Ifosfamide alkylating agent

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... 

Risk factors for the development of AML include exposure to environmental toxins, Hispanic ethnicity, and genetics.6 Of greater concern is the increased prevalence of AML as a secondary malignancy, resulting from chemotherapy and radiation treatment for other cancers. Alkylating agents, such as ifosfamide and cyclophosphamide, and topoisomerase inhibitors, such as etoposide, are linked to an increased risk of myelodysplastic syndrome (MDS) and AML.8... 

Ifosfamide (Ifex, Holoxan) [Antineoplastic/Alkylating Agent]... 

Mechanism of action Cyclophosphamide [sye kloe FOSS fa mide] is the most commonly used alkylating agent. Both cyclophosphamide and ifosfamide [eye FOSS fa mide] are first biotransformed to hydroxylated intermediates by the cytochrome P-450 system (Figure 38.13). The hydroxylated intermediates undergo breakdown to form the active compounds, phospho-ramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. [Note The therapeutic effect of these drugs is independent of the level of activity of the cytochrome P-450 system.]... 

Pharmacokinetics Unlike most of the alkylating agents, cyclophosphamide and ifosfamide are preferentially administered by the oral route. Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration. 

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

Ifosfamide is an alkylating agent belonging to the group of oxazaphosphorines. It is used to treat a variety of solid tumors in children, including rhabdomyosarcoma, soft tissue sarcomas, Wilms tumor, bone sarcomas, and neuroblastoma, and leukemias and lymphomas in adults. It is also sometimes used in combination with other drugs, such as doxorubicin or cisplatin and etoposide. 

Classic alkylating agents (mechlorethamine, melphalan, busulfan, chlorambucil, cyclophosphamide, ifosfamide)... 

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. ... 

In summary, ifosfamide, an alkylating agent with anti-neoplastic properties (1.2 g/mVday fV for 5 days), is indicated in the treatment of testicular cancer. In addition, ifosfamide has been used in lung cancer, Hodgkin s and non-Hodgkin s lymphoma, breast cancer, acute and chronic lymphocytic leukemia, ovarian cancer, and sarcomas. 

Two chiral drugs commonly used in the treatment of cancer are the alkylating agents cyclophosphamide and ifosfamide (Fig. 2). From a chemical perspective, both drugs are distinctive in that their chiral centers are phosphorous rather than carbon atoms. Another feature common to both drugs is that they are really prodrugs, as pharmacological action is attributable to metabolites formed by a specific pathway. 

A detailed NMR study has been reported of the hydrolysis, in aqueous solution at specific pH values, of the alkylating anti-tumour agent ifosfamide (85), and its metabolites (86), (87), and (88) The first step in each case is ring-opening by hydrolysis of the endo-cyclic P-N bond. In kinetic studies aimed at modelling enzyme-mediated formation of high-energy phosphates, the... 

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