Chemotherapy with oxazaphosphorines, such as cyclophosphamide (CYP), is often limited by unacceptable urotoxicity. Without uroprotection, hemorrhagic cystitis (HC) becomes dose-limiting. To compare the uroprotective efficacy of classical 2-mercaptoethanesulfonic acid (Mesna) treatment with dexamethasone in CYP-induced HC, male Wistar rats (150-200 g; N = 6 in each group) were treated with saline or Mesna (40 mg/kg, ip) immediately and 4 and 8 h after ip administration of CYP (200 mg/kg). One, 2 or 3 doses of Mesna were replaced with dexamethasone (1 mg/kg, ip). The animals were sacrificed 24 h later. Cystitis was evaluated by determining the changes in bladder wet weight (BWW) and by macroscopic and microscopic analysis. CYP treatment induced a marked increased in BWW (162%, P<0.05), which was significantly inhibited by treatment with 3 doses of Mesna (P<0.05; 80%). The replacement of 1 or 2 doses of Mesna with dexamethasone reduced the increase in BWW by 83.3 and 95%, respectively. Macroscopic analysis of the bladder of rats with CYPinduced HC showed severe edema and hemorrhage, confirmed by microscopic analysis, that also showed mucosal erosion, inflammatory cell infiltration and ulcerations. The replacement of 1 or 2 doses of Mesna with dexamethasone inhibited the CYP-induced increase in BWW and almost abolished the macroscopic and microscopic alterations, with no significant difference between the effects of Mesna and dexamethasone, indicating that both drugs were efficient in blocking HC. However, although the replacement of all Mesna doses with dexamethasone reduced the edema, it did not prevent HC, suggesting that Mesna is necessary for the initial uroprotection.

Aim : Hemorrhagic cystitis (HC) is a limiting side-effect of chemotherapy with ifosfamide (IFS). In the study presented here, we investigated the use of dexamethasone in combination with mesna for the prevention of IFS-induced HC. Methods : Male Wistar rats (150-200 g; 6 rats per group) were treated with saline or mesna 5 min (i.p.) before and 2 and 6 h after (v.o.) administration of IFS. One, two or three doses of mesna were replaced with dexamethasone alone or with dexamethasone plus mesna. Cystitis was evaluated 24 h after its induction by the changes in bladder wet weight and by macroscopic and microscopic analysis.Results : The replacement of the last dose or the last two doses of mesna with dexamethasone reduced the increase in bladder wet weight induced by IFS by 84.79% and 89.13%, respectively. In addition, it almost abolished the macroscopic and microscopic alterations induced by IFS. Moreover, the addition of dexamethasone to the last two doses of mesna was more efficient than three doses of mesna alone when evaluated microscopically. Conclusion : Dexamethasone in combination with mesna was efficient in blocking IFS-induced HC. However, the replacement of last two doses of mesna with saline or all of the mesna doses with dexamethasone did not prevent HC.

-Context -Methotrexate and other anticancer agents can induce intestinal mucositis, which is one of the most common limiting factor that prevent further dose escalation of the methotrexate. Objectives -To evaluate the gastric emptying and gastrointestinal transit of liquids in methotrexate-induced intestinal mucositis. Methods -Wistar rats received methotrexate (2.5 mg/kg/day for 3 days, subcutaneously) or saline. After 1, 3 and 7 days, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage and myeloperoxidase activity (biochemical marker of granulocyte infiltration). Others rats were pre-treated with methotrexate or saline, gavage-fed after 3 or 7 days with a standard test liquid meal, and sacrificed 10, 20 or 30-min later. Gastric and small intestine dye recoveries were measured by spectrophotometry. Results -After 3 days of methotrexate, there was an epithelial intestinal damage in all segments, with myeloperoxidase activity increase in both in duodenum and ileum. Seven days after methotrexate, we observed a complete reversion of this intestinal damage. There was an increase in gastric dye recoveries after 10, 20, and 30-min post-prandial intervals after 3 days, but not after 7 days, of methotrexate. Intestine dye recoveries were decreased in the first and second segments at 10 min, in the third at 20 min, and in the second and third at 30 min, only after 3 days of methotrexate treatment. Conclusion -Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats. HEADINGS -Mucositis. Methotrexate. Gastric emptying. Gastrointestinal transit. Rats.