Avaliação da associação pentoxifilina e tocoferol em modelo de osteonecrose dos maxilares induzido pela administração de ácido zoledrônico em ratos

Abstract

Bisphosphonate-induced osteonecrosis of the jaws (ONJ) is a painful and debilitating condition, resulting in mucosal ulceration and bone necrosis, which has not yet been established. In this work was evaluated the effect of the association of the drugs pentoxifylline and tocopherol on ONJ in the mandible of rats. For this, 35 Wistar rats (180-200g) were divided into 5 groups in experimental protocol 1: Control (C), Zoledronic acid + Extraction (AZ + EX), Zoledronic acid + Extraction + Pentoxifylline (AZ + EX + P), Zoledronic acid + Exodontia + Tocopherol (AZ + EX + T) and Zoledronic acid + Exodontia + Pentoxifylline + Tocopherol (AZ + EX + PT), animals with ONJ were pre-treated with pentoxifylline (15 mg / kg / day; ip ) or tocopherol (5.5 mg / kg / day, ip) or with two drug combination (15 mg / kg / day of Pentoxifylline + 5.5 mg / kg / day of Tocopherol, ip) 2h before extraction of the first molar bottom left (1MIE). In the second experimental protocol, 28 animals were divided into 4 groups: C, AZ + EX, AZ + EX + Prophylactic PT (pre-treatment with PT) and AZ + EX + PT Therapeutic (post-treatment with PT). ONJ was induced through the administration of AZ (0.2 mg / kg, e.v) on days 0, 7, 14 and 49. On the 42nd day, 1MIE extraction was performed. The post-treated group received PT daily from day 43 until the end of the experimental period. The animals were euthanized on day 70. Histopathological analyzes of the mandibles, liver and kidney were performed. Serum calcium (Ca), phosphorus (P), alkaline phosphatase (FAO), AST, ALT and analysis of the oxidative stress of drugs in the hepatic and renal tissues were also performed. In the histopathological analysis, animals pretreated with PT showed a significant improvement in bone condition at the tooth extraction site when compared to the group with ONJ (p <0.05), however when comparing the association of drugs in the pre and post-treatment, the group of animals that received PT after 1MIE extraction showed a significant increase in the number of viable osteocytes and a reduction in the number of empty gaps (p <0.05). In the pre-treatment, the group of animals that received only tocopherol had higher levels of FAO and the groups that received pentoxifylline had higher levels of serum P when compared to the group with ONJ (p <0.05). The pretreated groups showed a reduction in blood ALT when compared to the group with ONJ (p <0.05). The association of PT in animals with ONJ showed a significant reduction in liver enzymes ALT when compared to the AZ + EX group (p <0.05), while the AST levels were significantly different only in the therapeutic group (AZ + EX + Therapeutic PT). The administration of PT, both before and after treatment, significantly reduced the levels of hepatic malondialdehyde when compared to the group with ONJ (p <0.05). Our results suggest that the association of the drugs pentoxifylline and tocopherol improves bone condition at the site of the tooth extraction site and does not present systemic toxicity in rats with ONJ.