phenanthrenes and Heart-Diseases

Halofantrine is an antimalarial drug which is widely prescribed for the treatment of infections with chloroquine-resistant strains of Plasmodium falciparum. Chemically, it is a phenanthrene methanol, belonging to the aryl-amino-alcohol family. It has recently been recognized that this drug may induce rare but serious, cardiotoxic effects, including lengthening of the QTc interval, 'torsade de pointes' and induction of late ventricular potentials. These events are thought to be related to a quinidine-like action of the drug. In addition, severe haemolytic accidents have been reported, mimicking blackwater fever and indicating an immunological process. As a result of these side-effects, new guidelines for prescription and more cautious use of halofantrine, particularly as a stand-by treatment for febrile access among travellers, are required.

Topics: Antimalarials; Electrocardiography; Heart Diseases; Hemolysis; Humans; Malaria, Falciparum; Phenanthrenes; Prospective Studies

Halofantrine is an antimalarial drug widely prescribed for chloroquine-resistant strains of Plasmodium falciparum. It has been recognized to cause serious deleterious effects which have dampened early enthusiasm for this compound. Basically, the adverse effects involve lengthening of the QTc interval, torsade de pointes and induction of late ventricular potentials. These side effects are related to the quinidine-like effect of the drug which has a chemical structure similar to quinine and quinidinic drugs. More recently, severe haemolytic accidents have been reported suggesting an autoimmunization mechanism. These side effects imply new rules for prescription and more prudent use of halofantrine, especially for prophylaxic therapy against malarial attacks in travellers.

Topics: Antimalarials; Drug Prescriptions; Heart; Heart Diseases; Hemolysis; Humans; Phenanthrenes

Burn injury induces multiple signaling pathways leading to a significant inflammatory storm that adversely affects multiple organs, including the heart. Poly (ADP-ribose) polymerase inhibitor 1 (PARP1) inhibition, with specific agents such as N-(5,6-Dihydro-6-oxo-2-phenanthridinyl)-2-acetamide (PJ34), is effective in reducing oxidative stress and cytokine expression in the heart. We hypothesized that PARP1 inhibition would reduce inflammatory signaling and protect against burn injury-induced cardiac dysfunction.. Male Sprague-Dawley rats (8 weeks old, 300 to 350 g) were randomly assigned to sham injury (Sham), 60% total body surface area burn (24 hours post burn), or 60% total body surface area burn with intraperitoneal administration of PJ34 (20 mg/kg, 24 hours post burn + PJ34) and sacrificed 24 hours after injury. Cardiac function was determined using Vevo 2100 echocardiography. Genetic expression of 84 specific toll-like receptor-mediated signal transduction and innate immunity genes were examined using microarray to evaluate cardiac tissue. Qiagen GeneGlobe Data Analysis Center was used to analyze expression, and genetic clustering was performed using TreeView V2.0.8 software. Real-time quantitative polymerase chain reaction was used to validate identified differentially expressed genes.. Burn injury significantly altered multiple genes in the toll-like receptor signaling, interleukin-17 signaling, tumor necrosis factor signaling, and nuclear factor-κB signaling pathways and led to significant cardiac dysfunction. PARP1 inhibition with PJ34 normalized these signaling pathways to sham levels as well as improved cardiac function to sham levels.. PARP1 inhibition normalizes multiple inflammatory pathways that are altered after burn injury and improves cardiac dysfunction. PARP1 pathway inhibition may provide a novel methodology to normalize multiple burn injury-induced inflammatory pathways in the heart.

Topics: Animals; Antineoplastic Agents; Heart Diseases; Male; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Rats; Rats, Sprague-Dawley

Triptolide (TP), a principal bioactive component extracted from traditional Chinese medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted wide attention of its therapeutic effects on inflammation and autoimmune diseases. However, the therapeutic application of TP is hindered by severe cardiomyocyte toxicity and narrow therapeutic window. We previously identified that the p53 was an indispensable contributor in TP-induced myocardial injury. p53 has an inhibitory effect on IKKβ-NF-κB pathway that regulates glucose transporters (GLUT) expression. Based on these evidences, we speculate that p53 mediates TP-disturbed glucose uptake by blocking IKKβ-NF-κB signaling. This study focused on the effect of TP on cardiac glucose uptake and the role of p53 in glucose metabolism in cardiomyocytes, and p53

Topics: Animals; Apoptosis; Cardiotoxicity; Cell Line; Diterpenes; Energy Metabolism; Epoxy Compounds; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 4; Heart Diseases; I-kappa B Kinase; Mice, Knockout; Myocytes, Cardiac; NF-kappa B; Phenanthrenes; Rats, Sprague-Dawley; Signal Transduction; Tumor Suppressor Protein p53

The cardiotoxicity of doxorubicin (DOX) reduces the quality of life and prognosis of cancer patients, and therefore its clinical application has been largely restricted. This study aimed to assess the effects of cryptotanshione (CPT) on DOX-induced rat cardiac insufficiency.. CPT treatment significantly suppressed apoptosis. Transcriptomic profiling and bioinformatics analysis can be used to evaluate the cardio-protective effect of CPT through inactivating p53 signaling pathway in the doxorubicin-mediated myocardial damage model.. F-actin staining and flow cytometry were used to assess the effects of CPT on cardiomyocytes.

