Ifosfamide toxicity

Springate J and Taub M. Ifosfamide toxicity In cultured proximal renal tubule cells. Pediatr Nephrol 22 358-365,2007. 

Furusawa S, FujimuraT, Sasaki K, Takayanagi Y, Potentiation of ifosfamide toxicity by chlo-rdiazepoxidfi, diazepam, and oxazepam, Chem Pham Bull (Tokyo) (1989) 73,342CC2. 

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. 

Ifosfamide -alkylating agent noncell cycle specific -bone marrow suppression -hemorrhagic cystitis (need Mesna uroprotection) -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -CNS toxicity—lethargy, stupor, coma, seizures... 

Kleinerman, E.S. et al., Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide Tolerability, toxicity, and immune stimulation, J. Immunother. Emphasis. Tumor Immunol., 17, 181, 1995. 

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. 

Cyclophosphamide and ifosfamide cause urothelial toxicity (haemorrhagic cystitis) which is caused by metabolite acrolein. Mesna reacts with this metabolites in the urinary tract to prevent toxicity and is used in prevention of toxicity to the urinary passage caused by oxazaphosphorins e.g. ifosfamide and cyclophosphamide. 

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. 

IFOSFAMIDE H2 RECEPTOR BLOCKERS -CIMETIDINE t adverse effects of alkylating agent, e.g. myelosuppression Additive toxicity Monitor more closely monitor FBC regularly... 

CANNABIS CYTOTOXICS -CYCLOPHOSPHAMIDE, DOXORUBICIN, IFOSFAMIDE, LOMUSTINE, VINCA ALKALOIDS Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

In 12 of 52 patients treated with ifosfamide there was neurocortical toxicity greater than grade 2 (6). They were successfully treated with intravenous methylthioninium chloride (methylene blue) 50 mg 3-hourly, which was also prophylactic in three patients. 

It has been thought that the metabolism of ifosfamide to chloroacetaldehyde is the mechanism whereby ifosfamide causes renal damage. However, this was not confirmed in a study of repeated doses of 6-9 g/m in 15 children, in whom there was no correlation between the pharmacokinetics of ifosfamide or its metabolites and either acute renal toxicity or chronic renal toxicity at either 1 or 6 months after treatment (8). However, there were changes in the metabolism of ifosfamide with time, particularly a reduction in dechloroethylation, which correlated with the risk of chronic nephrotoxicity. 

Beta-lactam induced renal toxicity can results from their use in monotherapy or when used in combination with other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, cyclosporine, furosemide, ifosfamide, vancomycin and nephrotoxic p-lactams. While the risk of nephrotoxic injury from monotherapy with p-lactams is relatively low, this risk is substantially increased when multiple drug combinations are required. 

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,... 

However, appropriate hydration and the sulfhydryl compound mesna are effective in decreasing the urotox-icity of ifosfamide [100, 101]. Less frequently asymptomatic renal functional abnormalities are reported following treatment with ifosfamide when used at a dose below 1.5 gr/m body skin surface [102, 103]. Acute renal failure secondary to tubular necrosis has been described when high-dose therapy [>5 gr/ m2] is administered, especially if patients were treated previously with cisplatin [104,105]. With escalating doses of a 96 hours infusion of ifosfamide, renal toxicity is dose limiting at 18 gr/ m2 [106]. 

Mohrmann M,AnsorgeS,Schmlch U, Schonfeld B,and Brandis M.Toxicity of Ifosfamide, cyclophosphamide and their metabolites in tubular cells In culture. Pediatr Nephrol 8 157-163,1994... 

Suarez A, McDowell El, NIaudet P, Comoy E, and Flamant F. Long term follow up of Ifosfamide renal toxicity in children treated for malignant mesenchymal tumors an International society of pediatric oncology report. J Clin Oncol, 9 2177-2182,1991... 

Van Dyck JJ, Falkson EIC,Van der Merwe AM, and Falkson G. Unexpected toxicity In patients treated with Ifosfamide. Cancer Res 32 921-924,1972... 

Falkson G, Van Dick JJ, Stapelberg R and Falkson EIC. Mesnum as protector against kidney and bladder toxicity with high-dose ifosfamide treatment. Cancer Chemother Pharmacol 9 81 -84,1982... 

Major risk factors for renal toxicity in cancer patients include nephrotoxic chemotherapy drugs, age, nutritional status, concurrent use of other nephrotoxic drugs (e.g., aminoglycoside antibiotics), and preexisting renal dysfunction. Drugs with a high risk for renal toxicity include cisplatin, ifosfamide,... 

Chen N, Aleska K, Woodland C, Rieder MJ, Koren G (2007) The effect of N-acetylcysteine on ifosfamide-induced toxicity in vitro studies in renal tubular cells. Transl Res 150 51-57... 

Cyclophosphamide and ifosfamide are nitrogen mustard derivatives, and are widely used alkylating agents (Table 124—14). They are closely related in structure, clinical use, and toxicity. Neither agent is active in its parent form and must be activated by mixed hepatic oxidase enzymes. The active metabolite of cyclophosphamide is phosphoramide mustard. Another metabolite, 4-hydroxycyclophos-phamide is cytotoxic, but is not an alkylating agent. Ifosfamide is hepaticaUy activated to ifosfamide mustard. Acrolein, a metabolite of both cyclophosphamide and ifosfamide, has little antitumor activity, but is responsible for some of their toxicity. ... 

Mesna dose is typically 60-100% of ifosfamide dose (1 1 for continuous infusion ifosfamide) ifosfamide and mesna are physically compatible and may be delivered in same IV bag CNS toxicity and nausea and vomiting may be more severe with rapid infusion case reports suggest methylene blue may be effective treatment for CNS toxicity Antidote for extravasation sodium thiosulfate very short stability in aqueous solutions, about 1 hour Used as topical solution or in compounded ointments for mycosis fungoides... 

The addition of other active chemotherapy agents in patients who have relapsed following PE have provided minimal improvement in survival. The addition of ifosfamide improved survival, but also toxicity. The addition of pachtaxel to PE resulted in similar overall survival, while adding pachtaxel to CE increased overall survival only in hmited-disease SCLC patients. The addition... 

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