Drugs ifosfamide

V. Gilard, R. Martino, M. Malet-Martino, U. Niemeyer, J. Pohl, Chemical Stability and Fate of the Cytotoxic Drug Ifosfamide and Its ALDechlorinated Metabolites in Acidic Aqueous Solutions ,./. Med. Chem. 1999, 42, 2542 - 2560. 

Mesna (Mesnex) [Uroprotectant/Antidote] Uses Prevent hem-orrhagic cystitis d/t ifosfamide or cyclophosphamide Action Antidote, reacts w/ acrolein and other metabolites to form stable compounds Dose Per protocol dose as % of ifosfamide or cyclophosphamide dose Oral 20% IV dose at 0, 4, 8 h (mix w/ juice) Caution [B /—] Contra Thiol sensitivity Disp Inj, tabs SE -i- BP, allergic Rxns, HA, GI upset, taste p v sion EMS Antidote for two antineoplastic drugs (ifosfamide and cyclophosphamide) OD May cause D, muscle tremors, SOB, bluish skin color, and Szs symptomatic and supportive... 

Electrochemical oxidation of anticancer drugs ifosfamide and cyclophosphamide produced in high yield methoxylated analogues of the key hydroxy-metabolites of these oxazaphosphorine prodrugs (Scheme 19). ... 

Blaschke et al. reported on metabolic studies of the anticancer drug ifosfamide [7] using Chirasil-val as a chiral stationary phase (49). In urine extracts of cancer patients, the K-enantiomer was found to be enriched. 

Solutes containing asymmetric sulfur atomes or asymmetric phosphorous atoms can be resolved v/ith or without an aromatic moiety in the molecule. For example, the anticancer drug ifosfamide, an oxazaphos-phorane not containing an aromatic moiety, has been resolved on this type of CSP (73). In addition, these are excellent CSPs for the resolution of enantiomeric molecules with an axis of dissymmetry (atrop isomers) (9-11). 

What drug is missing from his ifosfamide orders ... 

Salvage regimens incorporate drugs not used as initial therapy. Commonly used regimens include DHAP r/examethasone, Mgh-dose cytarabine, and cisplatin), ESHAP (etoposide, methylprednisolone, Mgh-dose cytarabine, and cisplatin), and MINE (mesna, ifosfamide, mitoxantrone, and etoposide). None is clearly superior to the others. 

Lu, H., Wang, J., Chan, K. and Young, D. (1998). Effects of phenobarbital of stereoselective metabolism of ifosfamide in rats. Drug Metab. Dispos. 26 476-482. 

That the metabolism of melphalan occurs by the same reaction mechanism as that of mechlorethamine has been demonstrated in in vitro studies [65]. Under physiological conditions of temperature and pH, formation of the first and second aziridinium intermediates en route to the bis(hydroxyethyl) metabolite occurred with rate constants of ca. 0.017 and 0.041 min-1, respectively. After 60 min, ca. 2/3 of the drug had been converted to the monohydroxy and dihydroxy products in comparable amounts. In the presence of a phosphate buffer, competition between hydrolysis and phosphatolysis was seen, such that at completion of the reaction (4 h) the two major products were the dihydroxy and the hydroxy/phosphate metabolites, with the dihydroxy derivative produced in small amounts. Similar hydrolytic dehalogena-tion has also been observed for ifosfamide in acidic aqueous solution [69]. 

Trabectedin is licensed for the treatment of advanced soft-tissue sarcoma when treatment with anthracyclines and ifosfamide has failed or is contraindicated. It is administered by intravenous infusion. Trabectedin may cause hepatobiliary disorders and for this reason hepatic function should be evaluated before starting treatment and during treatment. Dexamethasone is administered intravenously with trabectedin for its anti-emetic and hepatoprotective effects. As with other antineoplastic drugs, trabectedin causes nausea and vomiting and bone-marrow suppression as side-effects. 

Another review covered metabolic studies on cylophosphamide, ifosfamide and trofosfamide. The analytical techniques covered were GC/MS, LC/MS and LC/MS/MS [67]. The same class of drugs has been determined in urine by GC/MS/MS with on-column injection and LC/MS/MS with LLE [68,69]. Chiral derivatisation has been used in conjunction with HPLC to measure the ratio of cyclophosphamide enantiomers [70]. 

Ifosfamide is an experimental drug that is analogous to cyclophosphamide. Synonyms of this drug are goloxan and mitoxan. 

Metastatic osteosarcoma has a poor prognosis unless the disease is confined to the lungs and is resectable. Palliative chemotherapy can be employed with a number of drugs including doxorubicin, cisplatin, carboplatin, methotrexate, ifosfamide and etoposide. 

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. 

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. 

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 1. ANTIBIOTICS-rifampicin 2. ANTICANCER AND IMMUNOMODULATING DRUGS - dexamethasone 3. ANTIDEPRESSANTS-St John s wort 4. ANTI EPILEPTICS -carbamazepine, phenytoin, phenobarbital t rate of biotransformation to 4-hydroxyifbsfamide, the active metabolite, but there is no change in AUC of 4-hydroxyifosfamide Due to t rate of metabolism and of clearance owing to induction of CYP3A4 and CYP2D6 Be aware - clinical significance may be minimal or none... 

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 the majority of cases, chirality results from the three dimensional orientation of four different substituents around a carbon atom forming the chiral center. In addition the orientation of atoms or groups around sulfur, phosphorus, and nitrogen atoms can sometimes form a chiral center. Examples of chiral drugs are numerous but include Certirizine (1), Rotigotine (2), and Ifosfamide (3). 

The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was "Posicor Withdrawal Reflects Complexity of Interaction Profile" (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vinblastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor s decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage. 

Five of thirty-two patients treated with the alternating drug regimen CAMBO-VIP (cyclophosphamide, doxorubicin, methotrexate, bleomycin, vincristine, etoposide, ifosfamide, and prednisolone) for non-Hodgkin s lymphoma developed blisters under the thickened skin of the palms and/or soles, followed by desquamation (28). 

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