Topics: Animals; Apoptosis; Cardiotonic Agents; Cardiotoxicity; Computational Biology; Databases, Genetic; Disease Models, Animal; Doxorubicin; Gene Expression Profiling; Heart; Heart Diseases; Metabolic Networks and Pathways; Myocytes, Cardiac; Phenanthrenes; Rats; Reactive Oxygen Species; Signal Transduction; Transcriptome

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-2-Associated X Protein; Cell Line; Diterpenes; Epoxy Compounds; Heart Diseases; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Myocardium; Myocytes, Cardiac; Phenanthrenes; Reactive Oxygen Species; Tumor Suppressor Protein p53

Clinical application of triptolide (TP), a main active ingredient of the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), is limited by a series of severe toxicities, including cardiotoxicity. In previous studies, we found the activation of sirtuin 3 (SIRT3) attenuated TP-induced toxicity in cardiomyocytes. Resveratrol (RSV), a polyphenol from the skins of grapes and red wine, is an activator of SIRT3. The current study aimed to investigate the protective effect of RSV against TP-induced cardiotoxicity and the underlying mechanisms. Mice were treated with a single dose of TP (2.5 mg/kg) via the intragastric (i.g.) route. After 24 h, TP induced abnormal changes of serum biochemistry, activity decrease of antioxidant enzymes and damage of heart tissue such as myocardial fiber rupture, cell swelling and interstitial congestion. In contrast, administration with RSV (50 mg/kg i.g. 12 h before and 2 h after the administration of TP) attenuated the detrimental effects induced by TP in BALB/c mice. Moreover, the cardiomyocyte protective effects of RSV on TP-induced heart injury were associated with the activation of SIRT3 and its downstream targets. In vitro study also indicated that RSV counteracted TP-induced cardiotoxicity through SIRT3-FOXO3 signaling pathway in H9c2 cells. Collectively, these findings suggest the potential of RSV as a promising agent in protecting heart from TP-induced damage.

Topics: Animals; Antioxidants; Apoptosis; Cardiotonic Agents; Cardiotoxicity; Cell Line; Diterpenes; Epoxy Compounds; Female; Forkhead Box Protein O3; Heart Diseases; Humans; Male; Mice; Mice, Inbred BALB C; Myocardium; Myocytes, Cardiac; Phenanthrenes; Resveratrol; Signal Transduction; Sirtuin 3; Stilbenes

Triptolide (TP), a major bioactive component isolated from the traditional Chinese herb Tripterygium wilfordii Hook f. (TWHF), has been shown to exert various pharmacological effects. However, the severe toxicity of TP prevents wide clinical use. In a previous study, we reported that TP-induced mitochondria-dependent apoptosis in cardiomyocytes is mediated by reactive oxygen species (ROS). Autophagy is a cellular self-digestion process and is one of the first lines of defense against oxidative stress. Additionally, recent evidence suggests that autophagy can selectively eliminate damaged mitochondria. This study investigated the role of autophagy in TP-induced cardiotoxicity. We investigated the effects of autophagy in combination with TP on apoptosis, ROS and mitochondrial function. Rat cardiomyocytes were pre-treated with chloroquine or rapamycin followed by TP. The augmentation of autophagy with rapamycin in the presence of TP substantially ameliorated the detrimental effects induced by TP, while suppression of autophagy by chloroquine accelerates TP-induced cellular damage. In addition, pre-treated with rapamycin before TP administration also attenuated TP-induced damage in Balb/c mice heart tissues. Taken together, these results suggest that TP-induced cell death can be modified by autophagy. Furthermore, induction of autophagy by rapamycin may be a potential cardioprotective role against TP-induced cardiotoxicity by facilitating removal of dysfunctional mitochondria.

