phenanthrenes and Arrhythmias--Cardiac

Halofantrine (HF) was considered an effective and safe treatment for multi-drug resistant falciparum malaria until 1993, when the first case of drug-associated death was reported. Since then, numerous studies have confirmed cardiac arrythmias, possibly fatal, in both adults and children. The aim of the study was to review fatal HF related cardiotoxicity.. In addition, to a systematic review of the literature, the authors have had access to the global safety database on possible HF related cardiotoxicity provided by GlaxoSmithKline.. Thirty-five cases of fatal cardiotoxicity related to HF, including five children, were identified. Females (70%) and patients from developing countries (71%) were over-represented in this series. Seventy-four percent of the fatal events occurred within 24 hours of initial exposure to HF. Twenty six patients (74%) had at least one predisposing factor for severe cardiotoxicity, e.g., underlying cardiac disease, higher than recommended doses, or presence of a concomitant QT-lengthening drug. All (100%) of the paediatric cases had either a contraindication to HF or an improper dose was given. In six cases there was no malaria.. A distinction should be made between common but asymptomatic QT-interval prolongation and the much less common ventricular arrhythmias, such as torsades de pointes, which can be fatal and seem to occur in a very limited number of patients. The majority of reported cardiac events occurred either in patients with predisposing factors or with an improper dose.Therefore, in the rare situations in which HF is the only therapeutic option, it can still be given after carefully checking for contraindications, such as underlying cardiac disease, bradycardia, metabolic disorders, personal or family history of long QT-interval or concomitant use of another QT-prolonging drug (e.g., mefloquine), especially in females.

Topics: Antimalarials; Arrhythmias, Cardiac; Humans; Phenanthrenes

To explore the impact of embryonic exposure to phenanthrene (Phe), a typical tricyclic polycyclic aromatic hydrocarbon, on cardiac development in next generation, fertilized zebrafish embryos were exposed to 0.05, 0.5, 5 and 50 nM Phe for 96 h, and then transferred to clear water and raised to adulthood. The cardiac development in F1 larvae generated by adult females or males mated with unexposed zebrafish was assessed. Malformation and dysfunction of the heart, such as increased heart rate, arrhythmia, enlarged heart and abnormal contraction, were shown in both paternal and maternal F1 larvae. A greater impact on the distance between the sinus venosus and bulbus arteriosus was exhibited in maternal F1 larvae, while paternal F1 larvae displayed a more severe impact on heart rate and arrhythmia. The transcription of genes related to cardiac development was disturbed in F1 larvae. DNA methylation levels in the promoter of some genes were associated with their transcription. The expression of acetylated histone H3K9Ac and H3K14Ac in maternal F1 larvae was no significantly changed, but was significantly downregulated in paternal F1 larvae, which might be associated with the downregulated transcription of tbx5. These results indicate that exposure to Phe during embryogenesis adversely affects cardiac development in F1 generation, and the effects and toxic mechanisms showed sex-linked hereditary differences, highlighting the risk of Phe exposure in early life to heart health in next generation.

Topics: Animals; Arrhythmias, Cardiac; Female; Heart; Larva; Male; Phenanthrenes; Water Pollutants, Chemical; Zebrafish

The three-ringed polycyclic aromatic hydrocarbon (PAH) phenanthrene (Phe) has been implicated in the cardiotoxicity of petroleum-based pollution in aquatic systems, where it disrupts the contractile and electrical function of the fish heart. Phe is also found adsorbed to particulate matter and in the gas phase of air pollution, but to date, no studies have investigated the impact of Phe on mammalian cardiac function.. Our objectives were to determine the arrhythmogenic potential of acute Phe exposure on mammalian cardiac function and define the underlying mechanisms to provide insight into the toxicity risk to humans.. Mouse hearts exposed to. To the best of our knowledge, this is the first evidence of direct inhibitory effects of Phe on mammalian cardiac electrical activity at both the whole-heart and cell levels. This electrical dysfunction manifested as an increase in arrhythmia susceptibility due to impairment of both conduction and repolarization. Similar effects in humans could have serious health consequences, warranting greater regulatory attention and toxicological investigation into this ubiquitous PAH pollutant generated from fossil-fuel combustion. https://doi.org/10.1289/EHP12775.

