Ifosfamide hemorrhagic cystitis with

In animal studies, NAC has been shown to prevent hemorrhagic cystitis that results from administration of cyclophosphamide or its position isomer ifosfamide. Hemorrhagic cystitis results from the toxic effect of acrolein, a metabolic product of cyclophosphamide or its position isomer ifosfamide. The mechanism whereby NAC prevents this toxicity may be prevention of the intracellular depletion of antioxidants, such as GSH, by acrolein. Concomitant administration of NAC with cyclophosphamide or ifosfamide does not impair antineoplastic activity, because both anticancer drugs are inactive until they are metabolized by the liver to their phosphoramide mustard metabolites. 

Drug therapy may also cause renal insufficiency due to lower urinary tract obstruction. Ureteral obstruction can be caused by calculi or retroperitoneal fibrosis. Bladder dysfunction with urinary outflow obstruction can result, particularly in males with prostatic hypertrophy, from anticholinergic drugs including tricyclic antidepressants and disopyramide. Bladder outlet and ureteral obstruction may result from bladder fibrosis following hemorrhagic cystitis with cyclophosphamide or ifosfamide therapy. Concurrent treatment with mesna can prevent cystitis and this complication. 

Clinical trials showed therapeutic efficacy in a broad spectrum of tumors these include SCLC, testicular tumors, sarcomas, breast cancer, renal cell cancer, pancreatic tumors and lymphomas. Ifosfamide is less myelosuppressive than cyclophosphamide but is more toxic to the bladder. Therefore it is recommended that ifosfamide is coadministered with the thiol compound mesna to avoid hemorrhagic cystitis and to reduce the risk of developing bladder cancer. Other side effects include neurotoxicity and myelosuppression. 

The use of effective prevention strategies can decrease the incidence of hemorrhagic cystitis to less than 5% in patients receiving cyclophosphamide or ifosfamide. There are three methods to reduce the risk administration of mesna, hyperhydration, and bladder irrigation with catheterization. 

A toxicity that is unique to cyclophosphamide and ifosfamide is cystitis. Dysuria and decreased urinary frequency are the most common symptoms. Rarely, fibrosis and a permanently decreased bladder capacity may ensue. The risk of development of carcinoma of the bladder also is increased. Large intravenous doses have resulted in impairment of renal water excretion, hyponatremia, and increased urine osmolarity and have been associated with hemorrhagic subendocardial necrosis, arrhythmias, and congestive heart failure. Interstitial pulmonary fibrosis may also result from chronic treatment. Other effects of chronic drug treatment include infertility, amenorrhea, and possible mutagenesis and carcinogenesis. 

Mechanism of Action An antineoplastic adjunct and cytoprotective agent that binds with and detoxifies urotoxic metabolites of ifosfamide and cyclophosphamide. Therapeutic Effect Inhibits ifosfamide- and cyclophosphamide-induced hemorrhagic cystitis. 

Like cyclophosphamide, ifosfamide causes a hemorrhagic cystitis in a high proportion of patients, with an occasionally fatal outcome. The damage to urinary bladder epithelium is caused by acrolein, a metabolite that is excreted in the urine. In bone marrow transplant recipients, prior administration of busulfan, which itself causes hemorrhagic cystitis, can increase this risk of oxazaphosphorines (12). Mesna (sodium... 

Experience with ifosfamide-contain-ing regimens has revealed a consistent clinical pattern of nephrotoxicity. Fanco-ni syndrome, which is characterized by acid, sodium, potassium, magnesium, and small molecular weight proteins, occurs in 1-5% of the children who have received repeated treatments of ifosfamide [94] [95]. In fact the development of rickets secondary to Fanconi syndrome has been reported following treatment with ifosfamide [96]. Patients who have received therapy with cisplatin or carboplatin in addition to ifosfamide may be at greater risk for development of Fanconi syndrome [97]. Hemorrhagic cystitis is a significant toxicity that occurs with ifosfamide administration [98,... 

Mesna is a cytoprotective agent. It is used to reduce the incidence of ifosfamide-induced hemorrhagic cystitis. Mesna disulfide is reduced to the free thiol compound, mesna, which reacts chemically with the urotoxic ifosfa-mide metabolites, resulting in their detoxification. It is indicated in prevention of ifosfamide-induced hemorrhagic cystitis. 

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