Topics: Animals; Apoptosis; Autophagy; Cell Line; Diterpenes; Epoxy Compounds; Heart Diseases; Mice; Mice, Inbred BALB C; Myocytes, Cardiac; Phenanthrenes; Rats; Sirolimus

Although doxorubicin (DXR) is an effective antineoplastic agent; the serious cardiotoxicity mediated by the production of reactive oxygen species has remained a considerable clinical problem. Our hypothesis is that tanshinone IIA sodium sulfonate (TSNIIA-SS), which holds significant affects on cardioprotection in clinic, protects against DXR-induced cardiotoxicity. In vitro investigation on H9c2 cell line, as well as in vivo study in animal model of DXR-induced chronic cardiomyopathy were performed. TSNIIA-SS significantly increased cell viability and ameliorated apoptosis of DXR-injured H9c2 cells using CCK-8 assay and Hoechst 33342 stain respectively. Furthermore, the cardio-protective effects of TSNIIA-SS were confirmed with decreasing ST-interval and QRS interval by electrocardiography (ECG); improving appearance of myocardium with haematoxylin and eosin (H&E) stain; increasing myocardial tensile strength using tension to rupture (TTR) assay and decreasing fibrosis through picric-sirius red staining comparing with those receiving DXR alone. These data have provided the considerable evidences that TSNIIA-SS is a protective agent against DXR-induced cardiac injury.

Topics: Abietanes; Animals; Antibiotics, Antineoplastic; Benzimidazoles; Cardiotonic Agents; Cell Line; Doxorubicin; Electrocardiography; Fibrillar Collagens; Fluorescent Dyes; Heart; Heart Diseases; Male; Mice; Myoblasts; Phenanthrenes; Rats; Tensile Strength

Reactive oxygen and nitrogen species are overproduced in the cardiovascular system during circulatory shock. Oxidant-induced cell injury involves the activation of poly(ADP-ribose) polymerase (PARP). Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the new potent phenanthridinone PARP inhibitor PJ34 [the hydrochloride salt of N-(oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide], we studied whether the impaired cardiac function in endotoxic shock is dependent upon the PARP pathway. Escherichia coli endotoxin (lipopolysaccharide, LPS) at 55 mg/kg, i.p., induced a severe depression of the systolic and diastolic contractile function, tachycardia, and a reduction in mean arterial blood pressure in both rats and mice. Treatment with PJ34 significantly improved cardiac function and increased the survival of rodents. In addition, LPS-induced depression of left ventricular performance was significantly less pronounced in PARP-1 knockout mice (PARP(-/-)) as compared with their wild-type littermates (PARP(+/+)). Thus, PARP activation in the cardiovascular system is an important contributory factor to the cardiac collapse and death associated with endotoxin shock.

Topics: Animals; Death; Disease Models, Animal; Drug Interactions; Endotoxins; Enzyme Activation; Gene Deletion; Heart Diseases; Heart Function Tests; Lipopolysaccharides; Male; Mice; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar

The crystal and molecular structures and absolute configuration of (-)-halofantrine hydrochloride were determined by X-ray diffraction. The absolute configuration of the single chiral center of (-)-halofantrine was established to be in the S configuration. Thus, (+)-halofantrine, the more cardiotoxic isomer, has the R configuration. The carbon atom adjacent to the aromatic ring has the same configuration in both (+)- halofantrine and quinidine, suggesting a stereospecific component to the cardiotoxicity produced by both agents. The intramolecular N ... O distance is 4.177 +/- 0.006 A (1 A = 0.1 nm), which is close to the N ... O distance found in the crystal structure of (+/-)-halofantrine hydrochloride, even though the N-H group points in opposite directions in racemic halofantrine and (-)-halofantrine. Both the hydroxyl group and the amine group form hydrogen bonds with the chloride anions. The crystallographic parameters for (-)-halofantrine hydrochloride were as follows: chemical formula, C26H31Cl2F6NO+. Cl-; Mr, 492.4; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 6.290 +/- 0.001 A, b was 13.533 +/- 0.003 A, and c was 30.936 +/- 0.006 A; volume of the unit cell, 2,633.2 +/- 0.7 A(3); number of molecules per unit cell, 4; calculated density, 1.354 g cm(-3); source of radiation, Cu K(alpha) (lambda = 1.54178 A); mu (absorption coefficient), 3.50 mm(-1); F(000) (sum of atomic scattering factors at zero scattering angle), 1,120; room temperature was used; final R (residual index), 4.75% for 2,988 reflections, with absolute value of Fo > 3sigma(F), where Fo is the observed structure factor and F is the structure factor.

Topics: Antimalarials; Crystallography, X-Ray; Heart Diseases; Hydrogen Bonding; Molecular Conformation; Phenanthrenes; Quinidine; Quinine; Stereoisomerism

Topics: Antimalarials; Drug Resistance; Heart Diseases; Humans; Malaria, Falciparum; Phenanthrenes; Travel

Three cases of long QT-interval due to halofantrine were documented in 1992 in France. Two of them had a congenital long QT-interval (Romano-Ward syndrome). We performed a prospective study of cardiac monitoring in 20 patients taking halofantrine. Minimal ECG changes were noted with lengthening of the QT-interval. Systematic ECG is necessary before giving halofantrine.

Topics: Antimalarials; Electrocardiography, Ambulatory; Heart Diseases; Humans; Phenanthrenes; Prospective Studies