Topics: Action Potentials; Air Pollutants; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Humans; Mammals; Mice; Myocytes, Cardiac; Phenanthrenes; Potassium

Phenanthrene (Phe) is one of the most abundant and ubiquitous polycyclic aromatic hydrocarbons in the aquatic environment. It is known that Phe has cardiotoxic effects, but knowledge concerning the mechanism of cardiac dysfunction caused by Phe is still limited. In this study, zebrafish embryos were exposed to environmentally relevant concentrations of Phe, and an increase of an irregular rhythm was observed in Phe treated embryos. Disordered calcium (Ca(2+)) handling characterized by impaired sarcoplasmic reticulum Ca(2+) uptake, and obvious Ca(2+) accumulation in the cytoplasm was observed in rat embryonic cardiac myoblasts (H9C2) exposed to Phe. The mRNA level as well as protein expression of the SERCA2a Ca(2+) pump in zebrafish hearts or H9C2 cells was significantly decreased by Phe exposure. The activity of Ca(2+)-ATPase in H9C2 cells was inhibited by Phe. Both the mRNA and protein levels of TBX5, a direct regulator of SERCA2a, were significantly decreased by Phe exposure. These results suggested that exposure to Phe could lead to arrhythmia in zebrafish embryos via perturbing the calcium handling pathway.

Topics: Animals; Arrhythmias, Cardiac; Calcium; Calcium Channels; Cell Line; Embryo, Nonmammalian; Gene Expression Regulation; Heart Rate; Myoblasts; Phenanthrenes; Rats; T-Box Domain Proteins; Water Pollutants, Chemical; Zebrafish

Hypoxia and subsequent re-oxygenation are associated with cardiac arrhythmias such as early afterdepolarizations (EADs), which may be partly explained by perturbations in cytosolic calcium concentration. Transient receptor potential melastatin 4 (TRPM4), a calcium-activated non-selective cation channel, is functionally expressed in the heart. Based on its biophysical properties, it is likely to participate in EADs. Hence, modulators of TRPM4 activity may influence arrhythmias. The aim of this study was to investigate the possible anti-arrhythmic effect of 9-phenanthrol, a TRPM4 inhibitor in a murine heart model of hypoxia and re-oxygenation-induced EADs.. Mouse heart was removed, and the right ventricle was pinned in a superfusion chamber. After a period of normoxia, the preparation was superfused for 2 h with a hypoxic solution and then re-oxygenated. Spontaneous electrical activity was investigated by intracellular microelectrode recordings.. In normoxic conditions, the ventricle exhibited spontaneous action potentials. Application of the hypoxia and re-oxygenation protocol unmasked hypoxia-induced EADs, the occurrence of which increased under re-oxygenation. The frequency of these EADs was reduced by superfusion with either flufenamic acid, a blocker of Ca(2+) -dependent cation channels or with 9-phenanthrol. Superfusion with 9-phenanthrol (10(-5) or 10(-4)  mol·L(-1) ) caused a dramatic dose-dependent abolition of EADs.. Hypoxia and re-oxygenation-induced EADs can be generated in the mouse heart model. 9-Phenanthrol abolished EADs, which strongly suggests the involvement of TRPM4 in the generation of EAD. This identifies non-selective cation channels inhibitors as new pharmacological candidates in the treatment of arrhythmias.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels; Female; Flufenamic Acid; Heart Ventricles; In Vitro Techniques; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Patch-Clamp Techniques; Phenanthrenes; Potassium Channels; TRPM Cation Channels

Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart.. The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects.. Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine.. In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.

Topics: Animals; Antimalarials; Arrhythmias, Cardiac; Guinea Pigs; Heart; Heart Conduction System; Mefloquine; Phenanthrenes; Quinidine; Quinine; Time Factors

Tanshinone IIA is an active component of a traditional Chinese medicine based on Salvia miltiorrhiza, which reduces sudden cardiac death by suppressing ischaemic arrhythmias. However, the mechanisms underlying the anti-arrhythmic effects remain unclear.. A model of myocardial infarction (MI) in rats by ligating the left anterior descending coronary artery was used. Tanshinone IIA or quinidine was given daily, before (7 days) and after (3 months) MI; cardiac electrical activity was monitored by ECG recording. Whole-cell patch-clamp techniques were used to measure the inward rectifying K(+) current (I(K1)) in rat isolated ventricular myocytes. Kir2.1 and serum response factor (SRF) levels were analysed by Western blot and microRNA-1 (miR-1) level was determined by real-time RT-PCR.. Tanshinone IIA decreased the incidence of arrhythmias induced by acute cardiac ischaemia and mortality in rats 3 months after MI. Tanshinone IIA restored the diminished I(K1) current density and Kir2.1 protein after MI in rat ventricular myocytes, while quinidine further inhibited I(K1)/Kir2.1. MiR-1 was up-regulated in MI, possibly due to the concomitant increase in SRF, a transcriptional activator of the miR-1 gene, accounting for decreased Kir2.1. Treatment with tanshinone IIA prevented increased SRF and hence increased miR-1 post-MI, whereas quinidine did not.. Down-regulation of miR-1 and consequent recovery of Kir2.1 may account partially for the efficacy of tanshinone IIA in suppressing ischaemic arrhythmias and cardiac mortality. These finding support the proposal that miR-1 could be a potential therapeutic target for the prevention of ischaemic arrhythmias.

