Targeting SRD5A1 and MMP-2/NLRP3/TGF-ß1 axis alleviates the amlodipine-induced gingival hyperplasia in rats: Emerging role of saw palmetto and folic acid.

Saw palmetto (SAW), the herbal drug used to treat prostatic hyperplasia, exerts its antiproliferative effects by blocking steroid 5 alpha-reductase (SRD5A1) activity, that has also been involved in gingival hyperplasia (GH) pathogenesis. Concurrently, folic acid (FA) could reduce GH prevalence via its antioxidant and anti-inflammatory effects. Thus, this study tended to assess the potential therapeutic efficacy of SAW, alone and along with FA, against amlodipine-induced gingival inflammation and overgrowth in rats. Rats were grouped into (CONT, AIGH, SAW, SAW-treated, FA-treated, and SAW + FA-treated). SAW and FA were administered once daily for 4 weeks. Gingival SRD5A1, CTGF, GSK-3ß, and NLRP3 expressions, as well as T, DHT, MDA, TAC, ET-1, and MMP2 levels were determined. In addition, histopathological and immunohistochemical analyses of TNF-α, IL-6, TGF-ß1, and α-SMA were documented. Results declared that SAW and FA administration markedly ameliorated amlodipine-associated GH and may be presenting a novel therapeutic avenue in the future.

Cyclosporine A-induced gingival overgrowth in renal transplant patients accompanied by epithelial-to-mesenchymal transition.

OBJECTIVE: To investigate the association between the prevalence of cyclosporin A-induced gingival overgrowth and the expression of the epithelial-to-mesenchymal transition factors in the gingival tissues of renal transplant patients. BACKGROUND: Gingival overgrowth (GO) is a frequent complication in organ transplant patients treated with the immunosuppressant cyclosporin A (CsA). The epithelial-to-mesenchymal transition (EMT) is considered a factor contributing to CsA-induced GO. However, current knowledge on this topic is sparse. METHODS: Sixty-three renal transplant patients were divided into two groups according to the occurrence of GO: those with gingival overgrowth (GO+ group) and those without gingival overgrowth (GO- group). Data on age, sex, and use of immunosuppressant and calcium channel blocker medications, serum creatinine values, peak concentrations of blood CsA, and gingival hyperplasia scores were recorded to identify clinically pathogenic factors. Gingival tissues from five patients with CsA-induced GO and five healthy subjects were selected for histomorphological observation with hematoxylin-eosin staining, Masson staining, and immunohistochemical staining. The mRNA expression of EMT factors was detected with reverse transcription-quantitative PCR. RESULTS: The use of CsA significantly increased the prevalence of GO in renal transplant patients. The expression of α-SMA, SMAD4, and TGM2 was upregulated and that of E-cadherin was downregulated in the gingival tissues of patients with CsA-induced GO compared with those of the corresponding controls. CONCLUSION: Treatment with CsA is closely related to the occurrence of GO in renal transplant patients and EMT plays an important role in CsA-induced gingival tissue hyperplasia.

Cyclosporine-induced gingival overgrowth-Review.

Drug-induced gingival overgrowth (DIGO) is an undesirable effect resulting from the therapy of one of the three groups of drugs: phenytoin, calcium channel blockers, and cyclosporine A (CsA). It is caused by a fibrous overgrowth leading to gingivitis, periodontitis, and even tooth loss. Possible consequences include tooth decay worsening, pain and difficulty in eating, bleeding gums, and bad breath. The pathomechanism of the hypertrophy is unknown, but there is a correlation between insufficient oral hygiene and the severity of this phenomenon. The gender and age predilection of gingival hyperplasia as a result of CsA therapy is also noticeable. It is most common in children and adolescents of the male sex. The beneficial effect of the removal of tartar and local irritants in reducing the above symptoms has been demonstrated. One of the treatments for DIGO is conventional gingivectomy. The paper is a review article about cyclosporine-induced gingival hyperplasia.

Role of histopathology in the management of the gingival enlargement in a patient on antihypertensive therapy based on calcium channel blockers: a case report.

