dihydropyridines and Gingival-Overgrowth

The use of calcium channel blockers (CCBs) is associated with gingival enlargement, which adversely affects oral function, hygiene and aesthetics. Although CCB-induced gingival enlargement is a known adverse effect, it is rarely or never caused by some CCBs. In this paper, we report the case of a late 80's female patient with hypertension who experienced amlodipine-induced gingival enlargement. The patient's antihypertensive medication was changed from amlodipine to another CCB of the same class, benidipine, which has not been reported to cause gingival enlargement. The patient also received periodontal therapy. A significant improvement in gingival enlargement was noted, and blood pressure control was maintained. This case indicates that it might be beneficial for patients with hypertension presenting CCB-induced gingival enlargement to switch from the CCB that caused gingival enlargement to another CCB with little to no risk.

Topics: Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Female; Gingival Hyperplasia; Gingival Overgrowth; Humans; Hypertension

This study analyzed the role of the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) pathway in dihydropyridine-induced gingival overgrowth (DIGO) fibroblasts.. Tissue samples were obtained through surgical dissection from five DIGO patients and five healthy individuals. Cell cultures were conditioned with nifedipine (Nif) (0.34 µM) and stimulated with IL-1β (10 ng/ml) to clarify whether IL-6 upregulates extracellular matrix overproduction or has an impact on the cell proliferation rate of DIGO fibroblasts. STAT3 was knocked down using short hairpin (sh)RNA to determine its role in collagen (Col) type I alpha 1 (Colα1(I)) synthesis.. Results showed that phosphorylated (p)STAT3 nuclear translocation was activated by a simulated autocrine concentration (50 ng/ml) of IL-6, and application of an anti-IL-6 antibody significantly decreased the pSTAT3/STAT3 ratio in DIGO fibroblasts. STAT3 knockdown significantly decreased STAT3 and Colα1(I) expressions in DIGO cells. DIGO tissues presented stronger proliferating cell nuclear antigen (PCNA) expression than did healthy individuals under the effect of IL-1β/Nif treatment.. Gingival inflammation (e.g., IL-1β) and taking dihydropyridine (e.g., Nif) may additively stimulate Col overproduction through the IL-6-STAT3-Colα1(I) cascade in DIGO cells. IL-6-STAT3 signaling may be considered a target for the control of DIGO.

Topics: Dihydropyridines; Fibroblasts; Gingival Overgrowth; Humans; Interleukin-6; STAT3 Transcription Factor

NF-κB plays a crucial role in collagen overproduction in dihydropyridine-induced gingival overgrowth (DIGO) fibroblasts. We aim to investigate the role of the kappa B (IκB) kinase (IKK)-NF-κB pathway and downstream collagen type I (Col I) synthesis in DIGO cells and to demonstrate the therapeutic strategy of interference of this pathway with proteasome inhibitors.. Gingival fibroblasts from DIGO (n = 5) and healthy (n = 5) patients were selected and stimulated with IL-1β, nifedipine, or both. All experiments were run in triplicate and independently for each primary cell sample.. The results demonstrated that both drugs additively mediated NF-κB activity by activating IKKα/β phosphorylation. They also triggered nuclear translocation of NF-κB, Rela, and p50 (*p < .05) and increased Col I production in both healthy and DIGO cells. The addition of proteasome inhibitors, including bortezomib and MG132, promoted the accumulation of phosphorylated p-IκBα, prevented the subsequent cytosol-to-nuclear translocation of p50 and Rela (*p < .05), and abbreviated the biosynthesis of Col I in DIGO cells.. We suggested that IKK-IκBα activation is mediated by proinflammatory cytokines and CCBs in DIGO cells and triggers downstream NF-κB-Col I synthesis. Proteasome inhibitors may strategically interfere with the IKK-IκBα-NF-κB-Col I pathway and inhibit the etiopathogenesis of DIGO.

Topics: Bortezomib; Cells, Cultured; Collagen Type I; Dihydropyridines; Fibroblasts; Gingival Overgrowth; Humans; I-kappa B Proteins; Leupeptins; NF-kappa B; Phosphorylation; Proteasome Inhibitors

