva of rats. METHODS: Fifty 6-week-old male Sprague-Dawley (SD) rats (weight 120 to 150 g) were randomly distributed into five groups. All groups received various drugs via gastric feeding for 7 weeks. The first group (Mo group) received mineral oil for 7 weeks as a control; the CsA group received CsA in mineral oil for 7 weeks (dosage 30 mg/kg); the CsA/Mo group received CsA in mineral oil for 6 weeks and mineral oil only for the seventh week; the CsA/AZI group received CsA in mineral oil for 6 weeks and AZI (dosage 10 mg/kg) in mineral oil simultaneously with CsA in the seventh week; and the Mo/AZI group received mineral oil for 6 weeks and AZI in mineral oil for the seventh week. All animals were sacrificed for clinical and histological analyses. Gingival fibroblasts were cultured at the fourth passage, and the amount of collagen was measured. Type I collagen and collagenase mRNA were measured by reverse transcription-polymerase chain reaction. Collagen phagocytosis assay also was performed. RESULTS: Clinically, CsA induced gingival overgrowth in rats, whereas AZI reduced gingival overgrowth. Histological results of the CsA group showed a marked increase of tissue volume compared to the other groups. High collagen amounts were found when gingival overgrowth was induced. However, type I collagen mRNA and collagenase mRNA expressions did not statistically differ among groups. Phagocytosis assay showed that CsA decreased phagocytic activity of gingival fibroblasts, whereas AZI increased the activity. These results suggest that the induction and reduction of CsA-induced gingival overgrowth were closely associated with phagocytic activity. CONCLUSION: Cyclosporin A decreases collagen degradation by lowering phagocytic activity of rat gingival fibroblasts. Azithromycin partially compensates for this lowered phagocytic activity.

Clinical evaluation of marginal parodontium condition in patients after kidney graft treated with calcineurine inhibitors and calcium channel blockers.

Renal transplantation is a method of treating the chronic renal failure. Gingival overgrowth is a common side effect of immunosuppressive treatment with cyclosporine A. Calcium channel blockers also cause gingival overgrowth or intensify it. Tacrolimus is a new inhibitor of calcineurine used as an alternative to cyclosporine A. 124 patients were treated with cyclosporine A, and 38 patients were given tacrolimus. At the same time, patients were given calcium channel blockers. Impact of age, sex, calcineurine inhibitors dosage, sort of calcium channel blocker used as well as treatment duration on gingival overgrowth were studied. Also, periodontal status: oral cavity hygiene, gingivitis degree as well as extent and level of gingival overgrowth were evaluated. Gingival overgrowth of different degree was present in 58 patients (46.7%) treated with CsA and in none of the patients treated with tacrolimus. Hygiene and inflammation indices were significantly higher in the group of patients with gingival overgrowth as compared to the group without gingival overgrowth treated with CsA. In the group of patients treated with tacrolimus, these indices were the lowest, and the gingivae were sort of shrunk and paler. Patients with risk factors in gingival overgrowth and patients with severe overgrowth should be converted to tacrolimus treatment.

Amlodipine-induced gingival overgrowth: periodontal responses to stopping and restarting the drug.

A case history of a woman with gingival overgrowth (GO) induced by amlodipine is presented. A 49-year-old Japanese woman, who was taking amlodipine, had gingival overgrowth and swelling on examination. No specific periodontal treatment was provided to the patient for the GO; however, the amlodipine was replaced with an ACE inhibitor after consultation with her medical practitioner. Within two months, the suspension of amlodipine resulted in a significant improvement in her periodontal condition. Failure to control the hypertension caused the physician to re-prescribe amlodipine. After three months, the gingival overgrowth returned; however, its severity was less when compared with the original periodontal condition, due to reduction in drug dose and periodontal therapy. This experience suggests that temporary suspension of a drug which can induce GO can improve the periodontal condition without the aid of surgical treatment.

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.