Pulpal lesions in normal and cyclosporin a treated rats

The objective of this study was to examine the development of pulpal lesions in the lower molar of control and cyclosporin A (CyA) treated rats. The pulps of the first lower molars of 20 normal and 20 CyA treated rats were exposed and left open into the oral cavity. Five animals of each group were killed at 7, 14, 21, and 28 days after the pulp exposure. The specimens were sectioned sagittally at a thickness of 7 μm and stained with hematoxylin and eosin. The pulpal lesions were similar for both normal and CyA treated rats in all studied periods and the differences between both groups were not statistically significant by the Student t test at the 5% (0.05) level of significance, indicating that the immunosuppression did not alter the evolution of the inflammatory process. Copyright © 1997 by The American Association of Endodontists.

Morphometric evaluation of gingival overgrowth and regression caused by cyclosporin in rats

Cyclosporin A is a selective immunosuppressant, used in organ transplants to prevent graft rejection. Cyclosporin A can cause various side effects including gingival overgrowth. The aim of this work was to evaluate gingival overgrowth of rats treated daily with 10 mg/kg body weight of Cyclosporin A for 60 days, as well as the regression after the interruption of treatment. All rats treated with Cyclosporin A developed gingival overgrowth, with increased thickness of the epithelium, height and width of the connective tissue. The density of fibroblasts and collagen fibers also increased. Five to 90 days after the interruption of treatment with Cyclosporin A, there was a progressive reduction of the gingival volume and of collagen fibers and fibroblast densities. The reduction was more pronounced in the initial periods and after 90 days did not return to the normal values.

Morphological evaluation of combined effects of cyclosporin and nifedipine on gingival overgrowth in rats

It has previously been shown that, while cyclosporin A (CsA) and nifedipine both cause gingival overgrowth in the rat. the combined use of these drugs increases the severity of overgrowth. The aim of this study was to describe the histometry and densities of fibroblasts, collagen fibers and vessels in the gingival tissue of rats that were treated with CsA and nifedipine, either alone or in combination. Rats were treated for 60 days with a daily subcutaneous injection of 10 mg/kg body weight of CsA and/or with 50 mg/kg body weight of nifedipine added to the chow. The results confirmed that CsA causes a more severe overgrowth than nifedipine, and that the combined use of these drugs increases the overgrowth severity. All the rat groups that were studied showed that, as the severity of overgrowth increased, there was a parallel increase in fibroblasts and collagen, and a decrease in vessel content. Therefore, independently of whether the gingival overgrowth was caused by CsA alone, nifedipine alone, or both treatments in combination, the fibroblast and collagen density increased in parallel with the severity of the overgrowth. © Blackwell Munksgaard, 2002.

Combined effects of cyclosporin and nifedipine on gingival overgrowth in rats is not age dependent

Background: Cyclosporin A and nifedipine cause gingival overgrowth in rat, and the combined use of these drugs increases the overgrowth severity. Objective: The purpose of this study was to compare gingival overgrowth of rats of differents ages treated with cyclosporin A and nifedipine alone or given concurrently. Materials and methods: Rats 15, 30, 60 and 90 d old were treated with 10 mg/kg body weight of cyclosporin A and/or 50 mg/kg body weight of nifedipine in the chow. Results: Young rats showed evident gingival overgrowth with nifedipine, cyclosporin A, and cyclosporin A and nifedipine given concurrently. Adult rats did not show significant gingival alterations when treated with cyclosporin A and nifedipine alone. Nevertheless evident gingival overgrowth with alterations of the epithelium and connective tissue were observed when treated simultaneously with cyclosporin A and nifedipine. Conclusion: These results suggest that the combined effects of cyclosporin A and nifedipine on gingival overgrowth in rat is not age dependent.

Influence of age on combined effects of cyclosporin and nifedipine on rat alveolar bone

Background: There is some evidence showing that cyclosporin A (CsA) and nifedipine (NIF) affect bone metabolism. The purpose of this work was to study the effects of CsA and NIF, given alone or concurrently, on alveolar bone of rats of different ages. Methods: Rats 15, 30, 60, and 90 days old were treated daily with 10 mg/kg body weight of CsA subcutaneously injected and/or 50 mg/kg body weight of NIF/day given orally for 60 days. Alveolar bone of the first lower molars was morphologically and stereologically evaluated in serial 5 μm bucco-lingual paraffin sections, stained with hematoxylin and eosin. Serum calcium and alkaline phosphatase levels were measured in all animals at the end of the experimental period. Results: Rats treated with CsA or NIF alone or CsA and NIF concurrently showed decreased alveolar bone density. CsA was more effective than NIF. A significant decrease in serum calcium was found only in animals treated with CsA or CsA/NIF. The results were similar regardless of age. Conclusions: These results indicate that the decrease in the alveolar bone volume in rats caused by CsA and NIF alone or concurrently is not age dependent. Furthermore, NIF (50 mg/kg) did not further increase the loss of alveolar bone volume induced by CsA (10 mg/kg).

