Drug-induced gingival overgrowth (DIGO), induced by certain immunosuppressive drugs, antihypertensive agents, and antiepileptic drugs, may contribute to the formation of deeper periodontal pockets and intractableness in periodontitis. To date, multiple factors such as enhanced matrix production, inflammation, and reduced matrix degradation might be involved in the pathogenesis of DIGO. We have previously reported that SPOCK-1, a heparan sulfate proteoglycan, could affect gingival thickening by promoting epithelial-to-mesenchymal transition (EMT) in gingival keratinocytes. However, few studies have investigated whether a combination of these factors enhances the DIGO phenotype in animal models. Therefore, we investigated whether SPOCK-1, periodontal inflammation, and cyclosporin-A (CsA) could cooperatively promote gingival overgrowth. We first confirmed that Spock-1 overexpressing (Spock1-Tg) mice showed significantly thicker gingiva and greater alveolar bone loss than WT mice in response to ligature-induced experimental periodontitis. DIGO was induced by the combination of CsA administration and experimental periodontitis was significantly enhanced in Spock1-Tg mice compared to that in WT mice. Ligature-induced alveolar bone loss in CsA-treated Spock1-Tg mice was also significantly greater than that in CsA-treated WT mice, while being accompanied by an increase in Rankl and Col1a1 levels and a reduction in matrix metalloprotease expression. Lastly, SPOCK-1 promoted RANKL-induced osteoclast differentiation in both human peripheral blood mononuclear cells and murine macrophages, while peritoneal macrophages from Spock1-Tg mice showed less TNFα and IL-1β secretion than WT mice in response to Escherichia coli lipopolysaccharide. These results suggest that EMT, periodontal inflammation, and subsequent enhanced collagen production and reduced proteinase production contribute to CsA-induced DIGO pathogenesis.

Drug-induced gingival overgrowth (DIGO) is one of the side effects produced by therapeutic agents, most commonly phenytoin, nifedipine and cyclosporin A. However, the precise mechanism of DIGO is not entirely understood. A literature search of the MEDLINE/PubMed databases was conducted to identify the mechanisms involved in DIGO. The available information suggests that the pathogenesis of DIGO is multifactorial, but common pathogenic sequelae of events emerge, i.e., sodium and calcium channel antagonism or disturbed intracellular handling of calcium, which finally lead to reductions in intracellular folic acid levels. Disturbed cellular functions, mainly in keratinocytes and fibroblasts, result in increased collagen and glycosaminoglycans accumulation in the extracellular matrix. Dysregulation of collagenase activity, as well as integrins and membrane receptors, are key mechanisms of reduced degradation or excessive synthesis of connective tissue components. This manuscript describes the cellular and molecular factors involved in the epithelial-mesenchymal transition and extracellular matrix remodeling triggered by agents producing DIGO.

Periodontal diseases include periodontitis and gingival overgrowth. Periodontitis is a bacterial infectious disease, and its pathological cascade is regulated by many inflammatory cytokines secreted by immune or tissue cells, such as interleukin-6. In contrast, gingival overgrowth develops as a side effect of specific drugs, such as immunosuppressants, anticonvulsants, and calcium channel blockers. Human gingival fibroblasts (HGFs) are the most abundant cells in gingival connective tissue, and human periodontal ligament fibroblasts (HPLFs) are located between the teeth and alveolar bone. HGFs and HPLFs are both crucial for the remodeling and homeostasis of periodontal tissue, and their roles in the pathogenesis of periodontal diseases have been examined for 25 years. Various responses by HGFs or HPLFs contribute to the progression of periodontal diseases. This review summarizes the biological effects of HGFs and HPLFs on the pathogenesis of periodontal diseases.

UNASSIGNED: Drug-induced gingival overgrowth is associated with the intake of three classes of drugs: anticonvulsants, immunosuppressants, and calcium channel blockers. It is clinically characterized by hyperplasia of the gingival connective tissue which appears edematous, bloody, and purplish-red in color. In more severe cases, drug-induced gingival hyperplasia negatively affects the patient\'s quality of life, making it difficult to eat and practice good oral hygiene. Drug-induced gingival overgrowth therapy is controversial and, in fact, no studies in the literature highlight a well-defined therapeutic protocol. The therapies that are described provide primarily for non-surgical periodontal treatment and second-line surgical treatment. The aim of this work is to highlight a case of drug-induced gingival hyperplasia which was completely resolved thanks to photodynamic therapy which is completely free from side effects.
UNASSIGNED: Photodynamic therapy was performed on an 18 year-old female patient with LEDs at a power of 450-470 nm and 5500 mW/cm2 + 7500 mW/cm2, combined with a Curcuma longa-based photosensitizer. A single session was performed, with applications of approximately 30 s for each interdental papilla.
UNASSIGNED: The patient improved markedly after only one cycle of PDT. There was an absence of clinically detectable inflammation, edema, and rubor of the involved dental papillae. At the 4, 6, and 12 week follow-ups there were no recurrences.
UNASSIGNED: This case report highlights the first case of drug-induced gingival hypertrophy entirely treated with photodynamic therapy to be described in the literature. Therefore, although it is only a case report, this therapy which is free from side effects should be investigated as an alternative to current therapies.

