ABSTRACT
OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.
Subject(s)
Cardiovascular System/drug effects , Coronavirus Infections/therapy , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , Pneumonia, Viral/therapy , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Anti-Arrhythmia Agents/toxicity , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/toxicity , Anticholesteremic Agents/pharmacology , Anticholesteremic Agents/therapeutic use , Anticholesteremic Agents/toxicity , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/toxicity , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , COVID-19 , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channel Blockers/toxicity , Drug Interactions , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/toxicity , Humans , Pandemics , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/toxicity , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic use , Vasodilator Agents/toxicityABSTRACT
The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450) kinetics, especially CYP3A4, have received wide concern in recent years. Flavonoids, a group of important natural substances with various pharmacological activities, distribute widely among vegetables, fruits and herbs. The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions. However, little is known about activation effects of flavonoids on CYP3A4. The aim of this study was to investigate activation of CYP3A4 by flavonoids, explore the molecular mechanism, and assess the biological effects on dronedarone (DND) induced toxicity. The results showed that flavone, tangeretin, sinensetin and 6-hydroxyflavone increased the cell viability by decreasing DND-induced cytotoxicity. These four flavonoids could activate the metabolism of DND in hamster pharmacokinetics study. Furthermore, both molecular docking and circular dichroism analysis partially illustrated the molecular mechanism of heterotropic activation. Finally, the pharmacophore model suggested B aromatic ring, hydrophobic groups at 7-position and hydrogen bond acceptors at 4-position may play a vital role in activation of flavonoids on CYP3A4. Taken together, our findings would provide useful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.
Subject(s)
Anti-Arrhythmia Agents/toxicity , Cell Survival/drug effects , Cytochrome P-450 CYP3A/metabolism , Dronedarone/toxicity , Enzyme Activators/pharmacology , Flavonoids/pharmacology , Animals , Anti-Arrhythmia Agents/pharmacokinetics , Circular Dichroism , Cricetinae , Dronedarone/pharmacokinetics , Enzyme Activation , Herb-Drug Interactions , Hydrogen Bonding , Male , Mesocricetus , Models, Molecular , Molecular Docking SimulationABSTRACT
The proarrhythmic potency of drugs is usually attributed to the IKr current block. During safety pharmacology testing analysis of IKr in cardiomyocytes was replaced by human ether-a-go-go-related gene (hERG) test using automated patch-clamp systems in stable transfected cell lines. Aim of this study was to compare the effect of proarrhythmic compounds on hERG and IKr currents and on cardiac action potential. The hERG current was measured by using both automated and manual patch-clamp methods on HEK293 cells. The native ion currents (IKr, INaL, ICaL) were recorded from rabbit ventricular myocytes by manual patch-clamp technique. Action potentials in rabbit ventricular muscle and undiseased human donor hearts were studied by conventional microelectrode technique. Dofetilide, cisapride, sotalol, terfenadine, and verapamil blocked hERG channels at 37°C with an IC50 of 7 nM, 18 nM, 343 µM, 165 nM, and 214 nM, respectively. Using manual patch-clamp, the IC50 values of sotalol and terfenadine were 78 µM and 31 nM, respectively. The IC50 values calculated from IKr measurements at 37°C were 13 nM, 26 nM, 52 µM, 54 nM, and 268 nM, respectively. Cisapride, dofetilide, and sotalol excessively lengthened, terfenadine, and verapamil did not influence the action potential duration. Terfenadine significantly inhibited INaL and moderately ICaL, verapamil blocked only ICaL. Automated hERG assays may over/underestimate proarrhythmic risk. Manual patch-clamp has substantially higher sensitivity to certain drugs. Action potential studies are also required to analyze complex multichannel effects. Therefore, manual patch-clamp and action potential experiments should be a part of preclinical safety tests.