Periodontal pathology is often represented by increases in gingival volume, with pronounced inflammatory phenomena. These manifestations require a more accurate diagnosis and knowledge of the etiopathogenic factors involved. The periodontal treatment applied must be related with the etiopathogenic circumstances. Periodontal disease sometimes has a complex appearance, with intertwined local and systemic favorable factors that make it difficult to include it in a certain taxonomic form. Also, in general, the adult patients have associated chronic diseases that involve the administration of several drugs, which induce on long-term both therapeutic and side effects. Furthermore, diseases in the oral cavity may occur frequently, which require complex and associated dental and periodontal treatment, also occlusal rebalancing, which is a real interdisciplinary challenge. In this case report, periodontal status is determined by a combination of local and systemic favorable factors. However, the histopathological analysis of the gingival samples revealed inflammation without characteristic fibrous hyperplasia changes of the Amlodipine calcium channel blocker (CCB) administration, the antihypertensive medication of the patient. Thus, Amlodipine does not have a hyperplasic effect on gingival mucosa in all cases. Therefore, even if they are more expensive, investigations must be complex, if necessary, in establishing the involvement of the side effect of the systemic medication in periodontal pathological changes. CCB systemic medication is essential, even vital, for maintain the arterial pressure at normal values, should not be altered without the real indication and to the recommendation from a specialist doctor, and the periodontal treatment must be focused to eliminate the local factors.

Cyclosporine A-Induced Conchal Hyperplasia with Nasal Obstruction in a Patient with Membranous Nephropathy.

BACKGROUND The immunomodulatory and pharmacokinetic effects of cyclosporine A are used to treat diverse disease entities in different medical fields, including organ transplantation and/or autoimmune diseases. It is also applied in patients with nephrotic range proteinuria as an adjunct to steroids and supportive antihypertensive/antiproteinuric medications. Cyclosporine has a small therapeutic window and is dosed with respect to the underlying disease entity and severity via trough level adaptations. Among its most frequent adverse effects are hypertension, nephrotoxicity, neurotoxicity, and electrolyte disturbances. Hypertrichosis and gingival hyperplasia are obvious and widely recognized adverse effects. CASE REPORT We report on a 66-year-old woman who was treated with cyclosporine A for primary membranous nephropathy. During treatment with cyclosporine, she developed hirsutism and gingival hyperplasia. Later, she reported having impaired nasal breathing and dyspnea on mild physical exercise. Clinical, rhinoscopic, and radiological evaluations showed marked conchal hyperplasia as a potential cause of her symptoms. An extensive medical work-up did not show evidence of allergic, immunologic, or other drug adverse effects, suggesting cyclosporine-induced hyperplasia of the turbinates as a hypothetical causative factor. Dose reductions did not lead to resolution of symptoms but resulted in increasing proteinuria. Therefore, cyclosporine was stopped, and the patient was treated with rituximab. Thereafter, hirsutism and gingival and conchal hyperplasia gradually regressed over 2-4 months, showing complete resolution of conchal hyperplasia on computed-tomography follow-up after 6 months. CONCLUSIONS Cyclosporine can not only result in gingival hyperplasia but also in hyperplasia of the turbinates leading to impaired nasal breathing and shortness of breath on exertion. An extensive search for many other known causes of conchal swelling is warranted to finally suggest an adverse effect of cyclosporine. Discontinuation of cyclosporine resulted in complete remission of conchal hyperplasia as well as other adverse effects.

Drug-Induced Gingival Enlargement: A Review of Diagnosis and Current Treatment Strategies.

Drug-induced gingival enlargement (DIGE) is a biofilm-mediated gingival inflammatory condition associated with pharmacological agents. Specifically, calcium channel blockers, immunosuppressants, and anticonvulsants are among the primary medications associated with DIGE. Modifiable risk factors for DIGE include drug dose and dental biofilm, and the use of concomitant inducing medications. Although the clinical presentation of DIGE depends on these and patient-specific variables, its classical appearance is described as fibrotic, pink, bulbous, or mulberry-shaped overgrowths of the attached gingiva and dental papillae, with no bleeding on probing. The clinical manifestations of DIGE may worsen as the disease increases in severity. Likewise, the treatment strategies become more complex. The dental management of DIGE includes nonsurgical, surgical if necessary, and maintenance therapies. Drug substitutions, which may only be considered in consultation with the patient's family physician or primary healthcare provider, are a form of nonsurgical therapy. DIGE can be extremely debilitating, especially in its advanced stages, and make oral hygiene cumbersome, which translates to poorer oral and periodontal health outcomes. Therefore, DIGE must be properly identified and treated accordingly to re-establish a healthy and maintainable periodontium.

Gingival enlargement improvement following medication change from amlodipine to benidipine and periodontal therapy.

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.

Prevention and non-surgical periodontal therapy of calcium channel blockers induced severe gingival overgrowth. / A kalciumcsatorna-blokkoló gyógyszerek által indukált súlyos gingivahyperplasia konzervatív kezelése és megelozésének lehetoségei.