Effects of long-term cyclosporin therapy on the periodontium of rats

Background: 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. Objective: 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. Materials and methods: 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. Results: 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. Conclusion: 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. © Blackwell Munksgaard, 2004.

Effects of long-term cyclosporin therapy on gingiva of rats--analysis by stereological and biochemical estimation.

Cyclosporin A (CsA) is used as an immunosuppressive agent and its prominent side effect is the induction of gingival overgrowth, which remains a significant problem. The risk factors appraised include the duration of treatment. However, there are no stereological and biochemical studies exploring the effects of long-term CsA therapy on gingival tissue. The purpose of the present study was to investigate the level of TGF-beta1 in saliva and describe the densities of fibroblasts and collagen fibers in the gingival tissue of rats treated with CsA for long periods. Rats were treated for 60, 120, 180 and 240 days with a daily subcutaneous injection of 10 mg/kg of body weight of CsA. At the end of the experimental periods, saliva was collected for the determination of TGF-beta1 levels. After histological processing, the oral epithelium and the connective tissue area were measured as well as the volume densities of fibroblasts (Vf) and collagen fibers (Vcf). After 60 and 120 days of CsA treatment, there was a significant increase in Vf and Vcf as well as a significant increase in TGF-beta1 levels. After 180 and 240 days, reduction in the gingival overgrowth associated with significant decreases in the level of TGF-beta1, and also decreased Vf and Vcf, were observed. The data presented here suggest that after long-term therapy, a decrease in TGF-beta1 levels occurs, which might contribute to an increase in the proteolytic activity of fibroblasts in the gingiva, favoring the normality of extracellular matrix synthesis.

Cyclosporin but not tacrolimus significantly increases salivary cytokine contents in rats

Background: Cyclosporin (CsA) and tacrolimus (FK-506) are immunosuppressive drugs that specifically inhibit T-cell activation via calcineurin inhibition. Gingival overgrowth is a common side effect following the administration of CsA. The severity of gingival overgrowth seen in patients taking FK-506 is less than that observed with CsA. Little is known about the involvement of saliva in drug-induced gingival overgrowth. The purpose of this study was to investigate the salivary contents of tumor growth factor β1 (TGF-β1), epidermal growth factor (EGF), and interleukin-6 (IL-6) as well as the hystometry of gingival tissue obtained from rats treated with either FK-506 or CsA. Methods: For 30 or 60 days rats received daily subcutaneous injection doses of either CsA or FK-506 (10 mg/kg). The concentrations of TGF-β1, EGF, and IL-6 in saliva were determined by enzyme-linked immunosorbent assay, and after histological processing, the oral epithelium and connective tissue were assessed at the region of the lower first molars. Results: The levels of TGF-β1, EGF, and IL-6 in saliva were not significantly altered by any of the treatments after 30 days. After 60 days of treatment with CsA, gingival overgrowth and significant increase in salivary TGF-β1, EGF, and IL-6 concentrations were observed; no statistically significant changes were induced by FK-506. Conclusion: Within the limits of this experimental study, it can be concluded that CsA, but not FK-506, induced gingival overgrowth associated with an increase of the salivary levels of the cytokines TGF-β1, EGF, and IL-6.

Heteropterys tomentosa (A. Juss.) infusion counteracts Cyclosporin a side effects on the ventral prostate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cyclosporin A-induced new cementum formation: a morphometric evaluation in the periapical region of rats

Cyclosporin A (CsA) is a potent immunosuppressor used in organ transplantation and in the management of various autoimmune diseases. Recent studies have shown that CsA stimulates deposition of cementum on root surfaces. The aim of this study was to evaluate the periapical cementum thickness and the apical foramen width in CsA-treated rats. Rats weighing 50 g were treated with a daily injection of 10 mg/kg body weight of CsA in the chow for 60 days. The cementum of the mandibular 1st molars was histologically and morphometricaly examined by analysis of 5-microm-thick serial buccolingual paraffin sections stained with hematoxylin and eosin. Histometric and stereologic analyses revealed the presence of large amounts of cementum in all root surfaces, particularly abundant in the periapical region and obliterating the foramen. The volume density of cementoblasts did not increase. Five to 90 days after the termination of CsA therapy, there was no reduction of cementum thickness. These results suggest that cementum deposition is not reversible after cessation of CsA treatment.