Subject(s)
Action Potentials/drug effects , Anti-Arrhythmia Agents/toxicity , Heart Ventricles/drug effects , Ion Channels/metabolism , Myocytes, Cardiac/drug effects , Potassium Channel Blockers/toxicity , Animals , Drug Evaluation, Preclinical , ERG1 Potassium Channel/metabolism , Female , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Humans , Male , Myocytes, Cardiac/metabolism , Patch-Clamp Techniques , Phenethylamines/toxicity , Rabbits , Sotalol/toxicity , Sulfonamides/toxicity , Terfenadine/toxicity , Tissue Donors , Verapamil/toxicityABSTRACT
Dronedarone and amiodarone are structurally similar antiarrhythmic drugs. Dronedarone worsens cardiac adverse effects with unknown causes while amiodarone has no cardiac adversity. Dronedarone induces preclinical mitochondrial toxicity in rat liver and exhibits clinical hepatotoxicity. Here, we further investigated the relative potential of the antiarrhythmic drugs in causing mitochondrial injury in cardiomyocytes. Differentiated rat H9c2 cardiomyocytes were treated with dronedarone, amiodarone, and their respective metabolites namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA). Intracellular ATP content, mitochondrial membrane potential (Δψm), and inhibition of carnitine palmitoyltransferase I (CPT1) activity and arachidonic acid (AA) metabolism were measured in H9c2 cells. Inhibition of electron transport chain (ETC) activities and uncoupling of ETC were further studied in isolated rat heart mitochondria. Dronedarone, amiodarone, NDBD and NDEA decreased intracellular ATP content significantly (IC50 = 0.49, 1.84, 1.07, and 0.63 µM, respectively) and dissipated Δψm potently (IC50 = 0.5, 2.94, 12.8, and 7.38 µM, respectively). Dronedarone, NDBD, and NDEA weakly inhibited CPT1 activity while amiodarone (IC50 > 100 µM) yielded negligible inhibition. Only dronedarone inhibited AA metabolism to its regioisomeric epoxyeicosatrienoic acids (EETs) consistently and potently. NADH-supplemented ETC activity was inhibited by dronedarone, amiodarone, NDBD and NDEA (IC50 = 3.07, 5.24, 11.94, and 16.16 µM, respectively). Cytotoxicity, ATP decrease and Δψm disruption were ameliorated via exogenous pre-treatment of H9c2 cells with 11, 12-EET and 14, 15-EET. Our study confirmed that dronedarone causes mitochondrial injury in cardiomyocytes by perturbing Δψm, inhibiting mitochondrial complex I, uncoupling ETC and dysregulating AA-EET metabolism. We postulate that cardiac mitochondrial injury is one potential contributing factor to dronedarone-induced cardiac failure exacerbation.
Subject(s)
8,11,14-Eicosatrienoic Acid/analogs & derivatives , 8,11,14-Eicosatrienoic Acid/pharmacology , Anti-Arrhythmia Agents/toxicity , Cardiotonic Agents/pharmacology , Dronedarone/toxicity , Mitochondria, Heart/drug effects , Myocytes, Cardiac/drug effects , Adenosine Triphosphate/metabolism , Cell Line , Cell Survival/drug effects , Humans , Membrane Potential, Mitochondrial/drug effects , Mitochondria, Heart/metabolism , Myocytes, Cardiac/metabolismABSTRACT
Most traditional Chinese medicine prescription dosages are imprecise. This study analyzes the toxicities and adverse effects of a combination the active ingredients of licorice and Kushen medicine: oxymatrine (OMT) and diammonium glycyrrhizinate (DG). The median lethal dose (LD50) and mortality were analyzed in single-dose OMT (or DG) intraperitoneally injected mice with or without combination DG (or OMT). Body weight changes as well as levels of serum sodium and potassium, alanine transaminase (ALT), aspartate transaminase (AST), creatinine, and urea were measured in mice treated with a daily dose of OMT and/or DG for 14days. This study showed that the LD50 of OMT for males and females were 347.44 and 429.15mg/kg, respectively. The LD50 of DG were 525.10 and 997.26mg/kg for males and females, respectively. DG significantly decreased the mice LD50-induced mortality of the OMT, however OMT did not succeed in reducing the LD50-induced mortality rate of DG. The combination of OMT and DG obviously attenuated the changes of the body weight, serum sodium, and potassium induced by DG or OMT alone. These results suggested that toxicity and adverse effects of the OMT was significantly attenuated by DG. The OMT neutralized the adverse effects of the DG, but not the toxicity.