Gingival overgrowth (GO) is an adverse drug reaction in patients using calcium channel blockers (CCBs). Little is known about the effects of CCBs on the management of periodontal diseases. The aim of this study was to assess how the use of CCBs affects the long-term supportive treatment and outcomes in patients undergoing periodontal therapy.. All patients using CCBs during the initial treatment and/or the supportive periodontal therapy (SPT) were selected from a periodontal practice. Patients were scored using a Gingival Overgrowth Index (GOI). The effects of CCB types and dosages were assessed in terms of the frequency and the severity of GO, treatment responses, substitutions and extra treatment costs. Mean values, Standard Deviation (SD) and range were calculated. The Mann-Whitney test was used to assess statistically significant differences (p < 0.05) for GO between patients with good and poor oral hygiene, differences between before and after terminating or replacing the CCBs, possible differences between drug dosages (Dihydropyridine 5 mg and 10 mg) and differences between three drug combinations (CCB and inhibitors of the renin-angiotensin system (IRAS), CCB and non-IRAS, CCB and statins).. One hundred and twenty-four patients (58 females, 66 males, 4.6% of the patient population) were using CCBs. 103 patients were assessed. Average age was 66.53 years (SD. 9.89, range 42-88) and the observation time was 11.30 years (SD 8.06, range 1-27). Eighty-nine patients had GO, 75 of these required treatment for GO. Terminating or replacing with alternatives to CCBs resulted in significant decreases in GO (p = 0.00016, p = 0.00068) respectively. No differences were found between good and poor oral hygiene (p = 0.074), drug dosages or the various drug combinations. Surgical treatment was more effective than non-surgical treatment in controlling the GO. Long-term tooth loss was 0.11 teeth per patient per year. Forty-two patients needed re-treatments for GO, resulting in an extra life cost per patient of €13471 (discounted €4177).. The majority of patients (86.4%) using CCBs experienced GO. 47.2% of these experienced recurrence(s) of GO during the SPT and needed re-treatments with resulting added costs. The long-term tooth loss was considerably higher for patients using CCBs than for other patients groups from the same practice setting.

Topics: Adult; Aged; Aged, 80 and over; Calcium Channel Blockers; Chronic Periodontitis; Dihydropyridines; Drug Combinations; Drug Substitution; Female; Follow-Up Studies; Gingival Overgrowth; Health Care Costs; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Oral Hygiene; Recurrence; Renin-Angiotensin System; Retreatment; Tooth Loss; Treatment Outcome

Gingival overgrowth is, among other things, a side effect of the administration of dihydropyridine antihypertensives, generally associated with irritant factors of marginal periodontium. This case refers to a patient, female, who developed a large gingival enlargement that has a combined etiology: the systemic medication with lercanidipina and the presence of dental bridges, which are incorrectly adjusted to the dental cervix. The treatment for this case, involved a complex local treatment (antimicrobial, surgical, endodontic and prosthetic) and the collaboration with a specialist cardiologist. Maintaining the normal gingival parameters in time depends on the possibility of changing the antihypertensive medication, the accuracy of the new dental bridges and the periodic monitoring of the patient.

Topics: Calcium Channel Blockers; Dental Prophylaxis; Denture, Partial; Dihydropyridines; Female; Gingival Overgrowth; Gingivectomy; Humans; Hypertension; Middle Aged

Lin S-J, Lu H-K, Lee H-W, Chen Y-C, Li C-L, Wang L-F. Nitric oxide inhibits androgen receptor-mediated collagen production in human gingival fibroblasts. J Periodont Res 2012; 47: 701-710. © 2012 John Wiley & Sons A/S Background and Objective:  In our previous study, we found that flutamide [an androgen receptor (AR) antagonist] inhibited the up-regulation of collagen induced by interleukin (IL)-1β and/or nifedipine in gingival fibroblasts. The present study attempted to verify the role of nitric oxide (NO) in the IL-1β/nifedipine-AR pathway in gingival overgrowth..   Confluent gingival fibroblasts derived from healthy individuals (n = 4) and those with dihydropyridine-induced gingival overgrowth (DIGO) (n = 6) were stimulated for 48 h with IL-1β (10 ng/mL), nifedipine (0.34 μm) or IL-1β + nifedipine. Gene and protein expression were analyzed with real-time RT-PCR and western blot analyses, respectively. Meanwhile, Sircol dye-binding and the Griess reagent were, respectively, used to detect the concentrations of total soluble collagen and nitrite in the medium..   IL-1β and nifedipine simultaneously up-regulated the expression of the AR and type-I collagen α1 [Colα1(I)] genes and the total collagen concentration in DIGO cells (p < 0.05). IL-1β strongly increased the expression of inducible nitric oxide synthase (iNOS) mRNA and the nitrite concentration in both healthy and DIGO cells (p < 0.05). However, co-administration of IL-1β and nifedipine largely abrogated the expression of iNOS mRNA and the nitrite concentration with the same treatment. Spearman's correlation coefficients revealed a positive correlation between the AR and total collagen (p < 0.001), but they both showed a negative correlation with iNOS expression and the NO concentration (p < 0.001). The iNOS inhibitor, 1400W, enhanced IL-1β-induced AR expression; furthermore, the NO donor, NONOate, diminished the expression of the AR to a similar extent in gingival fibroblasts derived from both healthy patients and DIGO patients (p < 0.05)..   IL-1β-induced NO attenuated AR-mediated collagen production in human gingival fibroblasts. The iNOS/NO system down-regulated the axis of AR/Colα1(I) mRNA expression and the production of AR/total collagen proteins by DIGO cells.

