Adrenomedullin worsens skin necrosis in rats subjected to vincristine-induced extravasation

Abstract

Extravasation of vesicant drugs such as vinca alkaloids causes severe injury, which may range from erythema to skin necrosis or ulceration. The skin necrosis may not be fully evident until several weeks or months after the initial damage, and may require surgical intervention. The main treatments for vincristine extravasation are hyaluronidase injection and topical warming, and the aim of treatment is to increase the clearance of the drug from the extravasation site. To investigate the effect of adrenomedullin, a potent vasodilatory peptide, in rats subjected to vincristine-induced extravasation. In total, 36 Wistar albino rats were given intradermal injection of vincristine and saline. The rats were assigned to one of three treatment groups (adrenomedullin, adrenomedullin + hyaluronidase, or hyaluronidase), a control group given vincristine only, or a sham group (saline). Tissue superoxide dismutase (SOD), glutathione peroxidase, malondialdehyde (MDA) and protein content were evaluated in skin biopsies taken on day 22. The ulcer size and histopathological grading scores were also recorded. SOD levels were significantly increased by adrenomedullin and increased by hyaluronidase. Glutathione peroxidase levels were significantly decreased in all four vincristine groups. Tissue MDA levels were highest in the adrenomedullin group. In all four vincristine groups, MDA levels were reduced, indicating preservation from tissue injury. Protein carbonyl (PCO) content levels in the adrenomedullin group were significantly greater than in the other three study groups (P < 0.05). In contrast, PCO levels in the hyaluronidase group were significantly lower than in the other three groups. In this animal model of vincristine-induced extravasation, antioxidant status and histology were preserved by hyaluronidase but worsened by adrenomedullin.