Alternativas terapêuticas na prevenção da cistite hemorrágica induzida por Ciclofosfamida e Ifosfamida com drogas antiinflamatórias: um estudo experimental comparativo com o Mesna

Abstract

Hemorrhagic cystitis (HC) is a therapy-limiting side effect of antineoplastic agents such as cyclophosphamide (CYP) and ifosfamide (IFS). Mesna is the drug of choice to prevent HC. Previous data, from the Laboratory of Pharmacology of Inflammation and Câncer, of Federal University of Ceará, have demonstrated that nitric oxide, platelet-activating factor and cytokines, like tumor necrosis factor alpha and interleukin-1 are crucial mediators involved in inflammatory events of HC, as well as in the urothelial damage and hemorrhage. Thus, the present study aimed to evaluate the effects of antiinflammatory drugs (AID), such as glucocorticoids (dexamethasone), selective ciclooxigenase 1 and 2 inhibitors (indomethacin and meloxicam, respectively) and natural products, such as Myracrodruon urundeuva Fr.AII. (Aroeira do Sertão), Ageratum conyzoides L. (Mentrasto) and ternatin, a flavonoid isolated from Egletes viscosa Less. (Macela), for the prevention of CYP- and IFS- induced HC. For this, male Wistar rats (150-200 g; n=6 per group) were treated with saline or mesna immediately and 4 and 8 hours, or 2 and 6 hours after administration of CYP or ÍFS. In other experimental groups, 1, 2 or 3 doses of mesna were replaced with AID, or the last two doses of mesna were replaced with saline or with the association (mesna+dexamethasone). 24 h after de administration of CYP or IFS, HC was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP and IFS treatment induced a marked increase in BWW, which was significantly (p<0.05) inhibited by treatment with 3 doses of mesna, and also by the replacement of 2a or 3a doses of mesna with AID. The replacement of the last two doses of mesna with the association (mesna+dexamethasone) promoted a marked inhibition of the increased in BWW induced by IFS. Macroscopic analysis of the bladder of rats with CYP- or IFS-induced HC showed severe edema and hemorrhage and microscopic analysis showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 2a or 3“ doses of mesna with AID or the replacement of the last two doses of mesna with the association (mesna+dexamethasone) almost abolished the macroscopic and microscopic alterations. However, the replacement of 3 doses of mesna with AID or the replacement of the last two doses of mesna with saline, did not prevent HC. In conclusion, the replacement of the last two doses of mesna with AID or with the association (mesna+dexamethasone) could be therapeutic alternatives, if they were clinically tested for the prevention of CYP- or IFS- induced HC, however, mesna is necessary for the initial uroprotection.