Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Examples of toxic cardiomyopathies of various characteristics are presented. Daunomycin and doxorubicin, antineoplastic drugs, cause multifocal cardiomyopathies and intractable heart failure by cardiotoxic mechanisms; these effects are delayed and related to the cumulative dose. Cobalt caused diffuse vacuolar cardiomyopathy in chronic beer drinkers. The development of fulminant heart failure was the function of factors that increased the adsorption of cobalt or sensitized the myocardium to its cytotoxic effect. Beta-adrenergic receptor stimulant bronchodilators like isoproterenol or vasodilating antihypersensitive drugs like hydralazine are able to produce focal subendocardial necroses. This lesion is due to ischemia brought about by the acute exxagerated pharmacological effects of these compounds.
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PMID:Toxic cardiomyopathies. 79 2

Daunomycin, adriamycin and 5 semisynthetic anthracycline antibiotics inhibited oxygen consumption or ATP production of rat heart mitochondria in vitro. The no-effect levels varied depending on the substrate used and ranged from 1 nmole per mg mitochondrial protein. Mitochondrial functions were also studied in hearts of rats treated with repeated i.p. injections of the 7 antibiotics. Decrease in oxygen consumption without change in ATP production was observed with adriamycin and NSC-149584. Daunomycin, NSC-164011, NSC-143496 NSC-143114 affected primarily ATP production. The most potent compounds were daunomycin and adriamycin which damaged mitochondrial function at cummulative doses of approximately 10 mg/kg. ECGs were monitored in groups of equally treated rats. Cardiotoxicity manifested itself by progressive widening of the QRS complex often followed by the development of a S-wave trough. The most toxic compounds also induced intraventricular block, bradycardia and heart failure. The development of the ECG changes showed a good correlation with the impairment of mitochondrial function.
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PMID:Effects of seven anthracycline antibiotics on electrocardiogram and mitochondrial function of rat hearts. 121 14

The acute effects of daunomycin on the mechanical and energetic outputs of rabbit papillary muscles have been examined at 27 degrees C using a myothermic technique. Contrary to expectations, daunomycin, in concentrations ranging from 10 to 160 micrograms/ml, acted as a positive inotropic agent in terms of peak stress development and work output. The rate of stress development was, however, slightly depressed, and the major mechanical effect of the drug was to prolong the relaxation phase so that there were large drug-dependent increments in the stress-time integral. Daunomycin at a concentration of 80 micrograms/ml produced a 22% increment in peak stress development and a 74% increment in stress-time integral. The linear relationship between total (active + passive) stress and heat production was altered such that there was a 73% increment in the activation heat component (intercept) and a 37% increase in the energy cost per unit stress development (slope). In afterloaded isotonic contractions, daunomycin increased the mean work output (W; averaged over all load levels) by 49%, but there was an even greater increment in the associated energy expenditure, ET, which rose by 66%. Consequently, the overall mechanical efficiency (W/ET X 100%) fell slightly. It is concluded that, in the rabbit, daunomycin in the acute situation increases total calcium delivery to the myofilaments and decreases the "apparent" transduction efficiency. These acute effects are the opposite of those reported in papillary muscles taken from rabbits in cardiac failure induced by chronic daunomycin administration. The short-term effects of daunomycin in the rabbit differ substantially from those seen in the rat and guinea pig.
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PMID:Acute energetic effects of daunomycin on rabbit heart muscle. 241 Jun 90

The authors report a case of fatal Daunorubicin cardiotoxicity on initial phase of therapy for Acute Myeloblastic Leukemia at cumulative doses (225 mg/mq) considered still safe from the current literature. Despite the interruption of therapy and the interventions performed in support of cardiac functionality the patient came to exitus for heart failure 24 hours after the symptoms onset. This example represents a further confirmation of the utility of a steady monitoring with specific tests for the patients undergoing Daunorubicin therapy.
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PMID:[Early daunorubicin cardiotoxicity and fatal outcome in a child with acute myeloblastic leukemia (M2)]. 348 47