Subject(s)
Alkaloids/administration & dosage , Alkaloids/toxicity , Anti-Inflammatory Agents/administration & dosage , Glycyrrhizic Acid/administration & dosage , Quinolizines/administration & dosage , Quinolizines/toxicity , Alanine Transaminase/antagonists & inhibitors , Alanine Transaminase/blood , Alkaloids/antagonists & inhibitors , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/toxicity , Aspartate Aminotransferases/antagonists & inhibitors , Aspartate Aminotransferases/blood , Body Weight/drug effects , Body Weight/physiology , Female , Male , Mice , Mice, Inbred ICR , Mortality/trends , Quinolizines/antagonists & inhibitors , Random AllocationABSTRACT
Drug-induced QT prolongation is a major safety issue in the drug discovery process. This study was conducted to assess the electrophysiological responses of four substances using established preclinical assays usually used in regulatory studies (hERG channel or Purkinje fiber action potential) and a new assay (human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)-field potential). After acute exposure, moxifloxacin and dofetilide concentration-dependently decreased IKr amplitude (IC50 values: 102 µM and 40 nM, respectively) and lengthened action potential (100 µM moxifloxacin: +23% and 10 nM dofetilide: +18%) and field potential (300 µM moxifloxacin: +76% and 10 nM dofetilide: +38%) durations. Dofetilide starting from 30 nM induced arrhythmia in hiPSC-CMs. Overnight application of pentamidine (10 and 100 µM) and arsenic (1 and 10 µM) decreased IKr, whereas they were devoid of effects after acute application. Long-term pentamidine incubation showed a time- and concentration-dependent effect on field potential duration. In conclusion, our data suggest that hiPSC-CMs represent a fully functional cellular electrophysiology model which may significantly improve the predictive validity of in vitro safety studies. Thereafter, lead candidates may be further investigated in patch-clamp assays for mechanistic studies on individual ionic channels or in a multicellular Purkinje fiber preparation for confirmatory studies on cardiac conduction.
Subject(s)
Action Potentials/drug effects , Anti-Arrhythmia Agents/toxicity , Drug Evaluation, Preclinical/methods , Induced Pluripotent Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Action Potentials/physiology , Arsenic/toxicity , Dose-Response Relationship, Drug , Drug Discovery , Fluoroquinolones/toxicity , Humans , In Vitro Techniques , Induced Pluripotent Stem Cells/physiology , Long QT Syndrome/chemically induced , Moxifloxacin , Myocytes, Cardiac/physiology , Pentamidine/administration & dosage , Pentamidine/toxicity , Phenethylamines/toxicity , Risk Assessment , Sulfonamides/toxicityABSTRACT
The goals of this study were to investigate the effects of lipid emulsion (LE) on apoptosis induced by a toxic dose of verapamil in H9c2 cells and to elucidate the associated cellular mechanism. The effects of LE alone and combined with an inhibitor on the decreases in cell counts and viability induced by verapamil and diltiazem were examined using the MTT assay. The effects of verapamil alone, combined LE and verapamil treatment, and combined inhibitor, LE and verapamil treatment on cleaved caspase-3, caspase-8 and Bax expression, were examined using Western blotting. The effects of verapamil alone and combined with LE on the number of TUNEL-positive H9c2 cells were also examined. LE attenuated the decreases in cell counts and viability induced by verapamil and diltiazem. However, the magnitude of the LE-mediated attenuation of decreased cell viability was enhanced by verapamil compared with diltiazem treatment. Naloxone, naltrindole hydrochloride, LY294002 and MK-2206 inhibited the LE-mediated attenuation of increased cleaved caspase-3 and caspase-8 expression induced by verapamil. LE attenuated the increase in the number of TUNEL-positive cell induced by verapamil. These results suggest that LE attenuates apoptosis induced by verapamil via activation of the delta-opioid receptor, phosphoinositide 3-kinase and Akt.
Subject(s)
Apoptosis/drug effects , Fat Emulsions, Intravenous/pharmacology , Myocytes, Cardiac/drug effects , Phospholipids/pharmacology , Receptors, Opioid, delta/agonists , Soybean Oil/pharmacology , Verapamil/toxicity , Animals , Anti-Arrhythmia Agents/toxicity , Apoptosis/physiology , Cell Line , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Emulsions/pharmacology , Myocytes, Cardiac/physiology , Rats , Receptors, Opioid, delta/physiologyABSTRACT
AIM: The most recent European Society of Cardiology (ESC) update on atrial fibrillation has introduced vernakalant (VER) for pharmacological cardioversion of atrial fibrillation. The aim of the present study was to investigate the safety profile of VER in a sensitive model of proarrhythmia. METHODS AND RESULTS: In 36 Langendorff-perfused rabbit hearts, VER (10, 30 µM, n = 12); ranolazine (RAN, 10, 30 µM, n = 12), or sotalol (SOT, 50; 100 µM, n = 12) were infused after obtaining baseline data. Monophasic action potentials and a 12-lead electrocardiogram showed a significant QT prolongation after application of VER as compared with baseline (10 µM: +25 ms, 30 µM: +50 ms, P < 0.05) accompanied by an increase of action potential duration (APD). The increase in APD90 was accompanied by a more marked increase in effective refractory period (ERP) leading to a significant increase in post-repolarization refractoriness (PRR, 10 µM: +30 ms, 30 µM: +36 ms, P < 0.05). Vernakalant did not affect the dispersion of repolarization. Lowered potassium concentration in bradycardic hearts did not provoke early afterdepolarizations (EADs) or polymorphic ventricular tachycardia (pVT). Comparable results were obtained with RAN. Hundred micromolars of SOT led to an increase in QT interval (+49 ms) and APD90 combined with an increased ERP and PRR (+23 ms). In contrast to VER, 100 µM SOT led to a significant increase in dispersion of repolarization and to the occurrence of EAD in 10 of 12 and pVT in 8 of 12 hearts. CONCLUSION: In the present study, application of VER and SOT led to a comparable prolongation of myocardial repolarization. Both drugs increased the PRR. However, VER neither affect the dispersion of repolarization nor induce EAD and therefore did not cause proarrhythmia.
