Doxorubicin cardiomyopathy with

On the other hand, alteration of the drug distribution profile by linkage to nanospheres can, in some cases, considerably reduce the toxicity of a drug because of reduced accumulation in organs where the most acute toxic effects are exerted. This concept was indeed illustrated with doxorubicin, which displays severe acute and chronic cardiomyopathy. After intravenous administration to mice, plasma levels of doxorubicin were higher when the drug was adsorbed onto nanospheres and at the same time the cardiac concentration of the drug was dramatically reduced. In accordance with the observed distribution profile, doxorubicin associated with nanospheres was found to be less toxic than free doxorubidn. ... 

The development of anthracycline-induced cardiomyopathy is closely related to the cumulative lifetime dose of the anthracycline. The recommended maximum cumulative lifetime dose of doxorubicin is 450-550 mg/m (7) and of daunorubicin 400-550 mg/m intravenously in adults (1,2). About 5% of doxorubicin-treated patients develop congestive cardiac failure at this dose however, the incidence approaches 50% at cumulative doses of 1000 mg/m (7-9). These figures are derived from experience with doxorubicin administered as a bolus or by infusion of very short duration (under 30 minutes). The incidence of clinical cardiotoxicity falls dramatically with other schedules of administration (that is weekly doses or continuous infusion for more than 24 hours). 

Numerous neuroendocrine biomarkers correlate with severity of cardiac dysfunction. Heart failure is associated with increase in peripheral vascular resistance due to increases in sympathetic tone, norepinephrine, renin, angiotensin II, arginine vasopressin, and endothelin-1. The increased venous pressure causes atrial distension that stimulates production and release of atrial and brain natriuretic peptides (ANP, BNP) from the atria and ventricles, respectively. ANP inhibits the renin-angiotensin-aldosterone system. In humans and mammals, BNP has been found to be an early biomarker of left ventricular hypertrophy developing with doxorubicin cardiotoxicity, congestive heart failure, or occult dilated cardiomyopathy (Erkus et al. 2006 Walker 2006 Oyama, Sisson, and Solter 2007). 

Sparano JA. Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Semin Oncol (1998) 25 (Suppl 10), 66-71. 

Other studies have also suggested that the combination of mitomycin and doxorubicin may increase eardiotoxicity. In a randomised study, 2 of 39 patients treated with doxorubicin 45 mg/m once every 3 weeks and mitomycin 10 mg/m once every 6 weeks developed cardiomyopathy, compared with none of 42 patients treated with doxorubicin 75 mg/m once every 3 weeks alone. ... 

Anthracyclines Doxorubicin, epirubicin Myelosuppression, cardiomyopathy Alopecia, nausea, vomiting, stomatitis, ulceration necrosis with extravasation, red-colored urine, radiation-recall effect... 

Cystostatic antibiotics insert themselves into the DNA double strand this may lead to strand breakage (e.g., with bleomycin). The anthracycline antibiotics daunorubkin and adriamycin (doxorubicin) may induce cardiomyopathy. Bleomycin can also cause pulmonary fibrosis. 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Daunorubicin (Daunomycin and Cerubidine) and doxorubicin (Adriamycin) bind to and cause the intercalation of the DNA molecule, thereby inhibiting DNA template function. They also provoke DNA chain scission and chromosomal damage. Daunorubicin is useful in treating patients with acute lymphocytic or acute granulocytic leukemia. Adriamycin is useful in cases of solid tumors such as sarcoma, metastatic breast cancer, and thyroid cancer. These agents cause stomatitis, alopecia, myelosuppression, and cardiac abnormalities ranging from arrhythmias to cardiomyopathy. 

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2-3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500-550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy. 

Long-term complications such as cardiomyopathy (e.g., doxorubicin), leukemia (i.e., mechlorethamine), and infertility (alkylating agents) can also occur. Amelioration of certain side effects can be achieved with the judicious use of antiemetics and blood transfusions (or erythropoietin). 

DOXORUBICIN PACLITAXEL t risk of neutropenia, stomatitis and cardiomyopathy due to t plasma concentrations of doxorubicin t risk of neutropenia, stomatitis and cardiomyopathy due to t plasma concentrations of doxorubicin when paditaxel is given before doxorubicin Doxorubicin should be administered prior to paditaxel. The cumulative dose of doxorubicin should be limited to 360 mg/m2 when concurrently administered with paditaxel... 

Hypokinetic heart wall motion abnormalities and early signs of chronic cardiomyopathy have been identified as a significant toxic effect of mitoxantrone in patients who received cumulative doses of 32-174 mg (31). Electrocardiographic T wave inversion and cardiac complications have been described from intensive therapy with mitoxantrone 40 mg/m over 5 days and cyclophosphamide 1550 mg/m for 4 days, given before bone marrow transplantation for metastatic breast cancer. All the patients had had previous exposure to doxorubicin in cumulative doses that did not exceed 442 mg/m (19). 

Adverse effects associated with the intrapleural instillation of doxorubicin in doses of 10-40 mg consist of fever (11-15%), anorexia (24-29%), nausea (20-29%), and chest pain (28-29%) (94,96). Cardiomyopathy and myelosuppression were not reported (96). 

On-target effects vs. off-target effects Cardiomyopathy Doxorubicin/ Epirubicin Etoposide with similar pharmacology to Doxorubicin but does not cause cardiomyopathy Unpublished study... 

Cardiomyopathy is the most common chemotherapy-associated cardiac toxicity. Myocardial ischemia, pericarditis, arrhythmias, miscellaneous electrocardiogram (ECG) changes, and angina occur much less frequently. The anthracyclines (da-unorubicin, doxorubicin, epirubicin, and idarubicin) have the highest consistent risk for cardiomyopathy, which is cumulative dose related. There is evidence that high-dose cyclophosphamide, mitoxantrone, and fluorouracil also pose an increased risk of cardiac damage. The concurrent use of traztuzu-mab with an anthracycline and cyclophosphamide is associated with a risk of cardiac dysfunction, but the consequences of sequential use are not yet known. 

Dexrazoxane is a cardioprotective agent that reduces the incidence and severity of cardiomyopathy in female breast cancer patients who have received a cumulative doxorubicin dose of 300 mg/m and who may beneht from additional doxorubicin therapy. It is not recommended for use with the initiation of doxorubicin therapy. 

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