Összefoglaló. Bevezetés és célkituzés: A gingivahyperplasia a kalciumcsatorna-blokkoló gyógyszerek gyakori mellékhatása. Eredményeink közlésének célja, hogy bemutassuk, sebészi terápia nélkül, megfelelo egyéni szájhigiénia kialakításával és nem sebészi parodontalis terápiával milyen eredményt tudunk elérni az ínymegnagyobbodás kezelése során. Módszer: A Szegedi Tudományegyetem Fogorvostudományi Karának Parodontológiai Tanszékén 2015 és 2019 között 10 - 7 no és 3 férfi, átlagéletkoruk 56 év (50-69 év) volt -, kalciumcsatorna-blokkoló gyógyszer szedése során kialakuló, Grade III. ínyhyperplasiában szenvedo páciens kezelését végeztük konzervatív parodontalis módszerekkel, a gyógyszercsere mellozésével. A legfontosabb parodontalis értékeket rögzítettük, a tasakmélység, a vérzési index, a plakkindex és a fogmozgathatóság értékeit összegeztük vizsgálatunkban. A parodontium destrukciója mértékének megállapításához ortopantomogram és periapicalis röntgenfelvételeket értékeltünk. Eredmények: Minden parodontológiai paraméterben jelentos javulást tapasztaltunk. A nem sebészi parodontalis terápia eredményeként megszunt az elváltozás mind a 10 betegnél, és a szigorú fenntartó terápiának is köszönhetoen nem is újult ki. Következtetés: A nem sebészi terápia alkalmasnak bizonyult a súlyos gingivahyperplasia definitív kezelésére, ha az gingivitis vagy enyhe és középsúlyos parodontitis talaján alakult ki. Arra is következtethetünk az eredményeinkbol, hogy a gyógyszeres terápia megkezdése elott vagy azzal párhuzamosan parodontológiai terápiában részesülo páciensek nagy részénél a gingivahyperplasia - s ezzel a hosszú ideig tartó, drága kezelés - megelozheto lenne. Orv Hetil. 2022; 163(13): 506-512. INTRODUCTION AND OBJECTIVE: Gingival overgrowth is an adverse drug reaction in patients on long-term calcium channel blocker therapy. The aim of this study was to assess the efficacy of non-surgical pocket therapy in patients suffering from Grade III drug-related gingival overgrowth. METHOD: 10 (7 female and 3 male) patients (age between 50-69 years) diagnosed with severe, Grade III gingival overgrowth were treated in our department. Non-surgical periodontal therapy consists of improving of individual oral hygiene, scaling, polishing and subgingival mechanical debridement instrumentation. The main periodontal parameters (probing pocket depth, bleeding index, plaque index and mobility) were scored in this study. Bone loss was evaluated by orthopantomograms and periapical radiographs. Calcium channel blockers have not been replaced by any other medications during the whole course of periodontal treatment. RESULTS: Compared with baseline parameters, all scores improved after therapy. All patients showed decrease in the average probing pocket depth, deepest probing pocket depth, bleeding scores, plaque scores and tooth mobility. None of the patients needed further surgical treatment. In our followed-up patients, recurrence of gingival overgrowth has not been observed during the two-year meticulous supportive periodontal care in the patient group. CONCLUSION: Non-surgical periodontal treatment can be a potential definitive therapy in Grade III gingival overgrowth associated with gingivitis or moderate periodontitis. Periodontal screening and treatment before or simultaneously with the administration of calcium channel blockers can prevent the gingival enlargement in the majority of patient. These results outline the importance of the successful cause related periodontal therapy, started before or simultaneously with the administration of anithypertensive medications and in this way a series of further expensive therapies could be anticipated. Orv Hetil. 2022; 163(13): 506-512.

Lamotrigine-Induced Gingival Enlargement: An Older Problem Due to a Newer Drug - A Rare Case Report.

INTRODUCTION: Gingival enlargement (GE) due to anti-epileptic drugs (AEDs) shows a high prevalence rate. However, lamotrigine, a newer AED, has not shown to induce GE. The present case report describes a rare case of GE in a patient with epilepsy under lamotrigine therapy for the past 3 years. CASE PRESENTATION: In this report, successful management of lamotrigine-influenced GE in a 24-year-old patient with epilepsy by gingivectomy followed by stringent oral hygiene protocol is presented. CONCLUSION: The present case report suggests that, even this newer AED can cause GE and the oral hygiene status of the patients could be an important triggering factor.

Amlodipine Induced Gum Hypertrophy: A Rare Case Report.