Subject(s)
Anisoles/toxicity , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/chemically induced , Electrophysiologic Techniques, Cardiac , Heart Conduction System/drug effects , Pyrrolidines/toxicity , Acetanilides/toxicity , Action Potentials , Animals , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/physiopathology , Heart Conduction System/physiopathology , In Vitro Techniques , Models, Animal , Perfusion , Piperazines/toxicity , Potassium Channel Blockers/toxicity , Rabbits , Ranolazine , Risk Assessment , Risk Factors , Sodium Channel Blockers/toxicity , Sotalol/toxicity , Time FactorsABSTRACT
Amiodarone is a potent anti-arrhythmic drug used for the treatment of cardiac arrhythmias. Although, the effects of amiodarone are well characterized on post-ischemic heart and cardiomyocytes, its toxicity on extra-cardiac tissues is still poorly understood. To this aim, we have monitored the cytotoxicity effects of this drug on three cultured cell lines including hepatocytes (HepG2), epithelial cells (EAhy 926) and renal cells (Vero). We have investigated the effects of amiodarone on (i) cell viabilities, (ii) heat shock protein expressions (Hsp 70) as a parameter of protective and adaptive response and (iii) oxidative damage.Our results clearly showed that amiodarone inhibits cell proliferation, induces an over-expression of Hsp 70 and generates significant amount of reactive oxygen species as measured by lipid peroxidation occurrence. However, toxicity of amiodarone was significantly higher in renal and epithelial cells than in hepatocytes. Vitamin E supplement restores the major part of cell mortalities induced by amiodarone showing that oxidative damage is the predominant toxic effect of the drug.Except its toxicity for the cardiac system, our findings demonstrated that amiodarone can target other tissues. Therefore, kidneys present a high sensibility to this drug which may limit its use with subjects suffering from renal disorders.
Subject(s)
Amiodarone/toxicity , Anti-Arrhythmia Agents/toxicity , Epithelial Cells/drug effects , Hepatocytes/drug effects , Kidney/drug effects , Animals , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , HSP70 Heat-Shock Proteins/biosynthesis , Humans , Immunoblotting , Lipid Peroxidation/drug effects , Oxidative Stress/drug effects , Vero CellsABSTRACT
INTRODUCTION: Accumulating evidence suggest that drug-induced QT prolongation per se poorly predicts repolarisation-related proarrhythmia liability. We examined whether beat-by-beat variability of the QT interval may be a complementary proarrhythmia marker to QT prolongation. METHODS: Anaesthetised rabbits sensitized towards developing torsades de pointes (TdP) were infused for 30 min maximum with explorative antiarrhythmic compounds characterised as mixed ion channel blockers. Based on the outcome in this model the compounds were classified as having a low (TdPlow; n=5), intermediate (TdPintermediate; n=7) or high (TdPhigh; n=10) proarrhythmic potential. Dofetilide (n=4) was included as a representative of a selective IKr-blocking antiarrhythmic with known high proarrhythmic potential. QT interval prolongation and beat-by-beat QT variability (quantified as the short-term variability, STV) were continuously assessed during the infusion or up to the point where ventricular proarrhythmias were induced. RESULTS: All compounds significantly prolonged the QT interval. For TdPlow and TdPhigh compounds the QT interval maximally increased from 169 ± 14 to 225 ± 28 ms (p<0.05) and from 186 ± 21 to 268 ± 42 ms (p<0.01), respectively. Likewise, in the dofetilide-infused rabbits the QT interval maximally increased from 177 ± 11 to 243 ± 25 ms (p<0.01). In contrast, whereas the STV in rabbits administered the TdPhigh compounds or dofetilide significantly increased prior to proarrhythmia induction (from 1.6 ± 0.4 to 10.5 ± 5.6 ms and from 1.6 ± 0.5 to 5.9 ± 1.8 ms, p<0.01) it remained unaltered in the TdPlow group (1.3 ± 0.6 to 2.2 ± 0.9 ms). In the TdPintermediate group, rabbits experiencing TdP had a similar maximal QT prolongation as the non-susceptible rabbits whereas the change in the STV was significantly different (from 0.9 ± 0.5 to 8.7 ± 7.3 ms vs 0.8 ± 0.3 to 2.5 ± 1.1 ms). DISCUSSION: It is concluded from the present series of experiments in a sensitive rabbit model of TdP that increased beat-by-beat QT interval variability precedes drug-induced TdP. In addition, assessment of this potential proarrhythmia marker may be useful in discriminating highly proarrhythmic compounds from compounds with a low proarrhythmic potential.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/chemically induced , Electrocardiography , Long QT Syndrome/chemically induced , Torsades de Pointes/chemically induced , Animals , Cell Line , ERG1 Potassium Channel , Embryo, Mammalian , Ether-A-Go-Go Potassium Channels/metabolism , Heart/drug effects , Heart/physiopathology , Humans , Ion Channels/antagonists & inhibitors , Kidney , Long QT Syndrome/physiopathology , Male , Methoxamine/pharmacology , Models, Statistical , Phenethylamines/pharmacology , Phenethylamines/toxicity , Rabbits , Rats , Sulfonamides/pharmacology , Sulfonamides/toxicity , Torsades de Pointes/physiopathologyABSTRACT