Topics: Abietanes; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Down-Regulation; Drugs, Chinese Herbal; Electrocardiography; In Vitro Techniques; Male; MicroRNAs; Myocardial Infarction; Myocytes, Cardiac; Patch-Clamp Techniques; Phenanthrenes; Potassium Channels, Inwardly Rectifying; Quinidine; Rats; Rats, Wistar; Serum Response Factor

The antimalarial drug halofantrine has been associated with QT interval prolongation and with fatal and nonfatal arrhythmias in patients without known underlying cardiac abnormalities. A common target for QT interval-prolonging drugs is the human ether-a-go-go gene (HERG) which encodes the pore forming subunit of the rapidly activating delayed rectifier K(+) current (I(Kr)).. We studied the effects of halofantrine (0.1-1000 nM) and its major metabolite N-desbutylhalofantrine (3-1000 nM) on wild type HERG K(+) channels stably expressed in HEK 293 cells, using the whole cell patch-clamp recording technique.. Halofantrine and N-desbutylhalofantrine blocked HERG K(+) channels in a concentration-dependent manner with a half-maximal inhibitory concentration of 21.6 nM (n=31 cells) and 71.7 nM (n=18 cells), respectively. The development of drug block for both halofantrine and N-desbutylhalofantrine required channel activation indicative of open and/or inactivated state block. Drug washout or cell hyperpolarization resulted in minimal current recovery consistent with virtually irreversible binding. Using a ventricular action potential voltage clamp protocol, halofantrine and N-desbutylhalofantrine block of HERG current was greatest during phases 2 and 3 of the action potential waveform.. We conclude that both halofantrine and N-desbutylhalofantrine cause high affinity block of HERG K(+) channels. Although N-desbutylhalofantrine has been suggested to be a safer antimalarial agent compared to halofantrine, our results suggest that the gain in the safety margin for QT interval prolongation-related cardiotoxicity is minimal.

Topics: Action Potentials; Antimalarials; Arrhythmias, Cardiac; Cation Transport Proteins; Cell Line; DNA-Binding Proteins; Dose-Response Relationship, Drug; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Humans; Inhibitory Concentration 50; Kidney; Patch-Clamp Techniques; Phenanthrenes; Potassium Channels; Potassium Channels, Voltage-Gated; Trans-Activators; Transcriptional Regulator ERG; Transfection

Topics: AIDS-Related Opportunistic Infections; Antiviral Agents; Aristolochic Acids; Arrhythmias, Cardiac; Cytomegalovirus Retinitis; Dietary Supplements; Drug Labeling; Ganciclovir; Humans; Kidney Diseases; Methadyl Acetate; Narcotics; Opioid-Related Disorders; Phenanthrenes; Phytotherapy; Prodrugs; United States; United States Food and Drug Administration; Valganciclovir

The antimalarial drug halofantrine hydrochloride has been associated with cardiac arrhythmias. This is a report of a study on the cardiac effects of standard-dose halofantrine (24 mg/kg) on a sample of 48 patients selected from a group of 402 Dega (Montagnard) refugees treated for Plasmodium falciparum infection. Prolongation of the rate-corrected QT interval (QTc) on the electrocardiogram (ECG) was used as an indicator of risk for halofantrine-associated cardiac arrhythmias. We found that standard-dose halofantrine was associated with a lengthening of the mean QTc from 0.04 sec(1/2) to 0.44 sec(1/2). Two patients had a QTc increase of greater than 25%, but none had a follow-up QTc of more than 0.55 sec(1/2), an interval length generally considered to be a risk factor for ventricular arrhythmias. Regression analysis indicated that pretreatment ECGs were poorly predictive of QTc lengthening during therapy, although pretreatment ECGs may be useful to evaluate patients with pre-existing cardiac conditions. The manufacturer has recommended that the halofantrine dose not exceed 24 mg/kg and revised the list of medication contraindications to include some cardiac conditions. Clinicians should weigh a patient's risk, including history of cardiac disease and availability of alternative therapy before use of halofantrine.