Cardiotoxicity limits the use of anthracyclines which are potent anticancer agents. In the isolated rat heart, we investigated the mechanism of acute anthracycline cardiotoxicity and compared a new anthracycline, carminomycin, with daunomycin which is in established use. Daunomycin 1.75 X 10(-5) M produced a fall in cardiac output (36 +/- 2 versus 58 +/- 1 ml/min; p less than 0.01), left ventricular power production (9 +/- 0.7 versus 16 +/- 0.3 mJ/sec/g; p less than 0.01), and efficiency of heart work (3.3 +/- 0.2 versus 6.3 +/- 0.2 mJ/sec/ml O2; p less than 0.01; mean +/- S.E. 40 min after daunomycin). Carminomycin (1.75 X 10(-5) M) produced a greater fall in cardiac output than equimolar daunomycin (26 +/- 2 versus 36 +/- 2 ml/min; p less than 0.01). Daunomycin did not reduce coronary flow rate, heart rate, or oxygen consumption. From the preceding data, we inferred that, since afterload and preload were constant in this model, heart failure was due to a depressed inotropic state. Procedures that increased cytosolic calcium relieved heart failure namely, pretreatment with digoxin (62.4 micrograms), isoproterenol (10(-6) M), and increased perfusate Ca2+ (5 mM versus 2.5 mM) all prevented carminomycin-induced fall in cardiac output (41 +/- 1, 47 +/- 5, and 52 +/- 1, respectively, versus 26 +/- 2 ml/min; p less than 0.01). Acute anthracycline contractile failure was also associated with a fall in high-energy phosphate compounds which could also have contributed to the decreased inotropic state. We conclude that carminomycin is more cardiotoxic than daunomycin in equimolar concentrations and that a lowered cytosolic calcium and decreased energy stores might cause the contractile failure. The cytosolic calcium and high-energy phosphate compounds were lowered by separate mechanisms.
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PMID:Mechanism of acute anthracycline cardiotoxicity in isolated rat hearts: carminomycin versus daunomycin. 670 50

The cardiotoxic effects of Daunomycin (DM) ad Adriamycin (ADR), Anthracyclines (ATC), were studied mainly by echocardiography to evaluate their chronic cumulative cardiotoxicity and acute cardiotoxicity during consolidation therapy. Electrocardiographic findings were less sensitive and therefore less reliable for evaluation of the chronic cumulative cardiotoxicity and acute cardiotoxicity induced by ATCs during consolidation therapy. With echocardiography ESS/ESVI, the index of the left ventricular contraction, had the highest sensitivity among indices for cardiotoxicity. SF was useful for easy measurement and calculation of cardiotoxicity. Evaluation of the chronic cumulative cardiotoxicity of ATC drugs indicated that cumulative doses of 300 mg/m2 or more resulted in abnormally low ESS/ESVI levels suggesting cardiotoxicity in many cases, and doses of 500 mg/m2 or more caused abnormally low levels in all cases. Evaluation of acute cardiotoxicity showed that post-consolidation therapy ESS/ESVI levels were significantly lower than pre-consolidation therapy levels in the group treated with doses of 500 mg/m2 or more, but the condition was reversible except in those patients with heart failure. As for the relation between cumulative doses and cardiotoxicity, the indices studied showed no differences between DM and ADR. These results indicate that careful follow-up mainly by echocardiography is required after doses reaching 300 mg/m2 or more of ATC drugs.
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PMID:[Noninvasive evaluation of chronic cumulative and acute cardiotoxicity induced by anthracycline in children with acute leukemia. Assessment of mainly left ventricular contractile state by M mode echocardiography]. 804 95

Echocardiographic reports on 144 adults receiving anthracycline therapy and 18 controls were reviewed for the possible relationship between dosage and ejection fractions. The cardiotoxicity of each anthracycline drug was evaluated as follows: Pirarubicin = 0.8, Mitoxantrone = 3.4, Daunorubicin = 0.5, Aclarubicin = 0, and Epirubicin = 0.6 with Doxorubicin = 1 as a control. As a whole, the ejection fractions, which decreased subsequently compared with increasing amount of dosage, showed a remarkable decrease at the dosage level of 600 mg/m2. However, the ejection fractions differed among individual patients. It was predicted that heart failure would not develop when the ejection fractions exceeded 55%. It is desirable to stop anthracycline therapy when the ejection fractions drop to 55%.
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PMID:[Echocardiographic evaluation of cardiotoxicity induced by anthracycline therapy]. 908 92

