used in combination with other agents by i.v. infusion for treatment of acute myelogenous and lymphocyticleukemias (179-181).
220.127.116.11 Side Effects and Contraindications. It is not generally used i.m. or s.c. because of the severe tissue damage that may accompany extravasation (182). It is contraindicated when hypersensitivity reactions are present. Among the side effects that are encountered are severe cumulative myocardial toxicity that can include acute congestive heart failure after cumulative doses above 400-550 mg/m2 of body surface in adults and less in infants (183), severe myelosuppression (hemorrhage, superinfections), bone marrow suppression, secondary leukemia, renal/hepatic failure, carcinogenesis, mutagenesis, teratogenicity, and fertility impairment. The cardiomyopathy is characteristic of the anthracycline class and can occur long after therapy is concluded (184, 185). The highly colored nature of the drug can lead to urine discoloration that alarms the patient because of drug excretion. In addition, alopecia, rash, contact dermatitis, urticaria, nausea, vomiting, mucositis, diarrhea, abdominal pain, fever, chills, and (occasionally) anaphylaxis are observable. When given along with cyclophosphamide, its cardiotoxicity is enhanced and enhanced toxicity is seen when given concurrently with methotrexate.
18.104.22.168 Pharmacokinetics. On i.v. administration the drug is rapidly distributed into tissues but does not enter the central nervous system. Rapid liver reduction to daunomyci-nol is seen followed by hydrolytic or reductive loss of the sugar along with the oxygen atom with which it is attached to the ring system. These two reactions also can take place before reduction. Demethylation of the 0-methyl ether moiety also occurs followed by sulfation or glucuronidation of the resulting phenolic OH. These and other transformation products have lesser bioactivity (186). Patients with decreased liver function should receive smaller doses because they are not able to detoxify the drug effectively. The half-life is about 8.5 h and about 25% of the active drug is found in the urine along with about 40% in the bile (187). Liposomally encased daunorubicin ci-
3 Etarj Inhibiting Enzymes That Process DNA
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