Topics: Adolescent; Adult; Aged; Antimalarials; Arrhythmias, Cardiac; Electrocardiography; Female; Heart; Heart Rate; Humans; Least-Squares Analysis; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes; Refugees; Vietnam

Topics: Adult; Antimalarials; Arrhythmias, Cardiac; Electrocardiography; Humans; Male; Phenanthrenes

Topics: Adult; Antimalarials; Arrhythmias, Cardiac; Humans; Male; Phenanthrenes

Topics: Antimalarials; Arrhythmias, Cardiac; Humans; Malaria; Phenanthrenes; Self Medication

Topics: Adolescent; Adult; Antimalarials; Arrhythmias, Cardiac; Bradycardia; Electrocardiography; Heart; Heart Block; Humans; Malaria, Falciparum; Male; Middle Aged; Phenanthrenes

Incidence and malignant forms of imported Plasmodium falciparum malaria are increasing, and chemoprevention is more and more replaced by stand-by treatment and radical cure in preventing access on return from malaria areas. Halofantrine is recommended for this radical cure: it's an habitually well-tolerated amino-alcohol with very few side-effects. We report three cases of long QT-interval due to halofantine: three different young women coming back from Africa took halofantrine (500 mg (2 tablets) six hourly for three doses on the first and the seventh day) and all presented with syncopal episodes. Serum electrolyte concentrations and echocardiograms were normal. In one case only, a diagnosis of Plasmodium falciparum malaria was made, without severe manifestations, and in the two other cases, treatment was a radical cure. In two cases, several bursts of torsades de pointes ventricular tachycardia due to halofantrine were proven and electrophysiological cardiac tests concluded that they had a congenital long QT-interval/Romano-Ward syndrome). So far halofantrine cardiac toxicity was unknown with single dose of 24 mg/kg/d. This phenomenon can be very severe in case of preexisting cardiopathy. In spite of the rarity on the congenital Romano-Ward syndrome, systematic electrocardiogram is necessary before giving halofantrine.

Topics: Adult; Africa; Arrhythmias, Cardiac; Female; France; Heart Ventricles; Humans; Malaria, Falciparum; Phenanthrenes

Crisnatol is a novel lipophilic arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models which functions as a DNA intercalator. In this Phase I trial, a 6-h infusion of the drug was administered i.v. in 700 to 1500 ml of 5% dextrose in water every 28 days. Eighty-five courses at doses of 7.5 to 516 mg/m2 were administered to 43 patients with refractory solid tumors. Reversible neurological toxicity was dose limiting at 516 mg/m2 and was manifested as somnolence, dizziness, blurred vision, unsteady gait, and alpha-slowing on electroencephalogram at the end of infusion. All neurological signs and symptoms were reversible. No hematological toxicity was observed. Other toxicities included phlebitis, mild to moderate nausea and vomiting, reversible sinus node arrest in one patient, and hypertension. Crisnatol plasma concentrations were determined by high-pressure liquid chromatography. After infusion, plasma concentrations declined biexponentially with a terminal t1/2 of 2.9 h. Using a two-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 58.8 liters/m2 and 18.3 liters/h/m2, respectively, indicative of extensive tissue distribution and rapid hepatic clearance. Peak plasma levels occurred at the end of infusion and correlated with the onset of neurological toxicity. The recommended Phase II dose for this schedule is 388 mg/m2.

Topics: Adult; Aged; Antineoplastic Agents; Arrhythmias, Cardiac; Blood Pressure; Chrysenes; Digestive System; Drug Administration Schedule; Drug Evaluation; Electroencephalography; Female; Humans; Male; Middle Aged; Neoplasms; Nervous System; Phenanthrenes; Propylene Glycols

Topics: Amides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cats; Disease Models, Animal; Dogs; Epinephrine; Ethylamines; Female; Male; Phenanthrenes; Procainamide; Quinidine

Topics: Abietanes; Amides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Ethylamines; Phenanthrenes; Procainamide; Quinidine; Strophanthins

Topics: Abietanes; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Chlorides; Phenanthrenes; Rats; Research; Toxicology