BACKGROUND: DIGO or drug-induced gingival overgrowth occurs as a side effect of certain drugs. Until now, the etiology of drug-induced gingival overgrowth is not clearly understood. Among the calcium channel blockers, nifedipine has been shown to be most frequently associated with drug-induced gingival hyperplasia. Amlodipine is a comparatively newer calcium channel blocker that with a longer duration of action and lesser side effects as compared to nifedipine. There are only certain case reports of amlodipine-induced gum hyperplasia. CASE PRESENTATION: We report a case of amlodipine-induced gum hyperplasia in a 66-year-old hypertensive patient taking amlodipine at a dose of 5 mg once a day. There was significant regression of gum hypertrophy after substitution of amlodipine by Losartan. CONCLUSION: Amlodipine is one of the commonly prescribed antihypertensive drugs, and gingival hyperplasia is one overlooked side effect in patients taking amlodipine. Awareness of this potential side effect of amlodipine may be helpful to reduce the anxiety of patients and the cost of diagnostic procedures.

Non-surgical periodontal treatment for drug-influenced gingival enlargement: a four-year follow-up case report

ABSTRACT: Drug-influenced gingival enlargement is considered to be an important side effect related to the use of some medications and often produces important esthetic changes for patients, as well as clinical symptoms such as pain, bleeding, abnormal tooth movement and occlusion problems. Anticonvulsants, immunosuppressants and antihypertensive drugs have been reported as the main inducers of these periodontal disorders. This case report describes the 4-year clinical follow-up of a young patient with a history of excessive gingival enlargement as a consequence of drug therapy for epilepsy (phenytoin and phenobarbital); the nonsurgical periodontal treatment of the excessive gingival enlargement was associated with the replacement of the patient's epilepsy medications with valproic acid. We conclude that intensive mechanical control of bacterial biofilms, instruction on oral hygiene guidelines and behaviors and the substitution of alternative anticonvulsant medications are the best way to control the drug-influenced gingival enlargement.

Management of medication-induced gingival hyperplasia: a systematic review.

OBJECTIVE: Medication-induced gingival hyperplasia (MIGH) has been linked to several medications, with a reported prevalence ranging between 0.5% and 85%. The aim of this study was to systematically review the management approaches for MIGH and estimate recurrence rate and time to relapse. STUDY DESIGN: An electronic literature search was conducted using PICO questions (P = patients with medication-induced gingival hyperplasia; I = surgical and/or nonsurgical treatment options; C = no control is required; and O = partial or complete resolution and recurrence) and medical subject heading terms in the PubMed and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol up to December 2019. All English-language articles on MIGH surgical and nonsurgical management options were included. Eligible articles were systematically reviewed and assessed for bias using preset criteria and multiple levels of elimination. Data were extracted from eligible studies and analyzed. RESULTS: Twenty-two eligible articles were included in this study. Management approaches included discontinuation or change of the offending medication if medically feasible in addition to surgical and nonsurgical interventions. Nonsurgical approach included scaling and root planing, oral hygiene instructions, and antimicrobial mouthrinses. Persistent or relapsed cases had complete resolution with excision of hyperplastic gingiva. Laser-assisted surgeries combined with intensive plaque control measures demonstrated less risk of recurrence. CONCLUSIONS: Several treatment options for MIGH have been reported with variable outcomes. Duration and size of hyperplastic gingival tissue may have an effect on overall recurrence rate.

Massive gingival bleed: a rare manifestation of cyclosporine toxicity.

A 12-year-old patient of thalassaemia major developed autoimmune cytopaenia after undergoing haematopoietic stem cell transplantation. She was started on cyclosporine (CsA) in view of poor response to steroids. She developed CsA toxicity manifesting as gum hyperplasia with multiple episodes of gum bleed. During endotracheal intubation for an elective splenectomy, she developed significant bleeding from gums requiring massive transfusion. Postoperatively the gum bleed persisted even after embolisation of facial artery and multiple transfusions. The catastrophic sequelae include transfusion-related lung injury, acute circulatory failure with subsequent cardiac arrest and death. Gum hyperplasia is a commonly reported toxic effect of CsA. Lethal presentations of this toxicity with such severity are limited in the medical literature. Evaluation of the patient's medical and laboratory records, along with a review of literature, was very helpful in understanding more about the toxicity of CsA.