QT prolongation is the only clinically proven, yet insufficient, electrocardiogram (ECG) biomarker for drug-induced cardiac toxicity. The goal of this study is to evaluate whether JT area, i.e., total area of the T-wave, can serve as an ECG biomarker for drug-induced cardiac toxicity using both signal processing and computational modeling approaches. An ECG dataset that contained recordings from patients under control and sotalol condition was analyzed. In order to relate sotalol-induced ECG changes to its effect on ion channel level, i.e., blockade of the rapid component of the delayed rectifier potassium channel (I(Kr)), varied degrees of I(Kr) blockade were simulated in a slab of ventricular tissue. The mean JT area increased by 36.5% following the administration of sotalol in patients. Simulations in the slab tissue showed that sotalol increased action potential duration preferentially in the midmyocardium, which led to increased transmural dispersion of repolarization and JT area. In conclusion, JT area reflects the transmural dispersion of repolarization and may be a potentially useful surrogate/supplemental ECG biomarker to assess drug safety.
Subject(s)
Anti-Arrhythmia Agents/toxicity , Electrocardiography/methods , Action Potentials , Algorithms , Anti-Arrhythmia Agents/pharmacology , Biomarkers , Computer Simulation , Humans , Ion Channels/chemistry , Ions , Models, Statistical , Signal Processing, Computer-Assisted , Software , Sotalol/pharmacology , Time FactorsABSTRACT
INTRODUCTION: Current regulatory guidelines attempt to standardize the models used to assess the safety aspects of new test compounds. However, they do not address the means of deriving the critical data. With the increased data volume that is a result of more extensive safety scrutiny and continuous data assessment, especially in cardiovascular telemetry studies, there is a clear need to assess the automated ECG analysis tools currently available on the market. METHODS: Cardiovascular studies were conducted using implanted beagle dogs following the oral administration of E-4031 (0 and 1 mg/kg) and the animals were monitored for 22-24 h post-dose. The raw ECG data trace was converted into file formats accessible by Data Sciences International (DSI) Ponemah with pattern recognition option (PRO), EMKA ecgAuto and Notocord HEM. RESULTS: Validation using a reference signal generator showed comparable performance by the applications being evaluated. Significant increases in QT/QTcV (25-40 ms) were noted following treatment with 1 mg/kg E-4031 (T(max)=0.5 h). All software applications showed similar trends in QT/QTcV analyses. DISCUSSION: The choice of analysis applications is dependent on a number of variables, e.g., animal model used, the need for real-time analysis and visualization, flexibility, learning curve, etc. In our study, similar trends were observed for all three ECG software applications, but pattern recognition approaches were more amenable to adapting to ECG morphology changes over the course of 24 hour telemetry study.
Subject(s)
Electrocardiography/instrumentation , Software , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/pharmacokinetics , Anti-Arrhythmia Agents/toxicity , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Models, Animal , Pattern Recognition, Automated/methods , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Piperidines/toxicity , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Pyridines/toxicity , Reproducibility of Results , Telemetry/instrumentation , Telemetry/methodsABSTRACT
Tomato products containing lycopene are believed to be associated with decreased risk of chronic diseases including cancer, and its effects are suggested to be due to antioxidant effect of lycopene. The aim of this research was to study the effects of tomato extract on acetaminophen (APAP), amiodarone (ADN) and cyclosporine A (CsA)-induced liver, lung and kidney toxicity, respectively. Previous studies have shown that free radical reactions may play important roles in toxicity of these drugs. Rats received a single dose of APAP (750mg/kg, i.p.) before treatment with tomato extract (5mg/kg, oral) for seven consecutive days, ADN (100mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 10 consecutive days, or CsA (250mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 14 consecutive days. At the end of each treatment, the animals were sacrificed and the related organ tissues were collected for biochemical and histopathological examinations. Simultaneous treatment of tomato extract ameliorated tissue damage, biochemical indices, and oxidative stress parameters against APAP-induced acute hepatotoxicity, but had less beneficial effects on ADN-induced lung toxicity and little effect against CsA-induced nephrotoxicity. Therefore, tomato products may be beneficial for the prevention and therapy of toxicity induced by ADN and APAP.
