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To compare the classical uroprotective efficacy of mesna (2-mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline, CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP or IFS treatment induced marked changes in macroscopic and microscopic evaluation and in bladder wet weight (BWW), and these alterations were significantly inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1 or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with saline or all doses of mesna with ternatin or DMSO did not prevent HC. In conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently blocked CYP- or IFS-induced HC, however mesna is necessary for 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.

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

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. CONTEXTO: Metotrexato e outros agentes anticâncer podem induzir uma mucosite intestinal, que é um dos fatores de limitante mais comum que limitam o aumento escalonado da dose do metotrexato. OBJETIVOS: Avaliar o esvaziamento gástrico e o trânsito gastrointestinal de líquidos na mucosite intestinal induzida por metotrexato. MÉTODOS: Ratos Wistar, receberam metotrexato (2.5 mg/kg/dia por 3 dias, subcutâneo) ou salina. Após 1, 3 ou 7 dias, secções do duodeno, jejuno e íleo foram retirados para análise morfométrica e dosagem da atividade de mieloperoxidase (marcador bioquímico da infiltração de neutrófilos). Outros ratos foram pré-tratados com metotrexato ou salina, após 3 ou 7 dias, foram alimentados mediante gavagem com uma refeição teste e sacrificados após 10, 20 e 30 minutos. As retenções fracionais do corante no estômago e em três segmentos do intestino delgado foram determinados por espectrofotometria. RESULTADOS: Após 3 dias do metotrexato, houve lesão do epitélio intestinal em todos os segmentos, com aumento da atividade de mieloperoxidase, no duodeno e íleo. Sete dias após o metotrexato, foi observada completa reversão da lesão intestinal. Observou-se ainda retardo no esvaziamento gástrico após 10 min, 20 min e 30 min, após 3 dias, mas não após 7 dias do tratamento com metotrexato. A retenção fracional dos segmentos do intestino foi reduzida no primeiro e segundo segmentos após 10 min, e no terceiro segmento após 30 min da administração da refeição, somente 3 dias após o tratamento com metotrexato. CONCLUSÃO: A mucosite intestinal induzida por metotrexato retarda o esvaziamento gástrico e o trânsito gastrointestinal de líquidos em ratos acordados.

To compare the classical uroprotective efficacy of mesna (2-mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline, CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP or IFS treatment induced marked changes in macroscopic and microscopic evaluation and in bladder wet weight (BWW), and these alterations were significantly inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1 or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with saline or all doses of mesna with ternatin or DMSO did not prevent HC. In conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently blocked CYP- or IFS-induced HC, however mesna is necessary for initial uroprotection.