Immunoexpression of angiogenesis and proliferation markers in patients treated with cyclosporin A

In the present immunohistochemical study, the expression of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 in the gingival tissues of renal transplant patients treated with cyclosporin A was assessed. Gingival overgrowth (GO) frequently occurs in transplant patients receiving immunosuppressive drugs such as cyclosporine and this gingival inflammation might play an important role in the pathogenesis of drug-induced GO. Twenty-eight human gingival biopsies were taken from healthy patients with chronic periodontitis (N.=14 control group), and from renal transplant recipients treated with cyclosporin A (N.=14 test group). The retrieved specimens were immunohistochemically processed and stained for vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67. The levels of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 were found to be significantly different among groups (P>0.001), with patients treated with cyclosporin A showing higher levels of all the analyzed markers compared to control group. In summary, the data from this pilot study suggests that the investigated factors have a role in the inflammation processes associated to immunosuppressive therapy. However, further studies with a larger sample population need to be conducted for an exhaustive knowledge of the mechanisms leading to GO.

Experimental pancreas transplantation: the consequences of the portocaval shunt on the blood glucose, plasma insulin, and glucagon

A proposição foi realizada, no período pós-operatório imediato, em 40 ratos Wistar, distribuídos por sorteio em doi grupos: grupo NC, vinte ratos correspondentes ao grupo controle, não diabético, submetidos a operação simulada e o grupo PT, 20 ratos correspondentes ao grupo diabético que recebeu transplante de pâncreas heterotópico de ratos Wistar normais. Durante sete dias, antes do transplante, e 1, 3, 6, 12, 24, 48, 72, 96 horas após, determinava-se a glicose sanguínea, a insulina plasnática e o glucagon. Estes parâmetros eram obtidos também do grupo NC. Diabetes mellitus experimental era induzida pela administração intravenosa de aloxana. O grupo PT era imunosuprimido com ciclosporina A. O grupo NC apresentou níveis normais de glicose sanguínea, de insulina plásmica e de glucagon, durante todo o experimento. Foi encontrada nítida hiperinsulinemia no sangue venoso periférico do grupo PT. A insulina plasmática era significantemente maior no grupo PT comparada ao grupo NC começando 72 horas após o transplante. O glucagon plasmático, elevado no período pré-transplante, não se alterou após o transplante. Apesar de hiperinsulinemia e hiperglucagonemia, os níveis de glicose sanguínea eram elevados 6 horas após o transplante e mantiveram-se normais após este período. Considerando-se os níveis de glicose sanguínea 12 horas pós-transplante, não houve diferença estatisticamente significante entre os grupos PT e NC, até o sacrifício.

Exposição de fibroblastos da cápsula de Tenon de pterígios à ciclosporina 0,05%

OBJETIVO: Avaliar o comportamento dos fibroblastos da cápsula de Tenon de pterígios e normais em cultura, quando expostos a ciclosporina 0,05%. MÉTODOS: Estudo prospectivo, controlado, do qual participaram 20 portadores de pterígio primário. Foram colhidas amostras da cápsula de Tenon normal e proveniente do pterígio, ambas do mesmo indivíduo, colocadas para crescimento em cultura e expostas a ciclosporina 0,05%. As avaliações foram feitas aos 3, 6, 12 e 17 dias após a exposição. RESULTADOS: Das amostras colhidas, 7 foram utilizadas para exposição a ciclosporina - 6 provenientes de pterígios e 1 da Tenon normal. Houve redução significativa na proliferação celular das culturas de fibroblastos expostos a ciclosporina (p<0,05). CONCLUSÃO: A ciclosporina 0,05% é capaz de inibir a proliferação de fibroblastos provenientes da cápsula de Tenon de pterígio e também da Tenon normal. Novos estudos devem ser providenciados para definir o papel da ciclosporina no tratamento do pterígio.