Subject(s)
Analgesics, Non-Narcotic/toxicity , Oxidative Stress/drug effects , Solanum lycopersicum/chemistry , Acetaminophen/antagonists & inhibitors , Acetaminophen/toxicity , Amiodarone/antagonists & inhibitors , Amiodarone/toxicity , Analgesics, Non-Narcotic/antagonists & inhibitors , Animals , Anti-Arrhythmia Agents/antagonists & inhibitors , Anti-Arrhythmia Agents/toxicity , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/prevention & control , Cyclosporine/antagonists & inhibitors , Cyclosporine/toxicity , Glutathione/metabolism , Immunosuppressive Agents/antagonists & inhibitors , Immunosuppressive Agents/toxicity , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Kidney Diseases/prevention & control , Lipid Peroxidation/drug effects , Lung Diseases/chemically induced , Lung Diseases/pathology , Lung Diseases/prevention & control , Male , Plant Extracts/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
In the research and development for new therapeutic compounds, there has been a focus on detecting the changes of metabolites induced by drug administration and finding surrogate markers to assess its toxicity. We examined the suitability of urinary metabolic fingerprinting using Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS) for toxicological assessment in the amiodarone (AMD)-induced phospholipidosis (PLD) rat model. There were more than 400 different ion peaks detected in the negative ion mode analysis with FT-ICR MS. About 20% of the detected ions were altered more than 1.5 fold by AMD-treatment. On the scores plot of principal component analysis (PCA), the ion profiles of the treated were separated time-dependently. The loading plot revealed that the metabolites causing PCA results were m/z 178.05101, 191.01979, 192.06676, 212.00239, 258.9944 and 283.0820. The ion at m/z 178.05101 is considered to be hippurate (HA), 192.06676 is phenylacetylglycine (PAG) and 212.00239 is indican (IDN). These results indicate that PAG, IDN and HA are biomarkers for AMD-induced PLD in urinary metabolic fingerprinting using FT-ICR MS. These markers may be useful for evaluation of chemicals, which have the potential to induce PLD.
Subject(s)
Amiodarone/toxicity , Anti-Arrhythmia Agents/toxicity , Drug Evaluation, Preclinical/methods , Lipidoses/chemically induced , Phospholipids/urine , Spectroscopy, Fourier Transform Infrared/methods , Animals , Biomarkers/urine , Disease Models, Animal , Lipidoses/metabolism , Lung/drug effects , Lung/metabolism , Lung/pathology , Principal Component Analysis , RatsABSTRACT
INTRODUCTION: This project addresses the validation study design of a test system using a telemetered non-human primate model for cardiovascular safety pharmacology evaluation. METHODS: In addition to non-pharmacological validation including installation and operation qualifications, performance qualification (locomotor activity and cardiovascular evaluations) was completed on free-moving cynomolgus monkeys by quantifying the degree of cardiovascular response measured by the telemetric device to various positive control drugs following their intravenous administration. Remifentanil (0.0005, 0.001, 0.002, 0.004, 0.008 and 0.016 mg/kg) was given to induce bradycardia and hypotension. Medetomidine (0.04 mg/kg) was used to induce an initial phase of hypertension followed by hypotension and bradycardia. Esmolol (0.5, 1.0 and 2.0 mg/kg) was used to induce bradycardia. Dopamine (0.002, 0.008, 0.01, 0.02, 0.03 and 0.05 mg/kg/min) was infused over 30 min to induce an increase in arterial and pulse pressures and tachycardia. Amiodarone (0.4, 0.8 and 1.6 mg/kg/min) was infused over 10 min to induce QT interval prolongation. Potassium chloride (0.08 mEq/kg/min) was infused for periods of less than 30 min to induce electrocardiographic (EKG) changes characteristic of hyperkalemia. Reliability was evaluated over 60 days. RESULTS: Monitoring with a reference methodology and the telemetry system was important in order to evaluate precision and accuracy of the test system. Positive control drugs produced a wide range of cardiovascular effects with different amplitudes, which were useful in identification of the limits of the test system. DISCUSSION: Reference monitoring methods and selection of a battery of positive control drugs are important to ensure proper test system validation. Drugs inducing not only QT prolongation but also positive and negative chronotropic effects, positive and negative systemic arterial pressure changes and ECG morphology alterations were useful to identify test system limitations during performance qualification. ECG data processing at significantly elevated heart rates revealed that a trained observer should review all cardiac cycles evaluated by computer.