Topics: Aged; Case-Control Studies; Cells, Cultured; Collagen Type I; Dihydropyridines; Fibroblasts; Gingiva; Gingival Overgrowth; Humans; Interleukin-1beta; Middle Aged; Nifedipine; Nitric Oxide; Nitric Oxide Synthase Type II; Receptors, Androgen; Statistics, Nonparametric

To understand the role of the androgen receptor in gingival overgrowth, the effects of flutamide on interleukin-1 beta- and nifedipine-induced gene expression of connective tissue growth factor (CTGF/CCN2) and collagen production in gingival fibroblasts were examined.. Gingival fibroblasts from healthy subjects and patients with dihydropyridine-induced gingival overgrowth (DIGO) were used. Confluent cells were treated with nifedipine, interleukin-1 beta or both. The mRNA expression was examined using real-time polymerase chain reaction, and the concentration of total soluble collagen in conditioned media was analysed by Sircol Collagen Assay. In addition, the protein expressions of androgen receptor, CTGF/CCN2 and type I collagen in gingival tissue were determined by western blot.. Interleukin-1 beta was more potent than nifedipine in stimulating CTGF/CCN2 and procollagen alpha1(I) mRNA expression, and there was an additive effect of the two drugs. Healthy cells exhibited an equal or stronger response of procollagen alpha1(I) than those with DIGO, but DIGO cells displayed a stronger response in the secretion of soluble collagen in the same conditions. Flutamide, an androgen receptor antagonist, inhibited stimulation by nifedipine or interleukin-1 beta. Additionally, the protein expressions of androgen receptor and type I collagen were higher in DIGO gingival tissue than those in healthy gingival tissue.. The data suggest that both nifedipine and interleukin-1 beta play an important role in DIGO via androgen receptor upregulation and that gingival overgrowth is mainly due to collagen accumulation. Flutamide decreases the gene expression and protein production of collagen from dihydropyridine-induced overgrowth cells.

Topics: Androgen Antagonists; Calcium Channel Blockers; Case-Control Studies; Cell Culture Techniques; Cells, Cultured; Collagen; Collagen Type I; Collagen Type I, alpha 1 Chain; Connective Tissue Growth Factor; Culture Media, Conditioned; Dihydropyridines; Drug Synergism; Female; Fibroblasts; Flutamide; Gingiva; Gingival Overgrowth; Humans; Interleukin-1beta; Male; Middle Aged; Nifedipine; Receptors, Androgen; Time Factors

It is well known that severe gingival overgrowth (GO) is induced in patients taking certain calcium channel blockers (CCB) for the treatment of hypertension, angina pectoris, and other diseases. No case has been reported to date of severe GO induced by manidipine hydrochloride (manidipine), a second generation CCB. This case report describes severe GO induced by manidipine in a female patient (43 years old) with hypertension and Sjögren syndrome (SS). The patient was administered manidipine and carteolol hydrochloride (carteolol) as antihypertensive drugs, together with bromhexine hydrochloride for the treatment of SS.. At the initial periodontal examination, probing depth (PD, average 4.83 mm), plaque control record (PCR, 84.3%), bleeding on probing (BOP, 100%), and gingival overgrowth index (GOI, 2.42) were assessed. The patient received periodontal treatment without cessation or replacement of the causative drug. Initial treatment included oral hygiene and scaling and root planing (SRP) under local anesthesia. As corrective therapy, remaining pockets were surgically removed and fixed bridges placed to establish proper occlusion.. Obvious reductions in PCR (10.0%), PD (1.93 mm), GOI (0.02), and BOP (4.7%), together with a disappearance of GO, were obtained. Salivary secretion was increased after the periodontal and prosthetic treatments. Histological features were similar to those of nifedipine-induced GO.. This case indicated that manidipine may act as a potent inducer of severe GO, and that conventional periodontal treatments without a major change of the causative drugs can yield satisfactory clinical responses.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Dental Plaque Index; Dental Scaling; Denture, Partial, Fixed; Dihydropyridines; Female; Gingival Overgrowth; Gingivectomy; Humans; Hypertension; Nitrobenzenes; Oral Hygiene; Periodontal Index; Periodontal Pocket; Piperazines; Root Planing; Saliva; Sjogren's Syndrome