Cyclophosphamide toxicity

Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Characterising and avoiding the problem. Drugs... 

This interaction is not established with any certainty. The authors of the randomised study consider that, if necessary, allopurinol can be used safely to prevent hyperuricaemia with the chemotherapy regimens used for lymphomas. However, the other data introduce a note of caution. Be alert for increased cyclophosphamide toxicity if allopurinol is given. 

Fluconazole and itraconazole inhibit the metabolism of cyclophosphamide. There is some evidence that, compared with fluconazole, itraconazole might increase cyclophosphamide toxicity. Ketoconazole inhibits the metabolism of ifosfamide. This did not improve the ratio of active to inactive-toxic metabolites, and the possibility remains that ifosfamide efficacy could be reduced. 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

Alkylating Agents. Figure 2 Biotransformation of cyclophosphamide - formation of inactive ( ) and toxic ( metabolites. 

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. 

Fuchs VS, Golbs S, Kuhnert M, et al. 1976. [Studies into the prenatal toxic action of parathion methyl on Wistar rats and comparison with prenatal toxicity cyclophosphamide and trypan blue]. Arch Exp Vet Med 30 343-350. (German)... 

Increased toxicity has been noted when given concurrently with vincristine and prednisone. Decreased metabolism when used with cyclophosphamide. 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

EPA. 1986c. Final report on the evaluation of four toxic chemicals in an in vivo/in vitro toxicological screen Acrylamide, chlordecone, cyclophosphamide, and diethylstilbestrol. Research Triangle Park, NC U.S. Environmental Protection Agency, Health Effects Research Laboratory. EPA-600-1-86-002. 

Simmons JE, Berman E, Jackson M, et al. 1987. In vitro and in vivo toxicity A comparison of acrylamide, cyclophosphamide, chlordecone, and diethylstilbestrol. J Environ Sci Health A22(7) 639-64. 

Novel nitroxide malonate methanofullerenes (Fig. 1.3), thanks to the presence of nitroxide radicals and fullerene moiety, are able to protect cells from toxic side effects of cyclophosphamide (Gubskaya et al., 2007). Experiments were carried out on mice, in which leukemia P-388 was transplanted. Cyclophosphamide or fullerene individually injected did not increase the average life span of the animals, while the combination of the anticancer drug and nitroxide fullerene derivative resulted in the survival of 70% animals, classifying these compounds as promising modifiers of biological reaction for tumor therapy. 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

Mechlorethamine was the first nitrogen mustard. It is directly toxic. With its half-life of only a few minutes infusion directly into arteries supplying the tumor is the preferred mode of administration. Its spectrum of adverse effects is similar to that of cyclophosphamide. 

With chlorambucil and melphalan, although administered orally complaints of nausea and vomiting are minimal. The other toxic effects are comparable to those of cyclophosphamide. Chlorambucil has marked immunosuppressant activity. 

Bone marrow suppression that affects white blood cells more than platelets is the major dose-limiting toxicity. Maximal suppression of blood cell count occurs 10 to 14 days after drug administration recovery is generally seen 21 to 28 days after injection. Cyclophosphamide reduces the number of circulating lymphocytes and impairs the function of both humoral and cellular (i.e., B and T cell) aspects of the immune system. Chronic therapy increases the risk of infections. Nausea may occur a few hours after administration. Alopecia is more common than with other mustards. 

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. 

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