Subject(s)
Cardiovascular Diseases/physiopathology , Cardiovascular Physiological Phenomena/drug effects , Drug Monitoring/methods , Macaca fascicularis/physiology , Adrenergic alpha-2 Receptor Agonists , Adrenergic beta-Antagonists/administration & dosage , Adrenergic beta-Antagonists/toxicity , Amiodarone/administration & dosage , Amiodarone/toxicity , Analgesics, Opioid/toxicity , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/toxicity , Blood Pressure/drug effects , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/diagnosis , Consciousness , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Drug Monitoring/instrumentation , Electrocardiography/drug effects , Heart Rate/drug effects , Infusions, Intravenous , Injections, Intravenous , Medetomidine/administration & dosage , Medetomidine/toxicity , Piperidines/administration & dosage , Piperidines/toxicity , Propanolamines/administration & dosage , Propanolamines/toxicity , Remifentanil , Reproducibility of Results , Sinoatrial Node/drug effects , Sinoatrial Node/physiopathology , Telemetry/instrumentation , Telemetry/methodsABSTRACT
Dofetilide, a class III antiarrhythmic agent, is prescribed for conversion to and maintenance of normal sinus rhythm in patients with persistent atrial fibrillation or atrial flutter. Most antiarrhythmics have significant toxicities such as torsade de pointes, and patients should be closely monitored while receiving antiarrhythmic therapy. However, we know of no reports concerning management of intentional overdose of dofetilide that have been published. We report the case of a 33-year-old man who was treated for ingestion of approximately 5 mg of dofetilide as a suicide attempt. In addition, he had a known history of cocaine abuse. He came to the emergency department approximately 45 minutes after the ingestion; examination revealed a QTc interval of approximately 570 msec. He was treated with activated charcoal and sorbitol by nasogastric tube and received aggressive supplementation with potassium and magnesium. The patient was monitored by telemetry for several days and responded well. Cardiac toxicity is the utmost concern when treating dofetilide overdose. The mainstay of treatment focuses on supportive care and prevention of drug absorption. Ventricular dysrhythmias or torsade de pointes should be treated according to advanced cardiac life support guidelines.
Subject(s)
Anti-Arrhythmia Agents/toxicity , Cocaine-Related Disorders , Drug Overdose/drug therapy , Emergency Treatment/methods , Phenethylamines/toxicity , Suicide, Attempted , Sulfonamides/toxicity , Adult , Charcoal/therapeutic use , Drug Monitoring , Emergency Service, Hospital , Humans , Male , Sorbitol/therapeutic useABSTRACT
BACKGROUND AND AIMS: Amiodarone-induced thyrotoxicosis is a life-threatening condition. A prompt control of thyrotoxicosis is obtained by thyroidectomy. Preparation with iopanoic acid proved to be very effective in reducing cardiovascular complications. Nevertheless, general anesthesia and extensive surgery may affect negatively patients also after adequate preparation. Safety and efficacy of minimally invasive video-assisted thyroidectomy performed under regional anesthesia (bilateral modified deep cervical block) in patients with amiodarone-induced thyrotoxicosis was evaluated. PATIENTS AND METHODS: Eight patients with amiodarone-induced thyrotoxicosis (three with type I and five with type II), mean age 66.2 years, were prepared with iopanoic acid. There were five men and three women. Three patients had dilatative cardiomyopathy, three had heart failure secondary to severe myocardial infarction, and two had refractory unstable rhythm disorders. RESULTS: Minimally invasive video-assisted thyroidectomy was performed under regional anesthesia. Mean operative time was 55.5 min. During surgery, lung and heart function remained well and no surgical complications occurred. After surgery, all patients remained on amiodarone therapy and two patients were subsequently removed from the checklist for heart transplantation. CONCLUSION: Minimally invasive video-assisted thyroidectomy under regional anesthesia can be proposed as resolution of amiodarone-induced thyrotoxicosis in high risk patients with severe cardiac disorders, after preparation with iopanoic acid.