Daunorubicin (DNR) is one of the most important cytotoxic agents in the treatment of acute myeloid leukemia (AML). Its use is usually limited by drug-induced cardiotoxicity depending on the cumulative dose administered. Liposomal encapsulation of DNR (DaunoXome, DNX) seems to reduce the risk of this severe side effect. To investigate the toxicity of DNX in heavily pretreated patients, we conducted a phase I trial, including patients (pts) older than 60 years with relapsed or refractory AML. DNX was used at doses of 40, 60, 75 and 90 mg/m(2), biweekly. Fourteen patients with a median age of 69 years (range, 63-77) were enrolled. A total of 49 courses of DNX were administered [3 pts at 40 mg/m(2) (for a total of 13 courses), 5 at 60 mg/m(2) (20 courses), 4 at 75 mg/m(2) (12 courses), and 2 at 90 mg/m(2) (4 courses)]. The mean cumulative dose of DNX administered was 340 mg (range, 120-1200). A 20% decline in the left ventricular ejection fraction (LVEF) without clinical signs and symptoms of heart failure was noted in 2 patients after a cumulative DNX dose of 480 mg, both with pre-existing heart disease. Even at the highest cumulative doses of DNX, no further decline in LVEF was noted. Nausea, vomiting, alopecia and mucositis were absent. All patients had significant myelosuppression requiring transfusion support. During treatment, 3 patients showed a 25% reduction of leukemic blasts in the bone marrow, 3 patients had to be excluded due to AML progression after the 2nd DNX course, and 7 patients died during the first 6 weeks of treatment. We conclude from these data that DNX offers a less toxic alternative to DNR and other anthracyclines. Using DNX dosages of 40 to 90 mg/m(2) biweekly seems to have little anti-leukemic activity in a patient population heavily pretreated with anthracyclines.
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PMID:Phase I study of liposomal daunorubicin in relapsed and refractory acute myeloid leukemia. 1279 45

During chemotherapy with anthracyclines, attenuated neuregulin signaling by the erbB2 receptor inactivating antibody Trastuzumab enhances the heart failure risk. We compared the effects of attenuated neuregulin/erbB signaling and of daunorubicin on splicing of the Bcl-x gene and on mitochondrial activation of apoptosis in cardiomyocytes. Attenuating erbB signals in cultured neonatal rat cardiomyocytes by the erbB2 antagonist tyrphostin AG825, by the erbB1/4 antagonist AG1478 or by antisense-induced lowering of erbB2 receptors resulted in an augmented Bcl-xS/Bcl-xL ratio, mitochondrial release of cytochrome c, activation of caspase 9 and caspase 3, and nucleosome-sized DNA fragmentation. A similar DNA fragmentation and caspase 3 activation was induced by TNF-alpha, but without Bcl-xS/Bcl-xL increase, cytochrome c release or caspase 9 activation. A BH4-domain containing HIV TAT fusion protein added to cardiomyocytes under attenuated erbB signaling lowered the enhanced Bcl-xS/Bcl-xL ratio, the cytochrome c release, the caspase 3 activation and the DNA fragmentation, while apoptosis was not modified by the fusion protein in TNF-alpha treated cardiomyocytes. Enhancement of Bcl-xS/Bcl-xL by reducing Bcl-xL via siRNA transfection mimicked the mitochondrial apoptotic activation due to erbB signal attenuation. Daunorubicin also caused Bcl-xS/Bcl-xL enhancement and mitochondrial apoptotic activation in cultured cardiomyocytes; this was attenuated by BH4-fusion protein or by neuregulin-1 and augmented by siRNA-mediated Bcl-xL lowering. We conclude that activation of mitochondrial apoptosis due to altered Bcl-x splicing contributes as a common mechanism of anthracyclines and erbB signal attenuation to the enhanced heart failure risk under this combination.
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PMID:Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes. 1573 8