Background: The aim of this study was to compare the direct impact of different agents for immunosuppressive therapy on mouse fibroblasts as a possible cause of drug-induced gingival overgrowth (DIGO). Methods: 3T3 mouse fibroblasts were cultivated in cell-specific media (2 × 104 cells/mL) and treated for 6, 24, 48 and 72 h with one of three immunosuppressive drugs (IsDs): cyclosporin a (CsA), tacrolimus (TaC) and sirolimus (SiR). Different concentrations (10−750 ng/mL) were used to mimic serum levels under active immunosuppressive therapy conditions. Cell population characteristics (cell number, viability and morphology) were assessed using computer-assisted cell analysis. Expression of pro-collagen type I carboxy-terminal propeptide (PICP) was identified using an ELISA assay. Results: The influence of IsDs on the biological status of 3T3 fibroblasts was time- and dose-dependent. Comparing CsA and TaC, the total cell amount was enhanced using concentrations in the range of 10−150 ng/mL (p > 0.05). In contrast, treatment with SiR resulted in a decrease in the average cell number (p < 0.01). PICP and cell diameter of fibroblasts were not susceptible to IsD treatment (p > 0.05). Conclusions: Our results revealed time-dependent effects of IsDs, with distinct influences on cell number. The cell morphology and the PICP balance of the investigated fibroblast cell line remained unaffected. Hence, the potential role of IsDs is not a unilateral mechanism of action but rather a multifactorial process.

OBJECTIVE: The aim of this study was to establish an in vitro model of nifedipine-induced gingival overgrowth and characterize the anti-fibrotic effect of hepatocyte growth factor (HGF) using this model.
METHODS: Human gingival fibroblasts were cultured-treated with 0.1, 1, or 10 µg/mL nifedipine or 10 ng/mL IL-1β + 0.1, 1, or 10 µg/mL nifedipine (0.1N, 1N, 10N, IL + 0.1N, IL + 1N, IL + 10N). Cell proliferation and levels of type I collagen, TGF-β1, CCN2/CTGF, and α-SMA were measured 48 h after the simultaneous addition of 10 and 50 ng/mL HGF (10 and 50HGF) along with IL-1β and nifedipine. Type I collagen was measured after administration of anti-HGF neutralizing antibody.
RESULTS: Significant increases in type I collagen, TGF-β1, and CCN2/CTGF were observed after treatment in the 1N and IL + 0.1N groups. Levels of type I collagen and CCN2/CTGF differed significantly between the IL + 0.1N group and the IL + 0.1N + 50HGF group. Production of type I collagen increased significantly following addition of anti-HGF antibody.
CONCLUSIONS: This study demonstrated the establishment of an in vitro model of nifedipine-induced gingival overgrowth by showing increased collagen levels. Experiments using this model suggested that HGF exerts anti-fibrotic effects.

Drug-induced gingival overgrowth (DIGO) is a pathological growth of gingival tissue, primarily associated with calcium channel blockers and immunosuppressants. Consequently, it is mainly seen in cardiovascular and transplanted patients. Nifedipine remains the main calcium channel blocker related to the development of this unpleasant side-effect. As for immunosuppressants, cyclosporin is the leading causative agent, whereas other drugs from this drug-group, including tacrolimus, have better safety profiles. Accumulated collagen with inflammatory infiltrates is the histological hallmark of this condition. Several factors are involved in the pathogenesis and can increase the risk, such as male gender, younger age, pre-existing periodontal inflammation, and concomitant use of other DIGO-inducing medications. Patients with DIGO may experience severe discomfort, trouble with speech and mastication, pain, and teeth loss, aside from cosmetic implications. Furthermore, these patients also have an increased risk for cardiovascular diseases. The interdisciplinary approach and cooperation with dental care experts are necessary for patient management. Treatment includes discontinuing the drug and switching to one with a better profile, improving oral hygiene, and surgical removal of enlarged tissue. Recognizing the potential of commonly used medications to cause DIGO and its effect on patients\' health is necessary for early detection and adequate management of this complication.

In the modern world, men and women are very much concerned about their esthetic appearance. The gingival perspective of esthetics is more often concerned with the soft tissue envelope surrounding the teeth. Gingival enlargement/overgrowth is numerous in nature and often poses a clinical challenge by altering the function, resulting in poor oral health of an individual. Tacrolimus, an immunosuppressive drug, has been broadly used for organ-transplant rejection. It results in much less severe hypertension, hypertrichosis and gingival overgrowth compared to cyclosporine and calcium channel blocker-induced gingival enlargements. However, there is scanty literature available regarding the tacrolimus-induced gingival enlargements. Therefore, the present case report with a 6-month follow-up period describes the execution of the proper treatment plan and surgical protocol for the management of a severe case of generalized gingival enlargement attributed to tacrolimus-induced therapy following renal transplant.

Drug-induced gingival overgrowth (DIGO) secondary to chronic phenytoin intake for seizure control is a well-recognized phenomenon. Phenytoin-induced gingival overgrowth (PIGO) usually resolves gradually following cessation of phenytoin intake. It is usually seen throughout the dentate regions of the maxillary and mandibular dental arches, but more severely affect their anterior portions exposed to atmosphere. We report a rare case of PIGO predominantly involving hard palate and floor of oral cavity, which has not been reported in English literature till date.

Gingival overgrowth (GO) includes gingival enlargement and hyperplasia and may be induced by certain drugs, including calcium channel blockers (CCBs), particularly first-generation CCBs. However, to date, only few cases of GO induced by second- or third-generation CCBs have been reported. The present study reports on a case of a 48-year-old diabetic male who was admitted to the First Hospital of Jilin University (Changchun, China) due to poor blood glucose control. This patient was diagnosed with GO. Review of the patient\'s medical history revealed diagnoses of type 2 diabetes and hypertension, as well as the use of felodipine, a second-generation CCB, to control hypertension. The hypertensive drugs were replaced and the new drugs helped the patient control his blood glucose levels. Additionally, the patient was instructed on methods he could use to improve his oral hygiene, including rinsing of the teeth following each meal and increasing the frequency of tooth brushing per day. After 3 months, the clinical symptoms of GO were relieved. The relevant literature was also reviewed to gain an improved understanding of the correlation between GO and CCBs, as well as diabetes and poor oral hygiene.