Subject(s)
Amiodarone/toxicity , Anesthesia, Local , Anti-Arrhythmia Agents/toxicity , Autonomic Nerve Block , Goiter, Nodular/chemically induced , Goiter, Nodular/surgery , Heart Diseases/complications , Heart Diseases/drug therapy , Iopanoic Acid/administration & dosage , Minimally Invasive Surgical Procedures/methods , Thyroidectomy/methods , Thyrotoxicosis/chemically induced , Thyrotoxicosis/surgery , Video-Assisted Surgery/methods , Aged , Amiodarone/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/drug therapy , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/drug therapy , Female , Goiter, Nodular/blood , Health Status Indicators , Heart Failure/complications , Heart Failure/drug therapy , Humans , Male , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/drug therapy , Premedication , Thyrotoxicosis/blood , Thyroxine/blood , Triiodothyronine/bloodABSTRACT
INTRODUCTION: Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. METHODS: Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. RESULTS: E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E(max) model with an effect site. Maximum RT change (E(max)), free drug concentration at half of the maximum effect (EC(50)), and free drug concentration associated with a 10 ms RT prolongation (EC(10 ms)) were estimated. A linear correlation between EC(10 ms) and HERG IC(50) values was identified. DISCUSSION: The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I(Kr) inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.
Subject(s)
Cisapride/pharmacokinetics , Long QT Syndrome/etiology , Models, Biological , Piperidines/pharmacokinetics , Pyridines/pharmacokinetics , Terfenadine/pharmacokinetics , Animals , Anti-Arrhythmia Agents/blood , Anti-Arrhythmia Agents/pharmacokinetics , Anti-Arrhythmia Agents/toxicity , Atrioventricular Node/surgery , Bundle of His/surgery , Cardiac Pacing, Artificial , Catheter Ablation , Cisapride/blood , Cisapride/toxicity , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Electrocardiography/drug effects , Gastrointestinal Agents/blood , Gastrointestinal Agents/pharmacokinetics , Gastrointestinal Agents/toxicity , Histamine H1 Antagonists/blood , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/toxicity , Ion Channels/antagonists & inhibitors , Male , Models, Animal , Piperidines/blood , Piperidines/toxicity , Pyridines/blood , Pyridines/toxicity , Terfenadine/blood , Terfenadine/toxicityABSTRACT
INTRODUCTION: To assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety. METHOD: On two separate occasions, four male and two female beagle dogs were given vehicle or the test substance, dofetilide (0.25 mumol/kg), over a 3-h intravenous infusion. Cardiovascular parameters, including QT intervals, were recorded for 24-h using radiotelemetry. The QT interval was corrected individually for heart rate, vehicle treatment, and serial correlation (QT(c)). Exposure (plasma concentration) to dofetilide was measured and described by a two-compartment model. The individual concentration-time course of dofetilide was linked to the QT(c) interval via an effect compartment and a pharmacodynamic E(max) model, to account for the observed hysteresis. RESULTS: Dofetilide induced a concentration-dependent increase in the QT(c) interval, with an EC(50) of 9 nM (3-30 nM, 95% C.I.) and an E(max) of 59+/-9 ms. A hysteresis loop was observed by plotting plasma concentrations vs. QT interval in time order, indicating a delay in onset of effect. It was found to have an equilibrium half-life of 11+/-8 min. Based on the parameters potency and E(max), a representation was made of the drug-induced changes to the QT interval. DISCUSSION: An effect compartment model was found to accurately mimic the QT interval prolongation following administration of the test substance, dofetilide. The assessment of the individual concentration-effect relationship and confounding factors such as hysteresis might provide a better prediction of the safety profiles of new drug candidates.
Subject(s)
Anti-Arrhythmia Agents/pharmacokinetics , Drug Evaluation, Preclinical/methods , Long QT Syndrome/physiopathology , Models, Biological , Phenethylamines/pharmacokinetics , Sulfonamides/pharmacokinetics , Animals , Anti-Arrhythmia Agents/blood , Anti-Arrhythmia Agents/toxicity , Dogs , Female , Heart Conduction System/drug effects , Heart Conduction System/physiopathology , Infusions, Intravenous , Long QT Syndrome/chemically induced , Male , Phenethylamines/blood , Phenethylamines/toxicity , Sulfonamides/blood , Sulfonamides/toxicity , TelemetryABSTRACT
The acute toxicity of the immunostimulant derinat is very low: the LD50 value for intraperitoneal administration exceeds 1000 mg/kg. The drug effectively prevents from acute arrhythmia development upon occlusion in cats and produces antifibrillator effect on a model of reperfusive arrhythmia in a dose of 7.5 mg/kg. Derinat also exhibits the antiarrhythmic activity on the model of adrenalin-induced rhythm violations, but appears ineffective on the calcium chloride model.