Agrandamiento gingival inducido por fenitoínas / Phenytoin induced gingival enlargement

Se entiende por agrandamiento gingival el incremento en masa y volumen del tejido gingival. Se considera una condición benigna de la cavidad oral, por lo general de manejo rutinario, que logra regularse con medidas simples de control del biofilm microbiano. El agrandamiento gingival puede ser producido por diversas condiciones clínicas, hereditarias, deficiente higiene oral o fármacos. La epilepsia afecta a 1% de la población mundial y requiere el uso de fármacos antiepilépticos o anticonvulsivantes para lograr su control, dentro de éstos la fenitoína actúa como un bloqueador selectivo de los canales de sodio sensibles al voltaje y constituye uno de los fármacos más empleados por su capacidad en el control de crisis focales y generalizadas. La fenitoína se ha relacionado con los agrandamientos gingivales como uno de sus efectos adversos, los cuales se incluyen dentro de las enfermedades por fármaco inducidas en la cavidad oral. El objetivo de este artículo es brindar la información necesaria sobre el manejo correcto de pacientes con agrandamiento gingival producido por fenitoínas y a la vez poder conocer las consecuencias de estos fármacos en la cavidad oral (AU)

Gingival enlargement means the increase in mass and volumen of the gingival tissue. It is considered a benign condition of the oral cavity, usually of routine management, wich can be regulated with simple measures of biofilm control. The gingival enlargement can be produced by diverse clinical conditions, hereditary deficient oral higiene or drugs. Epilepsy affects 1% of the world population and requires the use of antiepileptic or anticonvulsant drugs to achieve its control, within these phenytoin acts as selective blocker or voltage ­ sensitive sodium channels and is one of the most used grugs for its ability to control focal and generalized crises. Phenytoin has been linked to gingival enlargement as one of its adverse effects which is included within the drug diseases induced in the oral cavity. The objective of this article is to provide the necessary information on the correct managment of patients with gingival enlargemen produced by phenytoins and at the same time to know the consequences of these drugs in the oral cavity (AU)

Drug-Induced Gingival Overgrowth: A Pilot Study on the Effect of Diphenylhydantoin and Gabapentin on Human Gingival Fibroblasts.

INTRODUCTION: The administration of several classes of drugs can lead to the onset of gingival overgrowth: anticonvulsants, immunosuppressants, and calcium channel blockers. Among the anticonvulsants, the main drug associated with gingival overgrowth is diphenylhydantoin. MATERIALS AND METHODS: In this study, we compared the effects of diphenylhydantoin and gabapentin on 57 genes belonging to the "Extracellular Matrix and Adhesion Molecule" pathway, present in human fibroblasts of healthy volunteers. RESULTS: Both molecules induce the same gene expression profile in fibroblasts as well as a significant upregulation of genes involved in extracellular matrix deposition like COL4A1, ITGA7, and LAMB3. The two treatments also induced a significant downregulation of genes involved in the expression of extracellular matrix metalloproteases like MMP11, MMP15, MMP16, MMP24, and transmembrane receptor ITGB4. CONCLUSIONS: Data recorded in our study confirmed the hypothesis of a direct action of these drugs at the periodontium level, inducing an increase in matrix production, a reduction in its degradation, and consequently resulting in gingival hyperplasia.

Phenytoin sodium-ameliorated gingival fibroblast aging is associated with autophagy.

BACKGROUND AND OBJECTIVE: Human gingival fibrolasts aging is an important cause of periodontal disease. Phenytoin sodium (phenytoin) has a side effect of gingival hyperplasia and an effect on the autophagy progress. This study investigated whether the effect of phenytoin on aging gingival fibroblast is related to the autophagy pathway. MATERIAL AND METHODS: The aging model of gingival fibroblast cell line HGF-1 was induced by hydrogen peroxide (H2 O2 ), and the treatment of phenytoin and 3-methyladenine (3-MA) was performed simultaneously. Cell viability, cell cycle, and intracellular calcium ion were measured by flow cytometry. Changes in expression of basic fibroblast growth factor (bFGF), P16INK4A , P21cip1 , and bFGF, P16INK4A , P21cip1 , LC3II, p62, and Beclin were tested by using reverse transcription polymerase chain reaction, western blot, and immunofluorescence staining. RESULTS: The results showed that aging HGF-1 proliferation was inhibited by H2 O2 , gene, protein expression of bFGF, P16INK4A , and P21cip1 were decreased, autophagy-related proteins LC3II, p62, and Becline were decreased, and the proportion of G0/G1 phase and intracellular calcium ion of cell cycle was increased. Phenytoin treatment could recovery above changes, but the effect of phenytoin could be blocked by 3-MA. CONCLUSION: We propose that phenytoin alleviates the aging of gingival fibroblasts induced by H2 O2 . This condition is related to the enhancement of autophagy pathway.